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INTRODUCTION

Metrics details. Genomes of men madwr women differ in only a limited number of genes located on the sex chromosomes, whereas the transcriptome is far more sex-specific. Identification of sex-biased gene expression will contribute to understanding the molecular basis of sex-differences in complex traits and common diseases. Sex differences in the human peripheral blood transcriptome were characterized using microarrays in 5, subjects, accounting for menopause status and hormonal contraceptive use.

Sex-specific expression was observed for autosomal genes, of which Sex-differences in gene expression were smaller in postmenopausal women, larger in women using hormonal contraceptives and not caused by sex-specific eQTLs, confirming the role of estrogen in regulating sex-biased genes. This study indicates that sex-bias in gene expression is extensive and may underlie sex-differences in the prevalence of common diseases.

Sexual dimorphism extends into marked cellular, metabolic, physiological and anatomical differences and leads to sex differences in disease prevalence, expression and severity of, for example, cardiovascular [ 1 ], and autoimmune [ 2 ] diseases, personality [ 3 ] and psychiatric disorders [ 4 ].

Sex inequalities are an increasingly recognized challenge in both basic research and clinical medicine [ 5 ], and understanding the molecular mechanisms behind sex differences may lead to new insights into sex-specific pathophysiology and treatment opportunities [ 6 ].

Sex differences at the DNA sequence level are restricted to the sex chromosomes. On the X-chromosome, most genes are equally expressed across sex due to X-inactivation in women [ 7 ]. The few unshared genes located on the Y chromosome are exclusively expressed sex the testes, or are housekeeping genes with X-chromosome homologues that escape X-inactivation [ 8 ].

However, genome regulation seems highly sex-specific at secondary epigenetic levels such as DNA methylation [ 9 ], DNase hypersensitivity [ 10 ], chromatin structure [ 11 ] and gene expression [ 1213 ]. Thus, a characterization of sex differences in genome regulation by gene expression will contribute to the understanding of the molecular basis of sexual dimorphism.

Animal studies have shown that sex-biased gene expression is highly tissue dependent [ 1415 ] and the evolution rates of sex-biased genes are higher than average [ 1216 ]. Two recent studies in mice reported sex differences in gene expression networks of correlated transcripts [ 1718 ].

Nonetheless, consistent evidence was obtained for sex-specific gene expression. Sex-differences in gene expression will depend on the hormonal status of the group considered. For instance, during menopause, much of the female-specific hormone production ceases, with downstream effects on gene expression in adipose tissue [ 23 ], monocytes [ 24 ], and bone [ 25 ].

Madar women using hormonal contraceptives, containing the hormones estrogen and progesterone, additional differences in gene expression may be evident as well. Although the sexes do not sex at the autosomal DNA bba level, sex differences in gene expression may be caused by sex-specific eQTLs [ 26 ] i.

The sample size was sufficiently large to account for menopause status and b contraceptive use. The identified sex-biased genes were characterized in terms of enrichment for functional gene ontology GO and disease categories, distribution across the autosomes and sex chromosomes, tissue specificity, evolution rates, participation in major gene expression networks and the extent to which sex differences in gene madar were caused by sex-specific eQTLs.

For all participants, genome-wide gene expression in peripheral blood was assessed using microarrays with 47, probe sets targeting 19, genes. For each probe set, mixed models including demographic, and several technical covariates were used to test for sex effects see Methods.

When considering 45, autosomal transcripts targeting 18, genes, transcripts from genes 3. The percentage of sex-biased genes increased when only genes with a mean expression above a certain threshold were considered. For example, a mean expression threshold of 5 log 2 intensity resulted in 5. In order to provide a comprehensive overview, we included all transcripts in the following analyses. Characterization of female- and male-biased genes. For each of the 47, transcripts the sex effect was determined using a mixed model, resulting in mafar.

From the sex-biased transcripts on the autosomes, Most absolute log e fold changes were smaller sex 0. On the X chromosome, transcripts from genes were measured. Out of these, transcripts from 51 genes were sex-biased; from 38 genes were female-biased, and 24 from 13 genes male-biased. Seventeen of the corresponding log e fold changes were madar bz 0. Of the 63 transcripts targeting 26 genes on the Y chromosome, 48 transcripts from 16 genes had expression levels in men that were higher than the noise measured in women; 12 transcripts had a log e fold change larger than 0.

For each chromosome we tested whether the genes on that chromosome enriched the sex- male- or female-biased genes. At the autosomes, the percentage of sex-biased genes differed only slightly between chromosomes, ranging from 1. The distribution of the male- and female-biased genes over the autosomes was more variable, ranging from 0.

As expected, female-biased genes were enriched for genes at the X-chromosome 5. Significant subcategories included response to cytokine stimulus Male-biased genes were not enriched for any BPGO category. Male-biased genes were enriched for 11 CCGO categories, with as top hit madar ab In Additional file 3 the hierarchical network structure of the significant GO categories is visualized. For each of the autosomal sex-biased transcripts, eQTLs were computed for men and women separately.

For the pooled eQTLs cis, trans eQTLs genotype-sex interactions were assessed using a mixed model that included data from men eex women. Thus, gene expression correlation structure is sex between men and women, and here we focus on properties of the intersection of the overlapping modules.

Interestingly, 7 of these intersected modules were highly enriched with female-biased or male-biased genes. The modules were highly enriched for several GO terms Madar file 7. We calculated the pairwise transcript correlations within each intersected module or men and women separately. Between transcript correlations are higher in males than in females for 2 modules. WGCNA Weighted Gene Co-Expression Network Analysis resulted in 9 modules with correlated transcripts, two of which were highly enriched for female-biased sex, and 3 for male-biased genes.

From the latter three, two modules contained genes from which the pair-wise correlations were stronger in males compared to females. To test whether sex-biased genes have evolved faster than non sex-biased eex, we tested for enrichment in two sets of genes that were previously identified as rapidly evolving: genes from the Human PAML Browser [ 29 ] and 40 genes from a study comparing human and chimpanzee genomes [ 30 ].

We downloaded analysis results of two human studies that sex sex-biased genes in muscle [ macar ] and in liver [ 21 ]. On the autosomes, there were transcripts differentially expressed between postmenopausal women and men.

From these transcripts female-biased ses male-biased overlapped with the sex-biased transcripts identified in non-hormonal contraceptives using premenopausal NHC women.

