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Sex-biased gene expression signatures (A) Pie charts showing the distributions of genes with both significant sex-biased mRNA expression and DNA methylation patterns for the 8 cancer types in the strong sex-effect group. The p-values were calculated from Fisher's exact test to assess the association between the sex-biased methylation and mRNA expression patterns. (B) The biological pathways identified by GSEA based on the sex-biased gene ranks of mRNA expression (left) and DNA methylation (right). Boxes highlight the statistically significant enriched pathways (mRNA: FDR ? 0.05; DNA methylation: FDR ? 0.2), and enrichment for female-biased and male-biased genes are shown in red and blue, respectively. The gene regulatory networks formed by the proteins with a sex-biased protein expression level (FDR ? 0.05) and their potential miRNA regulators in (C) HNSC and (D) KIRC. See Figure S2 and Table S4.
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An individual's sex has been long recognized as a key factor affecting cancer incidence, prognosis, and treatment responses. However, the molecular basis for sex disparities in cancer remains poorly understood. We performed a comprehensive analysis of molecular differences between male and female patients in 13 cancer types of The Cancer Genome Atl...
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... for protein expression, we found abundant sex-biased protein expression signals in HNSC and KIRC. Interestingly, 12 (of the 15) sex-biased proteins identified in HNSC or 18 (of the 25) sex-biased proteins identified in KIRC form well-connected regulatory networks ( Figure 4C and D); SRC and MAPK proteins take a central position in both networks. SRC plays a key role in regulating a variety of cellular signaling transduction pathways, and the frequent activation of the SRC kinase pathway has been observed in many caner types, especially in metastatic diseases (Dehm and Bonham, 2004). Thus, targeted inhibition of SRC signaling has been suggested as an effective therapeutic strategy and has been under intensive clinical investigation in several cancers, including renal cell cancer (Araujo and Logothetis, 2010;Suwaki et al., 2011). Indeed, the factor of female sex has been reported to predict the response of imatinib, an inhibitor of BRC-ABL tyrosine kinase that also affects the SRC/MAPK pathway, in patients with chronic myeloid leukemia (Deininger et al., 2003;Valeyrie et al., 2003). This finding may be relevant to the female-biased expression pattern observed ...
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... on the 8 cancer types in the strong sex-effect group, we further examined the genes identified by RNA expression (FDR ? 0.05), and found that in all the cancer types, the sex bias observed at the mRNA level of a gene tended to be the opposite of that at its DNA methylation level. This is consistent with the established role of DNA methylation in gene regulation: hypermethylation leads to gene silencing while hypomethylation results in the up-regulation of gene expression ( Figure 4A). To gain insight into the global patterns of the sex effect on gene expression, we performed a gene set enrichment analysis (GSEA) given the gene ranks according to the sex bias, and identified the affected pathways. In general, we observed biologically sensible, contrasting sex-bias patterns at the mRNA and DNA methylation levels ( Figure 4B). We obtained similar results after excluding the genes in the sex chromosomes ( Figure S2B). Thus, both gene-based and gene-rank-based pathway enrichment analyses indicated that the sex-biased mRNA expression patterns in the strong sex-effect cancers are partially the result of the corresponding sex-biased DNA ...
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... on the 8 cancer types in the strong sex-effect group, we further examined the genes identified by RNA expression (FDR ? 0.05), and found that in all the cancer types, the sex bias observed at the mRNA level of a gene tended to be the opposite of that at its DNA methylation level. This is consistent with the established role of DNA methylation in gene regulation: hypermethylation leads to gene silencing while hypomethylation results in the up-regulation of gene expression ( Figure 4A). To gain insight into the global patterns of the sex effect on gene expression, we performed a gene set enrichment analysis (GSEA) given the gene ranks according to the sex bias, and identified the affected pathways. In general, we observed biologically sensible, contrasting sex-bias patterns at the mRNA and DNA methylation levels ( Figure 4B). We obtained similar results after excluding the genes in the sex chromosomes ( Figure S2B). Thus, both gene-based and gene-rank-based pathway enrichment analyses indicated that the sex-biased mRNA expression patterns in the strong sex-effect cancers are partially the result of the corresponding sex-biased DNA ...
