Non-reproductive Cancers Research Articles

Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities

Abstract Background DNA methylation (DNAm) influences both sex differences and cancer development, yet the mechanisms connecting these factors remain unclear. Methods Utilizing data from The Cancer Genome Atlas, we conducted a comprehensive analysis of sex-related DNAm effects in nine non-reproductive cancers, compared to paired normal adjacent tissues (NATs), and validated the results using independent datasets. First, we assessed the extent of sex differential DNAm between cancers and NATs to explore how sex-related DNAm differences change in cancerous tissues. Next, we employed a multivariate adaptive shrinkage approach to model the covariance of cancer-related DNAm effects between sexes, aiming to elucidate how sex impacts aberrant DNAm patterns in cancers. Finally, we investigated correlations between the methylome and transcriptome to identify key signals driving sex-biased DNAm regulation in cancers. Results Our analysis revealed a significant attenuation of sex differences in DNAm within cancerous tissues compared to baseline differences in normal tissues. We identified 3,452 CpGs (Pbonf < 0.05) associated with this reduction, with 72% of the linked genes involved in X chromosome inactivation. Through covariance analysis, we demonstrated that sex differences in cancer are predominantly driven by variations in the magnitude of shared DNAm signals, referred to as “amplification.” Based on these patterns, we classified cancers into female- and male-biased groups and identified key CpGs exhibiting sex-specific amplification. These CpGs were enriched in binding sites of critical transcription factors, including P53, SOX2, and CTCF. Integrative multi-omics analyses uncovered 48 CpG-gene-cancer trios for females and 380 for males, showing similar magnitude differences in DNAm and gene expression, pointing to a sex-specific regulatory role of DNAm in cancer risk. Notably, several genes regulated by these trios were previously identified as drug targets for cancers, highlighting their potential as sex-specific therapeutic targets. Conclusions These findings advance our understanding of how sex, DNAm, and gene expression interact in cancer, offering insights into the development of sex-specific biomarkers and precision medicine.

OncoSexome: the landscape of sex-based differences in oncologic diseases.

The NIH policy on sex as biological variable (SABV) emphasized the importance of sex-based differences in precision oncology. Over 50% of clinically actionable oncology genes are sex-biased, indicating differences in drug efficacy. Research has identified sex differences in non-reproductive cancers, highlighting the need for comprehensive sex-based cancer data. We therefore developed OncoSexome, a multidimensional knowledge base describing sex-based differences in cancer (https://idrblab.org/OncoSexome/) across four key topics: antineoplastic drugs and responses (SDR), oncology-related biomarkers (SBM), risk factors (SRF) and microbial landscape (SML). SDR covers sex-based differences in 2051 anticancer drugs; SBM describes 12551 sex-differential biomarkers; SRF illustrates 350 sex-dependent risk factors; SML demonstrates 1386 microbes with sex-differential abundances associated with cancer development. OncoSexome is unique in illuminating multifaceted influences of biological sex on cancer, providing both external and endogenous contributors to cancer development and describing sex-based differences for the broadest oncological classes. Given the increasing global research interest in sex-based differences, OncoSexome is expected to impact future precision oncology practices significantly.

Cancer risk in patients treated with denosumab compared with alendronate: A population-based cohort study

BackgroundAntiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian cancer incidence and emerging data suggest that denosumab stimulates germ cell proliferation in the gonads. This study aims to determine the association between the use of denosumab and the risk of reproductive cancers compared with the use of alendronate. Research design and methodsUsing a cohort study design, we used the Danish nationwide registries to identify a population of subjects ≥50 years of age during 2010–2017 who started denosumab after being on alendronate treatment for at least six months. The cohort was matched 1:2 with patients who had been treated with alendronate alone for at least six months. The risk of reproductive cancers and the risk difference between groups were estimated using the Longitudinal Targeted Maximum Likelihood Estimation (L-TMLE) method. ResultsWe identified 6054 Danish individuals who underwent treatment with denosumab. These individuals were matched with 12,108 receiving alendronate. The absolute risk of reproductive cancer was 1.05 % (95 % CI 0.75–1.34) after three years for denosumab users and was not different 0.03 % (−0.34–0.39) than for alendronate users. In supplemental analyses, there was no increased risk of non-reproductive cancers associated with the use of denosumab (risk difference of 0.54 % (−0.41–1.19). Analysis comparing denosumab users with the general population gave similar results. ConclusionThere was no difference in the risk of cancer following treatment with denosumab compared to treatment with alendronate assessed after a short follow-up of 3 years.