When comparing the HC women with men, a much larger number of 2, differentially expressed transcripts were identified 1, female-biased, in male-biased. From these transcripts, were overlapping with the sex-biased transcripts identified in NHC women. For the transcripts identified in NHC women, log e fold changes were computed for the difference between each of the three groups of women NHC, HC, postmenopausal compared to men.

This shows that many gene expression differences between women and men become smaller when women reach menopause, and are larger when women use hormonal contraceptives, which reinforces the role of estrogen in regulating sex-biased genes. Sex-differences in gene expression are increased by the use of hormonal contraceptives, and decreased during menopause. Women were divided in three seex postmenopausal, hormonal contraceptive using HCand non hormonal contraceptive using NHC women. For the madwr transcripts identified in the comparison between males and NHC women, madwr changes were computed for the difference between the three groups of women and the men.

Positive fold changes are from female-biased genes, negative fold changes correspond to male-biased genes. Age has a strong influence on gene expression [ 32 ]. However, the fold changes between men and women of the sex-biased genes identified in the total sample were highly concordant between age ranges Additional file 10suggesting that the identified sex effects occur at all ages, but that some effects may be stronger at a certain age or may not have been identified due sex reduced power in the smaller groups of selected ages.

At the DNA autosomal sequence level sexes do not differ, as established by a well-powered meta-analysis [ 33 ], suggesting an important role for higher molecular levels, such as the transcriptome, in the manifestation of sexual dimorphisms. Indeed, animal madar have shown that the transcriptome is highly differential between sexes [ 141534mafar ]. On the autosomes, we identified genes 3. Of these genes, The autosomes sex rather similar proportions of sex-biased genes indicating the sex-biased genes can be found equally frequent across the entire genome, as opposed to what was found in liver [ 21 ] where several chromosomes enrich sex-biased genes.

It is important to note that the filter criteria used for selecting probe sets highly influences the number of sex-biased genes; the percentage of sex-biased genes increased with the threshold for mean expression level from 3.

Importantly, we have shown that hormonal ga and menopause status, which were not taken into account in previous studies in humans, highly influence the number and effect sizes of sex differences in gene expression.

Although it has been indicated that the percentage of sex-biased genes in non-human vertebrates maadr highly tissue dependent e. Peripheral sxe consists of a mixture of blood cell types the main types are lymphocytes, neutrophiles and monocyteshence the sex differences we identified must either be present in all subcell types or, when present in only one cell type, strong enough to be observed in the accumulative measurement.

By stratifying the sample into three age groups we showed that the size of the sex effects may be age dependent madar some genes, but the direction of the effects are highly concordant between age groups. We found a significant but small overlap of sex-biased autosomal genes identified in peripheral blood with those previously identified in muscle or liver, further confirming substantial tissue specificity of sex-biased genes.

Across tissue circulating exosomes contain RNA and could contribute to the overlapping expression profiles between muscle, liver and blood [ 36 ].

Sex-biased X chromosome genes showed bx larger overlap between tissues, indicating that escape from X-inactivation is highly similar between tissues.

Previous studies have reported that sex-biased genes may evolve more rapidly than average in vertebrates [ 12 ], human brain [ 37 ] and liver [ 21 ]. However, sex-biased genes in the peripheral blood transcriptome identified in our study did not include enrichment of fast evolving ab.

In women, most genes on one X chromosome are not expressed due to X chromosome inactivation [ 38 ]. Some genes escape X-inactivation and are expressed from both X chromosomes [ 7 ]. We showed that in peripheral blood the X chromosome is enriched for female-biased genes; 5.

This percentage, however, is only slightly sxe madar the average percentage identified at the autosomes 3. Estrogen is the primary female sex hormone and estrogenic activity is present at about two fold increased concentration in women as compared to men. Estradiol, the predominant estrogen in terms of absolute madar levels, activates estrogen receptors that bind to Sed sequences to activate or suppress gene expression, and many efforts have been made to find its target sex up to in MCF-7 cancer cell line [ 39 — 41 ] because of its role in breast cancer [ 42 ].

This suggests that these genes mediate the effect of estrogen and thereby may contribute to the sex differences in the related diseases. Second, we showed that the sex differences in gene expression depend largely on the hormonal status of the subgroup of women considered. In postmenopausal women, in which estradiol levels are similar to those in men, sex identified fewer sex-biased genes with smaller effect sizes as compared to premenopausal women.

In hormonal contraceptive using women, with increased estradiol levels, we identified more sex-biased genes and larger effect sizes as compared to women not using hormonal contraceptives. In liver, sex differences in gene expression are mainly caused by sex-specific growth hormone secretion [ 2153 ]. Growth hormones are regulated kadar estrogen [ 5455 ], hence the effect of estrogen on sex-specific gene expression in peripheral blood may also be mediated by growth hormone secretion.

The immune system function is known to be different between sexes; women produce more vigorous immune reactions and are more prone to autoimmune diseases [ 56 ]. Here we identified a large number of genes that potentially contribute to the immune system sex differences; From the 95 female-biased genes linked to the immune system, 45 are regulated by estradiol, which confirms the role of estrogen in the sex-specific immune system functioning [ 57 ].

Most interestingly, Ingenuity Pathway Analysis revealed that female-biased genes are highly enriched for genes involved in the toll-like receptor TLR4 and TLR3 pathways, known as LPS and poly I:C response patterns driven innate immune defense, suggesting some intrinsic innate immune activity sex differences.

Searches Related To "Sex Ba Madar"

Colorectal cancer is one of the most common causes of cancer morbidity both in men and in women. However, females over 65 years old show higher mortality and lower 5-year survival rate of colorectal cancer compared to their age-matched male counterparts.

The objective of this review is to suggest gender-based innovations to improve colorectal cancer outcomes in females. Women have a higher risk of developing right-sided proximal colon cancer than men, which is associated with more aggressive form of neoplasia compared to left-sided distal colon cancer. Despite differences in tumor location between women and men, most of scientific researchers do not consider sex specificity for study design and interpretation.

Also, colorectal cancer screening guidelines do not distinguish females from male, which may explain the higher frequency of more advanced neoplasia when tumors are first detected and false negative results in colonoscopy in females.

Moreover, socio-cultural barriers within females are present to delay screening and diagnosis. Few studies, among studies that included both men and women, have reported sex-specific estimates of dietary risk factors which are crucial to establish cancer prevention guidelines despite sex- and gender-associated differences in nutrient metabolism and dietary practices.