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Co-expression analysis is widely used to predict gene function and to identify functionally related gene sets. However, co-expression analysis using human cancer transcriptomic data is confounded by somatic copy number alterations (SCNA), which produce co-expression signatures based on physical proximity rather than biological function. To better u...
Citations
... Current understanding indicates that sex impacts CRC incidence, clinicopathological features like poor differentiation status, therapeutic outcomes, and tolerance of anticancer treatments [53]. Specifically, tumor biology in CRC differs between males and females due to sex hormones and sex chromosomes influencing immunity and regulating key proliferative pathways through estrogens [54,55]. Additionally, significant sex-associated differences exist in the pharmacokinetics of 5-FUbased chemotherapy [56]. ...
Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan–Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the “A/G” genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 “A/G” genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms.
... Then, we identify associations between various clinical and demographic factors and the abundance of fungi within the tumor. To mitigate potential confounding effects and enhance the robustness of our analyses, we employed both propensity scores and Inverse Probability of Treatment Weighting (IPTW) 16,17 .. ...
... First, we computed propensity scores using logistic regression based on the independent variables. Subsequently, we applied the Inverse Probability of Treatment Weighting (IPTW) scheme as performed in 16,17 . Categorical variables were subjected to one-hot encoding, and tumor stage was categorized into four levels (1,2,3,4) to facilitate the analysis (for example 3A, 3B and 3C were considered as 3). ...
Introduction: Recently, Narunsky-Haziza et. al. showed that fungi species identified in a variety of cancer types may have prognostic and diagnostic signficane. We used that data in order to better understand the effects of demographic factors (age, sex, BMI, and race) on the intratumor mycobiome composition.
Materials and Methods: We first tested the data in view of recent critiques of microbiome data processing procedures, and concluded that the batch correction and transformation used on it may produce false signals. Instead, we explored 14 combinations of data transformation and batch correction methods on data of 224 fungal species across 13 cancer types. Propensity scores were utilized to adjust for potential confounders such as histological type and tumor stage. To minimize false outcomes, we identified as positive results only those fungi species that showed significant difference in abundance across a demographic factor within a particular cancer type, using data normalized according to all 14 combinations.
Results and Discussion: We observed significant differences in fungal species abundance within tumors for certain demographic characteristics. Most differences were among races in specific cancers. The findings indicate that there are intricate interactions among the mycobiome, cancer types, and patient demographics. Our study highlights the need for accounting for potential confounders in order to further understanding of the mycobiome's role in cancer, and underscores the importance of data processing techniques.
... Over half of the genes targeted by FDA-approved cancer drugs revealed sex-based variation in molecular signatures, such as differences in somatic mutations, gene expressions, methylation patterns, copy number alterations, and protein abundance. 31 An analysis of molecular profiling data for patients treated with immune-checkpoint blockade therapies identified molecular disparities in immunotherapy responsiveness and revealed distinct patterns of sex bias in immune features across multiple cancer types. 32 Despite overall improvements in gender-based disparities in clinical studies, women are underrepresented in cancer trials. ...
The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.
... In addition, men having increased RCC mortality rates compared to women has been previously documented in Israel, but this study found no significant trend for either sex from 1980 to 2004 (17). While results are not definitive, recent findings suggest that molecular differences in RCC according to sex may impact pathogenesis (18). In addition, supportive data have found that women may have increased tumor-protective mechanisms, specifically increased expression of tumor suppressor genes (19). ...