Sexual dimorphism in medullary thyroid cancer aggressiveness.

Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1-40 mm (node metastasis and biochemical cure) and 10.1-40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27-41% (overall 24.0%) point difference, followed by biochemical cure with a -15-35% (overall -20.3%) point difference and extrathyroid extension with a 17-24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

Multivitamin use and all-cause and cause-specific mortality in cancer survivors.

Despite no sufficient evidence on benefits and harms of multivitamin use, cancer survivors use multivitamins as a self-care strategy to improve or maintain health. We examined if multivitamin use was associated with mortality in cancer survivors. 15,936 male and 7026 female cancer survivors in the NIH-AARP Diet and Health Study were included in the analysis. Types and frequency of multivitamin use at on average 4.6 years after cancer diagnosis were assessed. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression models. Multivitamin use was not associated with lower all-cause mortality risk in all female (RR = 0.94, 95% CI:0.87-1.01 daily vs. no use) or male cancer survivors (RR = 0.96, 95% CI:0.91-1.00); however, a modest inverse association for CVD mortality was observed in female survivors of reproductive cancers (RR = 0.75, 95% CI:0.61-0.92) and male survivors of non-reproductive cancers (RR = 0.81, 95% CI:0.70-0.94). Multivitamin use was also associated with a lower risk of cancer-specific mortality in survivors of skin (RR = 0.65, 95% CI:0.48-0.88) and breast (RR = 0.79, 95% CI:0.65-0.95) cancer. Multivitamin use may provide a modest survival benefit to some cancer survivors. Cancer care providers should talk with cancer survivors about potential benefits and harms of multivitamin use.

AXL receptor tyrosine kinase modulates gonadotropin-releasing hormone receptor signaling

BackgroundGonadotropin-releasing hormone (GnRH) receptors are essential for reproduction and are expressed in numerous urogenital, reproductive, and non-reproductive cancers. In addition to canonical G protein-coupled receptor signaling, GnRH receptors functionally interact with several receptor tyrosine kinases. AXL is a receptor tyrosine kinase expressed in numerous tissues as well as multiple tumors. Here we tested the hypothesis that AXL, along with its endogenous ligand Gas6, impacts GnRH receptor signaling.MethodsWe used clonal murine pituitary αT3-1 and LβT2 gonadotrope cell lines to examine the effect of AXL activation on GnRH receptor-dependent signaling outcomes. ELISA and immunofluorescence were used to observe AXL and GnRH receptor expression in αT3-1 and LβT2 cells, as well as in murine and human pituitary sections. We also used ELISA to measure changes in ERK phosphorylation, pro-MMP9 production, and release of LHβ. Digital droplet PCR was used to measure the abundance of Egr-1 transcripts. A transwell migration assay was used to measure αT3-1 and LβT2 migration responses to GnRH and AXL.ResultsWe observed AXL, along with the GnRH receptor, expression in αT3-1 and LβT2 gonadotrope cell lines, as well as in murine and human pituitary sections. Consistent with a potentiating role of AXL, Gas6 enhanced GnRH-dependent ERK phosphorylation in αT3-1 and LβT2 cells. Further, and consistent with enhanced post-transcriptional GnRH receptor responses, we found that Gas6 increased the abundance of Egr-1 transcripts. Suggesting functional significance, in LβT2 cells, Gas6/AXL signaling stimulated LHβ production and enhanced GnRH receptor-dependent generation of pro-MMP9 protein and promoted cell migration.ConclusionsAltogether, these data describe a novel role for AXL as a modulator of GnRH receptor signaling.5LYCavpivq5eiBQqEyV1BjVideo

Loss of Y chromosome in leukocytes can be regarded as a male-specific age predictor for age group estimation in forensic genetics.

Age prediction is an important field in forensic and aging research. Traditional methods used DNA methylation, telomere shortening, and mitochondrial DNA mutations to conduct age prediction models. Sex chromosomes, like the Y chromosome, have a significant role in aging as previously reported in hematopoietic disease and many non-reproductive cancers. Until now, there is no age predictor based on the percentage of loss of Y chromosome (LOY). LOY has been previously revealed to be correlated with Alzheimer's disease, short survival, and higher risk of cancer. The possible correlation of LOY between normal aging was not fully explored. In this study, we conducted age prediction by measuring LOY percentage by droplet digital PCR (ddPCR), based on 232 healthy male samples, including 171 blood samples, 49 saliva samples, 12 semen samples. The age group of samples ranges from 0 to 99years, with two individuals in almost every single age. Pearson correlation method was performed to calculate the correlation index. The result indicated a correlation index of 0.21 (p = 0.0059) between age and LOY percentage in blood samples, with the regression formula being y = -0.016823 + 0.001098x. The correlation between LOY percentage and age is obvious only when the individuals were divided into different age groups (R = 0.73, p = 0.016). In the studied saliva and semen samples, p-values of the correlation are 0.11 and 0.20, respectively, showing no significant association between age and LOY percentage in these two biological materials. For the first time, we investigated male-specific age predictor based on LOY. The study showed that LOY in leukocytes can be regarded as a male-specific age predictor for age group estimation in forensic genetics. This study might be indicative for forensic applications and aging research.