Furthermore, anti-cancer drug use for colorectal cancer treatment can cause toxicity to the reproductive system, and gender-specific recurrence and survival rates are reported. Therefore, by understanding sex- and gender-related biological and socio-cultural differences in colorectal cancer risk, gender-specific strategies for screening, treatment and prevention protocols can be madar to reduce the mortality and improve the quality of life.

Sex tip: The objective of this review is to suggest gendered innovations to improve colorectal cancer outcomes. Women are more prone to right-sided colon cancer than men, which is associated with more aggressive form of neoplasia compared to left-sided colon cancer. Genetic and epigenetic factors as well as dietary habits play roles in sex-specific differences in colorectal cancer risk. We also suggest that socio-cultural environments partly explain gender-specific differences in colorectal maadar risk.

Therefore, sex- and gender-specific strategies for research methods as well as protocols for screening, treatment, and prevention should be established to reduce the morbidity and mortality of colorectal cancer in women. Statistics from Korea and Japan indicated that colorectal cancer ranks number one cause of cancer morbidity in women sex more than 65 years old[ 23 ]. Also, the incidence and mortality of colorectal cancer in populations over 65 years old are higher in women than those in men implying that colorectal cancer is a major health threat among older women[ 1 ].

Considering the longer life expectancy of women compared to that of men, gender-targeted strategies to prevent and treat colorectal cancer should be properly delivered to improve the quality of life especially in older women. Colorectal cancer screening guideline in general does not apply gender-specific recommendations. However, scientists have suggested that right-sided proximal colon cancer is more aggressive type tumor compared to left-sided distal colon cancer[ 4 ], and patients with proximal colon cancer are more often females than males[ 5 ].

In advanced colonic neoplasia, proximal colonic tumors are more often flat, while distal colonic tumors are polypoid-type which is more distinguishable by colonoscopy[ 6 ] implying an alternative screening suggestion needs to be discussed.

Also, women possess a longer transverse colon compared to men posing lower detection rate in colonoscopy[ 7 ]. The sensitivity of fecal occult blood test iFOBTa most commonly used colorectal cancer screening test, is found to differ by sex[ 8 ]. The decreased gender-specificity of screening tools therefore may explain a higher mortality and shorter 5-year survival rate of women in many regions of the world.

Another crucial point that requires gender-specificity is dietary recommendations for cancer prevention. Dietary guidelines for cancer prevention are mostly derived from the summary findings of prospective cohort studies, which are less srx to selection or recall bias than case-control studies.

Despite gender-specific differences in dietary risk factors associated with cancer risk, the evidences to generate sex-specific summary estimates are limited. Also, cancer treatment plan needs to consider sex-specific responses towards anti-cancer drugs based on their biological and genetic characteristics.

Possible association between socioeconomic circumstances of women and cancer treatment also requires attention. Therefore, in this madad, we present the biological and socio-cultural differences between genders to provide strategies for gender-targeted colorectal cancer screening, treatment, and prevention.

The estimates of colorectal cancer madar greatly increase with older ages. The incidence and mortality of colorectal cancer in populations over 65 years old are higher in women than those in men[ 1 ]. Also, the 5-year survival rate of colorectal cancer among women sex lower than among men, which is particularly noteworthy in women over 70 years old[ 10 ].

These evidences imply that colorectal cancer is a major health threat among older women. However, the need for scientific researches on sex- and gender-associated differences in colorectal cancer development has not been properly emphasized. A recent systemic review reported that a higher proportion of women presents with right-sided colon cancer than men[ 4 ].

Right-sided colon cancer is often at a more advanced stage at diagnosis[ 4 ]. Therefore, the lower 5-year survival rate in women may be due to their increased incidence of right-sided cancer.

A major cohort study involving patients compared left-sided colon cancer to right-sided colon cancer for clinical and histological characteristics, progress after the operation, and survival[ 11 ]. The results revealed a higher incidence of right-sided colon cancer in women and in older subjects. Also, the effect of age was more significant baa women[ 11 ].

In the same study, patients with right-sided colon cancer exhibited vague symptoms and suffered from more associated diseases.

Right-sided colon cancer was more advanced and less differentiated compared to left-sided colon cancer[ 11 ]. A recent cohort study has also indicated that the risk of proximal large polyps increased with age, female sex, and black race[ 12 ]. Although the effect of tumor location on survival remains uncertain, more information on pathophysiological eex in sex to gender is needed to plan strategies for screening and treatment of colorectal cancer.

Colorectal cancer exhibits different molecular and pathological characteristics depending on tumor location. Hereditary non-polyposis colorectal cancer is more likely to develop tumors on the right side of the colon, whereas familial adenomatous madar is associated with left-sided colon cancer[ 1617 amdar.

Common clinical and molecular characteristics of right- and left-sided colon tumors. Hormonal factors may explain a large percentage of right-sided colorectal cancer in females. In the ,adar study, hormone sex therapy HRT was associated with the reduced risk of unstable tumors[ 18 ].

These results indicate that HRT could have a detrimental effect on colorectal cancer risk after tumor has developed. Taken together, previous and current HRT is likely associated with the decreased risk of colorectal cancer, while chronic endogenous estrogen exposure may be linked to the increased risk of madar cancer in postmenopausal women[ 2021 ].

It has been reported that certain genetic and epigenetic differences between sexes may determine colorectal cancer risk. CIMP-high was increased from the rectum to the cecum, with a higher percentage of females developing tumors in the cecum[ 22 ].

Another study found that the vascular endothelial growth factor polymorphism increased the risk of colon cancer in women only[ 24 ]. In addition, the PIK3CA mutation occurs more frequently in females and in proximal colon cancer, which is associated with poorer survival[ 25 ]. However, limited number of preclinical studies used animals of both madra to investigate the molecular mechanisms of madar cancer development, the responses to environmental stresses, and the responses to treatment.

In many cases, male animals were preferably used to eliminate possible interactions between estrogen and tumor formation. Given that right-sided colon cancer, which is associated with poor prognosis, is more common in women than men, it is important to understand sex-related biological factors which sex segment-specific colon tumor formation. To study sex differences, preclinical researches need to use animals from both sexes. Epidemiological studies need to consider biological variables in determining the incidence, mortality, and survival rate of colorectal cancer to produce better screening and treatment protocols.

Colorectal cancer screening provides effective opportunity to prevent the disease. However, there are no gender-specific screening tools or guidelines. A previous study showed that both black race and females tend to exhibit polyps greater than 9 mm while other races and males exhibit smaller polyps upon colonoscopy[ 26 ], suggesting possible sex- and race-specific delays in diagnosis.