Background/Aim: Renal cell carcinoma (RCC) accounts for 90% of malignant neoplasms of the kidney. Patients and Methods: In this report, the CDC WONDER database was accessed to retrieve age-adjusted mortality data from 1999 to 2020 due to RCC, defined as ICD-10 Code: C64 Malignant neoplasm of kidney except renal pelvis, for various demographics to investigate trends and potential disparities. Results: In 2020, the overall age-adjusted mortality rate (AAMR) due to RCC in the USA was 42.4 per 1,000,000. The average annual percent change (AAPC) for the USA from 1999 to 2020 was –0.6%. Notably, in 2020, men had a higher AAMR than women, 63.9 compared to 25.7, and a significant difference in AAPC trend was identified between men (–0.5%) and women (–1.0%). When investigating trends according to race in 2020, the Asian population displayed the lowest AAMR at 18.9. When determining AAPC from 1999 to 2020 according to race group, the American Indian group demonstrated the greatest decline in AAPC at –1.3%, followed by the Black (–1.2%) and White populations (-0.5%). The Asian population did not exhibit a significant AAPC. Moreover, the rates between these three groups were statistically significantly different- indicating disparities in trend based on race. Conclusion: This investigation assesses the AAMR for different demographic groups of the USA population to identify disparities and guide resource allocation strategies.
... To examine the clinical significance of the DEGs we identified, we searched the Drugbank database for 58 relevant targets of 33 commonly used (and FDA-approved) breast cancer drugs [42,43], namely, targets affected by hormone therapy, targeted therapy, chemotherapy, and immunotherapy. Based on transcriptomic, genomic, epigenomic, and proteomic data, we found that expression levels of six FDA-approved therapeutic target genes were inconsistent between MBC and FBC, showing sex bias (Fig. 9). ...
Background
Male breast cancer (MBC) is a rare malignancy with a worse prognosis than female breast cancer (FBC). Current MBC treatment strategies are based on those for FBC. However, molecular differences between MBC and FBC with respect to prognosis and drug responses remain unclear.
Methods
After controlling for confounding factors with propensity score matching (PSM), differences between MBC and FBC were comprehensively analyzed using many types of data: survival, immune microenvironments, sex hormone responses, drug sensitivity, transcriptomes, genomes, epigenomes, and proteomes.
Results
Overall survival (OS) and cancer-specific survival (CSS) were both worse for MBC than for FBC. Differentially expressed mRNAs were enriched in numerous cancer-related functions and pathways, with SPAG16 and STOX1 being as the most important prognosis-related mRNAs for MBC. Competing endogenous RNA (ceRNA) and transcription factor (TF)-mRNA regulatory networks contain potential prognostic genes. Nine genes had higher mutation frequencies in MBC than in FBC. MBC shows a comparatively poor response to immunotherapy, with five proteins that promote breast cancer progression being highly expressed in MBC. MBC may be more responsive than FBC to estrogen. We detected six United States Food and Drug Administration (FDA)-approved therapeutic target genes as being differentially expressed between MBC and FBC.
Conclusion
The poor prognosis of MBC compared to FBC is due to numerous molecular differences and resulting drug responses.
... In their recent manuscript, Richter and Bechmann from the University of Dresden (Germany) present their findings in a retrospective analysis, where they compared the distribution of PV and reported clinical features of PPGL in European and Asian populations and related to sex [4]. Several molecular differences have been described between males and females and among different populations in various tumors [5], and this study sheds light on the relevance of these in chromaffin tumors as well. These particularly intriguing perspectives further highlight the growing interest in personalized medicine. ...
... To overcome this problem, the use of ancestry-informative markers (AIMs) would be an option in future studies. In the field of population genetics, AIMs refer to specific sets of single-nucleotide polymorphisms distinguished by markedly varying frequencies among distinct populations [5]. ...
... Recent studies have begun to identify and characterize the sexual dimorphism in GBM and MGMT, which reveals that males and females with GBM have different outcomes [1,4,[9][10][11][12][13][14][15][16][17][18][19][20][21]. Primary GBM is 1.58 times more common among male than female patients and females have better outcomes when adjusted for clinical variables [1,20]. ...