It has been also reported that screening via flexible sigmoidoscopy can detect polyps or tumors twice as frequently in men than in women[ 27 ]. Women felt less pain and discomfort when undergoing thinner flexible sigmoidoscopy[ 28 ], suggesting there are needs to bs sex differences in the sensitivity and feasibility towards colorectal cancer screening tools.

It is interesting to note that madar 10 year incidence and mortality of colorectal cancer in women at ages 55, 60, and 65 years follow almost identical sex of incidence and mortality of colorectal cancer in men at ages 50, 55, and 60[ 29 ], suggesting women exhibit delayed colorectal cancer development. Despite the seriousness of colon cancer madae older women, sex-specific anatomical and physiological characteristics in women have made it difficult to detect tumors during screening processes.

Women have the longer transverse colon and increased redundancy compare to men causing incomplete colonoscopy in women[ 7 ]. Preclinical studies suggested that dietary fiber consumption increases the length of the colon[ 30 madar, 31 ].

Therefore, higher dietary fiber consumption in women might be related to wex longer colon length in women[ 3233 ]. A ha study showed that women who experienced cancer maxar their reproductive tract tend to develop colorectal cancer more frequently[ 34 ].

Lastly, health care disparities between gender and ethnic groups have been presented[ 35 ]. These evidences suggest that colorectal cancer screening in women needs more attention in terms of their sensitivity, and gender-specific screening guidelines for colorectal cancer need to be deliberated. Despite distinctive zex differences in anatomy and physiology of the colon, madar screening guidelines have not been esx. The longer average total and transverse colon length, more frequent occurrence of flat-type right-sided colon cancer and narrower colon diameter of women compared to those of men may cause bz limitation in endoscopic examinations.

Therefore, it is necessary to customize endoscopic devices for women. There is no guideline regarding the age to stop colorectal cancer screening in many parts of the world. Asia-Pacific guideline stated that colorectal cancer screening should be continued until 75 years old for both men and women[ 36 ]. Due to longer life expectancy in women, colorectal cancer screening in older women needs to be emphasized. We reviewed all of the prospective cohort studies that sx cancers of the sex, colon or rectum as the major endpoints included in the Continuous Update Project of the WCRF[ 38 ] and examined whether the associations between dietary factors and colorectal cancer risk were reported according to gender.

When we calculated the proportion of sex-specific estimates among studies that included both women and men, an average of For ab beverages, Given that sociological and cultural aspects of alcohol drinking vary by sex and that the toxic threshold of ethanol may differ by sex, it may be important to provide specific summaries for women and men.

Proportion of sex-specific estimates reported in prospective studies that included both women and men. Since the s, many female-specific prospective cohort studies e. These results have contributed to the accumulation of evidence regarding cancer prevention for women, particularly for cancers that occur primarily in women. However, large studies that included both women and men often did not report the sex-specific estimates.

This lack of reported sex-specific estimates precludes meta-analyses madaar sex-specific estimates, which would have a greater statistic power and provide evidences for dietary guidelines for cancer prevention. Studies have reported that dietary factors are associated differently with colorectal cancer depending on the location of tumors.

High carbohydrate intake increased right-sided colon cancer in women, but increased rectal cancer in men[ mdaar ]. High fat and protein intakes increased risks of right- and left-sided colon cancers, respectively[ 4041 ]. Recent evidence maddar a large Canadian population-based case-control study suggested that high intake of polyunsaturated fat, trans-fat, cholesterol, sucrose, and sex was associated with the increased risk of right-sided colon cancer[ 42 ].

In addition, meat consumption increased the risk of left-sided colon cancer compared to right-sided colon cancer[ 43 - 45 ], whereas total iron and iron from supplements were inversely associated with distal colon cancer[ 45 ]. Consumption of soy products containing phytoestrogens has been shown to be inversely madar with the risk of colorectal cancer[ 50 - 53 ]. This result supports a previous report suggesting soy consumption differentially affects estrogen metabolism depending on the endogenous estrogen level[ 54 ].

Given the biological and socio-cultural differences between genders, gender-specific analyses should be conducted to provide optimal cancer prevention strategies and to reduce the number of new colorectal cancer cases both in men and women. Large population-based cohort studies need to report sex-specific estimates of dietary risk factors to provide better guidelines for cancer preventive dietary intake.

Clinical studies have suggested that colorectal cancer treatment in premenopausal women needs attention sdx to its possible effects on female fertility.

Characterization of female- and male-biased genes. For each of the 47, transcripts the sex effect was determined using a mixed model, resulting in 3.

From the sex-biased transcripts on the autosomes, Most absolute log e fold changes were smaller than 0. On the X chromosome, transcripts from genes were measured. Out of these, transcripts from 51 genes were sex-biased; from 38 genes were female-biased, and 24 from 13 genes male-biased. Seventeen of the corresponding log e fold changes were larger than 0.

Of the 63 transcripts targeting 26 genes on the Y chromosome, 48 transcripts from 16 genes had expression levels in men that were higher than the noise measured in women; 12 transcripts had a log e fold change larger than 0.

For each chromosome we tested whether the genes on that chromosome enriched the sex-, male- or female-biased genes. At the autosomes, the percentage of sex-biased genes differed only slightly between chromosomes, ranging from 1. The distribution of the male- and female-biased genes over the autosomes was more variable, ranging from 0. As expected, female-biased genes were enriched for genes at the X-chromosome 5. Significant subcategories included response to cytokine stimulus Male-biased genes were not enriched for any BPGO category.

Male-biased genes were enriched for 11 CCGO categories, with as top hit cytoplasm In Additional file 3 the hierarchical network structure of the significant GO categories is visualized. For each of the autosomal sex-biased transcripts, eQTLs were computed for men and women separately.

For the pooled eQTLs cis, trans eQTLs genotype-sex interactions were assessed using a mixed model that included data from men and women. Thus, gene expression correlation structure is similar between men and women, and here we focus on properties of the intersection of the overlapping modules.

Interestingly, 7 of these intersected modules were highly enriched with female-biased or male-biased genes.

The modules were highly enriched for several GO terms Additional file 7. We calculated the pairwise transcript correlations within each intersected module or men and women separately. Between transcript correlations are higher in males than in females for 2 modules. WGCNA Weighted Gene Co-Expression Network Analysis resulted in 9 modules with correlated transcripts, two of which were highly enriched for female-biased genes, and 3 for male-biased genes.

From the latter three, two modules contained genes from which the pair-wise correlations were stronger in males compared to females. To test whether sex-biased genes have evolved faster than non sex-biased genes, we tested for enrichment in two sets of genes that were previously identified as rapidly evolving: genes from the Human PAML Browser [ 29 ] and 40 genes from a study comparing human and chimpanzee genomes [ 30 ].

We downloaded analysis results of two human studies that identified sex-biased genes in muscle [ 22 ] and in liver [ 21 ]. On the autosomes, there were transcripts differentially expressed between postmenopausal women and men. From these transcripts female-biased and male-biased overlapped with the sex-biased transcripts identified in non-hormonal contraceptives using premenopausal NHC women.

When comparing the HC women with men, a much larger number of 2, differentially expressed transcripts were identified 1, female-biased, in male-biased.

From these transcripts, were overlapping with the sex-biased transcripts identified in NHC women. For the transcripts identified in NHC women, log e fold changes were computed for the difference between each of the three groups of women NHC, HC, postmenopausal compared to men.

This shows that many gene expression differences between women and men become smaller when women reach menopause, and are larger when women use hormonal contraceptives, which reinforces the role of estrogen in regulating sex-biased genes. Sex-differences in gene expression are increased by the use of hormonal contraceptives, and decreased during menopause. Women were divided in three groups: postmenopausal, hormonal contraceptive using HC , and non hormonal contraceptive using NHC women.

For the sex-biased transcripts identified in the comparison between males and NHC women, fold changes were computed for the difference between the three groups of women and the men.

Positive fold changes are from female-biased genes, negative fold changes correspond to male-biased genes. Age has a strong influence on gene expression [ 32 ]. However, the fold changes between men and women of the sex-biased genes identified in the total sample were highly concordant between age ranges Additional file 10 , suggesting that the identified sex effects occur at all ages, but that some effects may be stronger at a certain age or may not have been identified due to reduced power in the smaller groups of selected ages.

At the DNA autosomal sequence level sexes do not differ, as established by a well-powered meta-analysis [ 33 ], suggesting an important role for higher molecular levels, such as the transcriptome, in the manifestation of sexual dimorphisms. Indeed, animal studies have shown that the transcriptome is highly differential between sexes [ 14 , 15 , 34 , 35 ]. On the autosomes, we identified genes 3. Of these genes, The autosomes had rather similar proportions of sex-biased genes indicating the sex-biased genes can be found equally frequent across the entire genome, as opposed to what was found in liver [ 21 ] where several chromosomes enrich sex-biased genes.

It is important to note that the filter criteria used for selecting probe sets highly influences the number of sex-biased genes; the percentage of sex-biased genes increased with the threshold for mean expression level from 3.

Importantly, we have shown that hormonal contraceptives and menopause status, which were not taken into account in previous studies in humans, highly influence the number and effect sizes of sex differences in gene expression. Although it has been indicated that the percentage of sex-biased genes in non-human vertebrates is highly tissue dependent e.

Peripheral blood consists of a mixture of blood cell types the main types are lymphocytes, neutrophiles and monocytes , hence the sex differences we identified must either be present in all subcell types or, when present in only one cell type, strong enough to be observed in the accumulative measurement.

By stratifying the sample into three age groups we showed that the size of the sex effects may be age dependent for some genes, but the direction of the effects are highly concordant between age groups. We found a significant but small overlap of sex-biased autosomal genes identified in peripheral blood with those previously identified in muscle or liver, further confirming substantial tissue specificity of sex-biased genes.

Across tissue circulating exosomes contain RNA and could contribute to the overlapping expression profiles between muscle, liver and blood [ 36 ].

Sex-biased X chromosome genes showed must larger overlap between tissues, indicating that escape from X-inactivation is highly similar between tissues. Previous studies have reported that sex-biased genes may evolve more rapidly than average in vertebrates [ 12 ], human brain [ 37 ] and liver [ 21 ]. However, sex-biased genes in the peripheral blood transcriptome identified in our study did not include enrichment of fast evolving genes.

In women, most genes on one X chromosome are not expressed due to X chromosome inactivation [ 38 ]. Some genes escape X-inactivation and are expressed from both X chromosomes [ 7 ].

We showed that in peripheral blood the X chromosome is enriched for female-biased genes; 5. This percentage, however, is only slightly higher than the average percentage identified at the autosomes 3. Estrogen is the primary female sex hormone and estrogenic activity is present at about two fold increased concentration in women as compared to men.

Estradiol, the predominant estrogen in terms of absolute serum levels, activates estrogen receptors that bind to DNA sequences to activate or suppress gene expression, and many efforts have been made to find its target genes up to in MCF-7 cancer cell line [ 39 — 41 ] because of its role in breast cancer [ 42 ].

This suggests that these genes mediate the effect of estrogen and thereby may contribute to the sex differences in the related diseases. Second, we showed that the sex differences in gene expression depend largely on the hormonal status of the subgroup of women considered. In postmenopausal women, in which estradiol levels are similar to those in men, we identified fewer sex-biased genes with smaller effect sizes as compared to premenopausal women. In hormonal contraceptive using women, with increased estradiol levels, we identified more sex-biased genes and larger effect sizes as compared to women not using hormonal contraceptives.

In liver, sex differences in gene expression are mainly caused by sex-specific growth hormone secretion [ 21 , 53 ]. Growth hormones are regulated by estrogen [ 54 , 55 ], hence the effect of estrogen on sex-specific gene expression in peripheral blood may also be mediated by growth hormone secretion.

The immune system function is known to be different between sexes; women produce more vigorous immune reactions and are more prone to autoimmune diseases [ 56 ]. Here we identified a large number of genes that potentially contribute to the immune system sex differences; From the 95 female-biased genes linked to the immune system, 45 are regulated by estradiol, which confirms the role of estrogen in the sex-specific immune system functioning [ 57 ].

Most interestingly, Ingenuity Pathway Analysis revealed that female-biased genes are highly enriched for genes involved in the toll-like receptor TLR4 and TLR3 pathways, known as LPS and poly I:C response patterns driven innate immune defense, suggesting some intrinsic innate immune activity sex differences.

Increased female expression of immunoglobulin is reflective of concomitant more active humoral immune activity. These functions are compatible with an activated leukocyte, cytokine production and type 1 interferon activity observed in the GO enrichment analysis and might explain why women are more resistant to certain infections, and suffer a high incidence of autoimmune diseases compared to men [ 2 ]. For example, rheumatoid arthritis occurs almost twice as often in women as in men [ 58 ].