... Primary GBM is 1.58 times more common among male than female patients and females have better outcomes when adjusted for clinical variables [1,20]. In contrast, females have higher incidence rates of secondary GBM and chemotherapy-related myelotoxicity [14,15]. ...
... The role of sex in differentially impacting the survival benefit of MGMT methylation status in gliomas is being increasingly recognized [1,4,[9][10][11][12][13][14][15][16][17][18][19][20][21]. The findings of this study highlight a profound sex difference in GBM patient outcomes in a sex-specific manner, whereby MGMT methylation is not prognostic in males and can markedly separate survival in female patients. ...
Simple Summary
Glioblastoma is a highly aggressive and lethal brain tumor that has seen marginal improvement in patient outcomes despite decades of concerted efforts. This study investigated the impact of tumor molecular features, sex, and their interaction on the survival of patients with newly diagnosed glioblastoma. Our findings show that females are more often found to have silencing of the MGMT promoter, but that they also receive a greater survival benefit, which is more clinically and statistically significant, associated with MGMT promoter silencing that is not reflected in males. These findings may significantly impact both our understanding as well as the clinical management of the disease. Rather than the established practice of using temozolomide to treat MGMT promoter methylated patients as a whole, our findings suggest that females accrue a disproportionate survival benefit compared to males who, regardless of methylation status, may experience better survival outcomes from alternative treatment options.
Abstract
Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan–Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19–93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT–sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45–2.95; p < 0.0001) and males (1.51; 95% CI, 1.14–2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01–1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG–sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation.
... For example, the X-linked lysine demethylases 6A and 5C, as well as the Y-linked paralogs lysine demethylase 5D, may be regulators of the incidence and prognosis of sex-specific cancer [13,14]. Analysis of the molecular data on multiple cancer types using The Cancer Genome Atlas (TCGA) database provided an opportunity to address this problem [15]. TC was identified as a cancer with a strong sex-biased gene signature. ...
... First, our interrogation of the TCGA database demonstrated a robust sex-biased signature in normal thyroid tissues with differential expression of sex-biased genes between male and female patients, in keeping with previous studies [15]. Subsequent analysis of the gene networks and signaling pathways demonstrated that sex-biased genes are involved in cellular proliferation through the regulation of ERK/MAPK and p70S6K signaling and have a role in epigenetic regulation. ...
Simple Summary
Thyroid cancer is the most common endocrine malignancy and is more frequently detected in women than in men. An understanding of the molecular features governing thyroid carcinogenesis in women and men may open avenues toward the development of sex-specific treatments for female and male patients with thyroid cancer. To this end, we performed an analysis of sex-biased genes in normal thyroids as well as benign and malignant thyroid tumors. We demonstrated that normal thyroid tissue has a sex-specific molecular signature, and the development of thyroid cancer is associated with the differential expression of sex-biased genes. In confirmatory studies, we demonstrated that the expression of histone lysine demethylases (KDMs) is strongly associated with sex. Together, our data demonstrate that the development of thyroid cancer may be associated with different sex-specific molecular changes. The sex-specific expression of KDMs, coupled with cancer-related alterations in their intracellular localization, may provide a clue for understanding the mechanisms underlying sex differences in thyroid tumorigenesis.