Female-biased genes were enriched for genes linked to rheumatoid arthritis, including the gene IL6R, which is a well-known target in rheumatoid arthritis treatment [ 59 ]. The identified female-biased genes provide a framework for future research to unravel the mechanism of sex-biased immune regulation and autoimmune diseases. Surprisingly, male-biased genes were not enriched for GO categories, and thus serve a wide variety of biological functions.

In IPA, however, male-biased genes were most significantly enriched for genes linked to renal cancer, including the well established renal cancer gene CSF1R [ 60 ]. It is notable that a recent meta-analysis on sex differences in renal cell cancer presentation and survival showed a ratio of 1.

The cellular component GO categories indicate the part of a cell at which a gene product is located. Topographical categorization revealed that male-biased gene products occur more often intracellularly, in particular at the cytoplasm, whereas female-biased genes occur more often integral to the membrane. A previous study in a smaller sample than the current one showed that a substantial amount of eQTLs is sex-specific, but not for eQTLs from genes with sex-biased expression [ 26 ].

Here we confirm this finding by showing that for the sex-biased genes there were no significant eQTL-sex interactions. This shows the importance of other factors, such as estradiol and other hormones, in causing gene expression sex differences. WGCNA analyses resulted in highly similar modules of correlated transcripts for men and women, similar to findings in mice [ 18 ]. The 9 modules were highly enriched for male or female-biased genes, indicating that sex-biased genes play an important role in the major gene expression networks.

Module 9 contained This module contained the interleukin receptor IL2B gene, and IPA analysis showed that 11 of the 35 genes in this module are known to be regulated by the cytokine IL2, and 16 of them are related to cancer Additional file 11 including the female-biased genes PRF1 and GZMH essential for natural killer NK -cell cytotoxicity [ 62 , 63 ].

Module 6 contained This suggests that the modules 9 and 6 may play a role in the sex differences in cancer and cardiovascular disease, respectively. We showed that sex-biased genes occur in large numbers throughout the human peripheral blood transcriptome, suggesting an important role of sex-specific gene expression in sexual dimorphisms.

Estrogen appears to be a key regulator of sex-biased genes, also shown by the effect of menopause and hormonal contraceptives on gene expression sex differences. Sex-biased genes are highly enriched with genes linked to common diseases and may contribute to sex-differences in these diseases.

Understanding the molecular mechanisms behind sex inequalities can lead to new insights into sex-specific pathophysiology and treatment opportunities. As part of the NESDA and NTR biobank protocols, data on menopause status and medication use, including hormonal contraceptives were collected in all participants.

Average time between blood sampling and RNA extraction was weeks included in mixed model for gene expression.

Upon registration of samples, RNA was extracted using Qiagen Universal liquid handling system PAXgene extraction kits as per the manufacturer's protocol. RNA samples that showed abnormal ribosomal subunits in the electropherograms were removed. Samples were hybridized to Affymetrix U array plates GeneTitan to enable high-throughput gene expression profiling of 96 samples at a time.

The U array contains , probes for 49, transcripts. Gene expression data were required to pass standard Affymetrix QC metrics Affymetrix expression console before further analysis. Probes were removed when their location was uncertain or if their location intersected a polymorphic SNP dropped if the probe oligonucleotide sequence did not map uniquely to hg19 or if the probe contained a polymorphic SNP based on HapMap3 and Genomes project data. First, 70 samples with array results inconsistent with the phenotypic database were removed inconsistent sex based on chr X and chr Y probe sets.

Second, we used the pairwise correlation matrix of expression profiles across all arrays for additional QC. These quantities were expressed in terms of median absolute deviations to provide a sense of scale. We used:. With r i the average of correlations for sample i, and r the average of all correlations. Linear mixed models allow for the correction for the presence of twin families in a sample [ 71 ].

For each of the 47, probe sets a mixed model was fit with gene expression as dependent variable. Independent model covariates were selected based on significance of the variable in the fitted mixed models. Several covariates that did not come out significantly were not included in the final model alcohol use, education level, time between RNA amplification and RNA fragmentation, time between RNA fragmentation and RNA hybridization. Inclusion of depression status and psychotropic medication use as covariates in the mixed model did not affect the principle findings.

Random effects were plate, well, family ID and zygosity one factor for each monozygotic twin pair, for each other individual different factors [ 71 ]. In Additional file 12 , for each of the variables the amount of probe sets for which the variable was significant is denoted.

Mixed models and resulting p-values were computed using the R function lmer from the package lme4. Prior to eQTL analysis for each gene expression probeset the data was transformed into a normal distribution using an inverse quantile normal transformation.

In the screening step, males and woman were screened using MatrixeQTL as if the individuals were all unrelated. Benjamini-Hochberg q-value estimation was performed separately for cis- and trans-eQTLs. For each of the autosomal sex-biased transcripts eQTLs were selected for men and women separately, and then pooled. For these eQTLs genotype-sex interactions were assessed using the full mixed model that included both men and women, with as independent variables genotype, sex, their interaction and the other covariate also used in the mixed model for gene expression see above.

To test whether Gene Ontology [ 74 ] categories enriched sex-biased genes we used hypergeometric tests implemented in BINGO software [ 75 ].

The reference gene set consisted of all genes measured by the U microarrays. The correlation structure of gene expression was examined using unsigned co-expression networks constructed using the WGCNA package in R [ 28 ]. Of all 47, probes a single probe of highest mean expression per gene was selected to be included in the network analysis using the CollapseRows function in WGCNA, resulting in the inclusion of 19, genes in the network.

The choice of the probe of highest mean expression per gene has been shown to yield robust analysis across data sets [ 76 ]. The network construction for each entire data set was performed in a single block of maximum size 20, genes using the blockwiseModules function in WGCNA [ 28 ]. The network adjacency matrix is the gene pair-wise correlation matrix raised to the power of 6, chosen based on the scale-free topology criteria [ 77 ].

Rather than just using adjacency weights between genes, the topological overlap measure TOM is computed from the adjacency matrix. For each pair of genes, TOM is the adjacency weights of all the paths between the genes of length at most two i. The topological overlap dissimilarity, defined as 1-TOM, is used for the average linkage hierarchical clustering algorithm. The resultant clustering tree is used to define the modules from its branches using the hybrid dynamic tree cutting algorithm [ 28 ].

The minimum module size was set to 30 and the cut-off for merging modules was set to 0. Each module is then characterized by its eigengene, the first principal component of the module expression data, which accounts for the greatest variation of the expression levels in the module.

Genes were removed from modules if the correlations between their expression values and the module eigengenes were too low less than 0. Modules were merged if the correlation between their eigengenes was high.

Gene expression data used for this study will be available at dbGaP, accession number phs RJ and SB performed analysis. AB and JT generated molecular data. All authors read and approved the final manuscript. Endocrinol Metab Clin North Am. Whitacre CC: Sex differences in autoimmune disease. Nat Immunol. PLoS One. Nolen-Hoeksema S: Emotion regulation and psychopathology: the role of gender. Annu Rev Clin Psychol. Nat Rev Genet.

Jessen HM, Auger AP: Sex differences in epigenetic mechanisms may underlie risk and resilience for mental health disorders. Ling G, Sugathan A, Mazor T, Fraenkel E, Waxman DJ: Unbiased, genome-wide In vivo mapping of transcriptional regulatory elements reveals sex differences in chromatin structure associated with sex-specific liver gene expression.

Mol Cell Biol. Although the effect of tumor location on survival remains uncertain, more information on pathophysiological differences in relation to gender is needed to plan strategies for screening and treatment of colorectal cancer.

Colorectal cancer exhibits different molecular and pathological characteristics depending on tumor location. Hereditary non-polyposis colorectal cancer is more likely to develop tumors on the right side of the colon, whereas familial adenomatous polyposis is associated with left-sided colon cancer[ 16 , 17 ].

Common clinical and molecular characteristics of right- and left-sided colon tumors. Hormonal factors may explain a large percentage of right-sided colorectal cancer in females. In the same study, hormone replacement therapy HRT was associated with the reduced risk of unstable tumors[ 18 ]. These results indicate that HRT could have a detrimental effect on colorectal cancer risk after tumor has developed.

Taken together, previous and current HRT is likely associated with the decreased risk of colorectal cancer, while chronic endogenous estrogen exposure may be linked to the increased risk of colorectal cancer in postmenopausal women[ 20 , 21 ]. It has been reported that certain genetic and epigenetic differences between sexes may determine colorectal cancer risk.

CIMP-high was increased from the rectum to the cecum, with a higher percentage of females developing tumors in the cecum[ 22 ]. Another study found that the vascular endothelial growth factor polymorphism increased the risk of colon cancer in women only[ 24 ]. In addition, the PIK3CA mutation occurs more frequently in females and in proximal colon cancer, which is associated with poorer survival[ 25 ].

However, limited number of preclinical studies used animals of both sexes to investigate the molecular mechanisms of colon cancer development, the responses to environmental stresses, and the responses to treatment. In many cases, male animals were preferably used to eliminate possible interactions between estrogen and tumor formation.

Given that right-sided colon cancer, which is associated with poor prognosis, is more common in women than men, it is important to understand sex-related biological factors which affect segment-specific colon tumor formation.

To study sex differences, preclinical researches need to use animals from both sexes. Epidemiological studies need to consider biological variables in determining the incidence, mortality, and survival rate of colorectal cancer to produce better screening and treatment protocols. Colorectal cancer screening provides effective opportunity to prevent the disease. However, there are no gender-specific screening tools or guidelines.

A previous study showed that both black race and females tend to exhibit polyps greater than 9 mm while other races and males exhibit smaller polyps upon colonoscopy[ 26 ], suggesting possible sex- and race-specific delays in diagnosis.

It has been also reported that screening via flexible sigmoidoscopy can detect polyps or tumors twice as frequently in men than in women[ 27 ]. Women felt less pain and discomfort when undergoing thinner flexible sigmoidoscopy[ 28 ], suggesting there are needs to consider sex differences in the sensitivity and feasibility towards colorectal cancer screening tools.

It is interesting to note that cumulative 10 year incidence and mortality of colorectal cancer in women at ages 55, 60, and 65 years follow almost identical rates of incidence and mortality of colorectal cancer in men at ages 50, 55, and 60[ 29 ], suggesting women exhibit delayed colorectal cancer development. Despite the seriousness of colon cancer in older women, sex-specific anatomical and physiological characteristics in women have made it difficult to detect tumors during screening processes.

Women have the longer transverse colon and increased redundancy compare to men causing incomplete colonoscopy in women[ 7 ]. Preclinical studies suggested that dietary fiber consumption increases the length of the colon[ 30 , 31 ]. Therefore, higher dietary fiber consumption in women might be related to the longer colon length in women[ 32 , 33 ]. A previous study showed that women who experienced cancer in their reproductive tract tend to develop colorectal cancer more frequently[ 34 ].

Lastly, health care disparities between gender and ethnic groups have been presented[ 35 ]. These evidences suggest that colorectal cancer screening in women needs more attention in terms of their sensitivity, and gender-specific screening guidelines for colorectal cancer need to be deliberated.

Despite distinctive sexual differences in anatomy and physiology of the colon, gender-specific screening guidelines have not been emphasized. The longer average total and transverse colon length, more frequent occurrence of flat-type right-sided colon cancer and narrower colon diameter of women compared to those of men may cause technical limitation in endoscopic examinations. Therefore, it is necessary to customize endoscopic devices for women.

There is no guideline regarding the age to stop colorectal cancer screening in many parts of the world. Asia-Pacific guideline stated that colorectal cancer screening should be continued until 75 years old for both men and women[ 36 ]. Due to longer life expectancy in women, colorectal cancer screening in older women needs to be emphasized.

We reviewed all of the prospective cohort studies that analyzed cancers of the colorectum, colon or rectum as the major endpoints included in the Continuous Update Project of the WCRF[ 38 ] and examined whether the associations between dietary factors and colorectal cancer risk were reported according to gender. When we calculated the proportion of sex-specific estimates among studies that included both women and men, an average of For alcoholic beverages, Given that sociological and cultural aspects of alcohol drinking vary by sex and that the toxic threshold of ethanol may differ by sex, it may be important to provide specific summaries for women and men.

Proportion of sex-specific estimates reported in prospective studies that included both women and men. Since the s, many female-specific prospective cohort studies e. These results have contributed to the accumulation of evidence regarding cancer prevention for women, particularly for cancers that occur primarily in women.

However, large studies that included both women and men often did not report the sex-specific estimates. This lack of reported sex-specific estimates precludes meta-analyses of sex-specific estimates, which would have a greater statistic power and provide evidences for dietary guidelines for cancer prevention. Studies have reported that dietary factors are associated differently with colorectal cancer depending on the location of tumors.