Abstract
Background: The incidence of thyroid cancer in women is 3–4-fold higher than in men. To characterize sex-specific molecular alterations in thyroid cancer, we examined the expression of sex-biased genes in normal thyroids and thyroid tumors. Methods: Ingenuity pathways analysis was used to define sex-biased gene networks using data from the Cancer Genome Atlas (TCGA). Confirmatory studies were performed through the analysis of histone lysine demethylases (KDMs) expression by real-time PCR and immunostaining. Results: In normal thyroids, 44 sex-biased genes were comparatively upregulated in male and 28 in female patients. The expressions of 37/72 (51%) sex-biased genes were affected in cancer tissues compared with normal thyroids. Gene network analyses revealed sex-specific patterns in the expressions of KDM5C, KDM5D, and KDM6A. In confirmatory studies, KDM5D mRNA and protein were detected only in males, whereas KDM5C and KDM6A were detected in samples from male and female patients. Nuclear staining with anti-KDMs was found in normal thyroids, but a loss of nuclear expression with a concomitant gain of cytoplasmic staining was observed in cancer tissues. Conclusions: Normal thyroids have a sex-specific molecular signature, and the development of thyroid cancer is associated with a differential expression of sex-biased genes. The sex-specific expression of KDMs, coupled with cancer-related alterations in their intracellular localization, may contribute to mechanisms underlying sex differences in thyroid tumorigenesis.
... The reasons for these sex disparities are partially attributed to the differences in exposure to established risk factors and expected protection by sex hormones for women [6]. On the other hand, the genetic and molecular biases contributing to these observations are equally critical, including diverse variations, gene expression, and DNA methylation [8][9][10]. Understanding these biases will contribute to the development of sex-specific clinical therapeutics. ...
... Previous studies have documented sex differences in the frequency and density of somatic mutations between male and female cancer patients by using The Cancer Genome Atlas Program (TCGA) and Pan-Cancer Analysis of Whole Genomes (PCAWG) databases [8][9][10]. Nevertheless, only limited functional variation events are found, and it still needs in-depth investigation of linking this molecular difference to the cancer outcomes between the sexes. ...
Background: Sex difference has long been recognized at cancer incidence, outcomes, and responses to therapy. Analyzing the somatic mutation profiles of large-scale cancer samples between the sexes have revealed several potential drivers of cancer with sex difference. However, it is still a demand for in-depth scrutinizing the sex-biased characteristics of genome instability to link the clinical differences for individual cancer type. Methods: Here, we utilized a published framework devised to specifically compare the copy number profiles between 2 groups to identify the sex-biased copy number alterations (CNAs) across 16 cancer types from the The Cancer Genome Atlas Program database, and dissected the impact of those CNAs. Results: Totally, 81 male-biased CNA regions and 23 female-biased CNA regions in 16 cancer types were found. Functional annotation analysis showed that several critical biological functions associated with sex-biased CNAs are shared in multiple cancer types, including immune-related pathways and regulation of cellular signaling. Most sex-biased CNAs have a substantial effect on transcriptional consequence, where the average of over 68% of genes have a linear relationship with CNAs across cancer types, and 14% of those genes are affected by the combination of the sex and copy number. Furthermore, 29 sex-biased CNA regions show latent capacity to be sex-specific prognostic biomarker such as CNA on 11q13.4 for head and neck cancer and lung cancer. Conclusions: This analysis offers new insights into the role of sex in cancer etiology and prognosis through a detailed characterization of sex differences in genome instability of diverse cancers.
... [69]. Διαφορές στα επίπεδα μεθυλίωσης του DNA διαφόρων γονιδίων έχουν παρατηρηθεί στους διάφορους ιστολογικούς υπότυπους καρκίνου του πνεύμονα [70][71][72][73], στην κατάσταση των μεταλλάξεων κοινών ογκογονιδίων [74], στο ιστορικό καπνίσματος [72][73][74][75], το φύλο [76], και τη φυλή [77,78]. Επιπλέον φαίνεται ότι μεθυλίωση του DNA μεμονωμένων γονιδίων ή ομάδων γονιδίων, καθώς και επιγενετικοί υπότυποι σχετίζονται με την πρόγνωση [79][80][81]. ...
Lung cancer is the most common among men and women, although overall survival rates remain low. One of the main reasons is the late diagnosis. DNA promoter methylation is a basic epigenetic mechanism of carcinogenesis. Alterations in methylation levels can be identified in different tissues, such as sputum and blood, and may be used for early diagnosis and prognosis of patients with lung cancer.