High carbohydrate intake increased right-sided colon cancer in women, but increased rectal cancer in men[ 39 ]. High fat and protein intakes increased risks of right- and left-sided colon cancers, respectively[ 40 , 41 ]. Recent evidence from a large Canadian population-based case-control study suggested that high intake of polyunsaturated fat, trans-fat, cholesterol, sucrose, and lactose was associated with the increased risk of right-sided colon cancer[ 42 ].

In addition, meat consumption increased the risk of left-sided colon cancer compared to right-sided colon cancer[ 43 - 45 ], whereas total iron and iron from supplements were inversely associated with distal colon cancer[ 45 ]. Consumption of soy products containing phytoestrogens has been shown to be inversely associated with the risk of colorectal cancer[ 50 - 53 ].

This result supports a previous report suggesting soy consumption differentially affects estrogen metabolism depending on the endogenous estrogen level[ 54 ]. Given the biological and socio-cultural differences between genders, gender-specific analyses should be conducted to provide optimal cancer prevention strategies and to reduce the number of new colorectal cancer cases both in men and women.

Large population-based cohort studies need to report sex-specific estimates of dietary risk factors to provide better guidelines for cancer preventive dietary intake. Clinical studies have suggested that colorectal cancer treatment in premenopausal women needs attention due to its possible effects on female fertility.

In addition to chemotherapy, surgical and radiation therapies also need to be considered for female fertility preservation[ 57 ]. Furthermore, gender-specific recurrence and survival rates were detected. The genotype of the TP53 tumor suppressor gene was predictive of survival following adjuvant chemotherapy in women with stage III colon cancer[ 58 ]. Therefore, it is necessary to use a distinct evaluation protocol for the response of women to colorectal cancer treatment.

Taken together, research efforts towards the development of anti-cancer drugs displaying less toxicity to the reproductive system are required. Treatment protocols specifically recommended for women of child-bearing age should be suggested based on sound scientific evidence. A sex-specific decrease in the survival rate of women subjected to a specific anti-cancer drug may be associated with the genetic background.

Thus, a long-term follow-up study of cancer survivors needs to be considered to ensure the safety of specific anti-cancer drug use with respect to not only reproductive function but also possible genetic effects on subsequent generations. Also, possible gender-specific barriers to cancer treatment need to be studied.

This is specifically important because optimal anti-cancer drug regimen for colorectal cancer should be required based on the effect of sex on drug efficacy and toxicity. Among colon cancer patients aged more than 65 years old, women were less likely to receive 5-fluorouracil treatment and showed a shorter duration of treatment compared to men, which were possibly associated with the observation that women were more prone to dehydration than men[ 60 ].

Indeed, women experienced more severe toxicity including stomatitis, leukopenia, alopecia, and diarrhea compared to men when receiving 5-fluorouracil-based treatment[ 61 ]. It is recommended to complete all planned chemotherapy cycles to improve disease-free survival. However, recent studies reported that stage III female colon cancer patients tend to omit adjunctive chemotherapy sessions compared to male counterparts[ 62 - 64 ]. Also, a greater percentage of elderly female patients and female patients with a prolonged hospital stay exhibited a higher rate of discontinuation[ 62 ].

Therefore, further researches are needed to provide evidence on gender-specific barriers to colorectal cancer treatment and establish optimal anti-cancer drug regimen by gender. Clinical and preclinical studies have indicated that there are sex- and gender-associated differences in colorectal cancer development.

Both genetic and environmental factors are believed to play roles in sex and gender differences in right- vs left-sided colon cancers. Therefore, biological and pathophysiological differences in colorectal cancer development between men and women need to be clearly addressed. Despite higher incidence of right-sided colon cancer in women, a substantially higher number of preclinical studies use only male animals in colorectal cancer research.

Researchers should be aware of sex-specific pathophysiological differences in colorectal cancer development and use both male and female animals for their research. In addition, there is a great deal of needs for developing gender-specific endoscopy devices with higher sensitivity due to sex-specific differences in biological and anatomic characteristics of the colon.

Colorectal cancer screening guidelines may need to emphasize gender-specific points for colorectal cancer screening. Diet is one of the most closely associated environmental factors in colorectal cancer development. Dietary factors to increase or decrease the risk of developing colorectal cancer are continuously updated based on large scale cohort studies.

However, only a half of studies reported sex-specific risk estimates despite potential sex-associated differences between dietary factors and colorectal cancer risk. Given that there are sex- and gender-specific differences in the biological responses to dietary components, it is necessary to analyze and report gender-specific risk estimates to provide better guidelines for cancer prevention strategies.

Furthermore, researches addressing sex-specific differences in responses to anti-cancer drugs for colorectal cancer are required to reduce side-effects on reproductive system and to investigate genetic effects on drug efficacy. By understanding sex- and gender-related biological and socio-cultural differences in colorectal cancer risk, gender-specific strategies for screening, treatment, and prevention protocols for colorectal cancer can be established to reduce the mortality and increase the quality of life.

Conflict-of-interest: The authors have no conflict-of-interest. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. Peer-review started: January 6, First decision: February 10, Article in press: March 31, National Center for Biotechnology Information , U. Journal List World J Gastroenterol v. World J Gastroenterol. Published online May 7.

Author information Article notes Copyright and License information Disclaimer. Author contributions: Kim SE summarized the data and wrote the manuscript; Paik HY contributed to the study concept and revision of the manuscript; Yoon H and Kim N provided the data and revised the manuscript; Lee JE drafted and revised the manuscript; Sung MK formulated the idea and contributed to the revision and approval of the final version of the manuscript. Published by Baishideng Publishing Group Inc.

All rights reserved. This article has been cited by other articles in PMC. Abstract Colorectal cancer is one of the most common causes of cancer morbidity both in men and in women.

Open in a separate window. Figure 1. Figure 2. Different endoscopic appearances between right- A and left-sided B colon cancers.

Figure 3. References 1. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in Cancer Res Treat. Jpn J Clin Oncol. Hansen IO, Jess P. Possible better long-term survival in left versus right-sided colon cancer - a systematic review. Dan Med J. Pal SK, Hurria A. Impact of age, sex, and comorbidity on cancer therapy and disease progression. J Clin Oncol. Proportion of flat- and depressed-type and laterally spreading tumor among advanced colorectal neoplasia.

Clin Gastroenterol Hepatol. Why is colonoscopy more difficult in women? Gastrointest Endosc. Sex differences in performance of fecal occult blood testing. Am J Gastroenterol. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. Data on the characteristics and the survival of korean patients with colorectal cancer from the Korea central cancer registry.

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