Sex differences in cancer incidence rates by race and ethnicity: Results from the surveillance, epidemiology, and end results (SEER) Registry (2000-2019).

10547 Background: Sex differences in cancer incidence are pronounced, with men having 2-3 times the rate of most non-reproductive cancers than women. However, whether the male predominance is due to differences in biological factors or behavior remains not well understood. This study investigated sex differences in cancer incidence by race and ethnicity to provide a greater understanding of whether differences are driven by biological factors or environmental exposures. Methods: Cancer incidence data from the Surveillance, Epidemiology and End Result (SEER) program (2000-2019) was used to calculate male-to-female incidence rate ratios (MF IRR) for each cancer site and histological subtype, stratified by race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian/Pacific Islander, American Indian/Alaskan Native, and Hispanic), and age-standardized to the 2000 U.S. population for individuals ages ≥20 years. Results: Most non-reproductive cancers had a male predominance across race and ethnicity, with the largest MF IRR seen for cancers of the tonsil, hypopharynx, larynx, and Kaposi sarcoma (MF IRR &gt; 4). Three cancers, gallbladder; peritoneum, omentum, mesenter; and thyroid, were more common among females than males across all race and ethnicity. Females had a higher incidence of anal cancer than males for all racial and ethnic groups except for non-Hispanic Black individuals where the MF IRR was &gt;1. Cancers of the stomach, skin (excluding basal and squamous cell), melanoma skin, and other non-epithelial, and myeloma had greater MF IRR among non-Hispanic White adults than all other racial and ethnic groups. Non-Hispanic Black individuals had higher MF IRR of cancers of the liver and lung and bronchus, compared to other racial and ethnic group. Non-Hispanic White males had the highest MF IRRs for esophagus adenocarcinoma and gastric cardia adenocarcinoma and the lowest MF IRR for esophagus SCC compared to other races and ethnicity. Conclusions: The MF IRR for most cancers in this study did not differ by race and ethnicity, suggesting the influence of biological factors. Differences in the MF IRR across race and ethnicity may indicate carcinogenic exposure differences leading to the development of non-sex-specific cancers. Further research is needed to identify biological drivers of cancer incidence for most non-reproductive cancers. Funding: Intramural Research Program of the Division of Cancer Epidemiology and Genetics in the National Cancer Institute, National Institutes of Health.

Abstract NG01: Dendritic cell intrinsic androgen receptor signaling reduces dendritic cell function and anti-tumor immunity

Abstract NG01: Dendritic cell intrinsic androgen receptor signaling reduces dendritic cell function and anti-tumor immunity

An overview of the risk, underlying factors, and mechanism of cancer progression in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder among women of reproductive age. PCOS is characterized by ovulatory dysfunction, clinical or biochemical features of hyperandrogenism, and polycystic ovaries. The risk of cancer among PCOS patients has been a topic of discussion for decades due to the overlapping metabolic and endocrine abnormalities. This review article focuses on the association of PCOS with various types of reproductive (such as endometrial cancer, ovarian cancer, and breast cancer) and non-reproductive cancers, considering different aspects, such as the risk of cancer progression in PCOS patients, the underlying factors, and the mechanism through which PCOS might progress to cancer. The information provided in this article would help create awareness among PCOS patients about the need to take risk-reducing measures. This article might also aid in the effort of identifying novel therapeutic targets to counteract the progression of cancer in PCOS.

Survival differences between women and men in the non-reproductive cancers: Results from a matched analysis of the surveillance, epidemiology, and end-results program.

Men with non-reproductive cancers have a discrepant outcome compared to women. However, they differ significantly in the incidence of cancer type and characteristics. Patients with single primary cancer who were 18 years or older and whose data were gathered and made accessible by the Surveillance, Epidemiology, and End Results (SEER) program were included in this retrospective analysis. Kaplan-Meier curves and Cox regression before and after propensity score matching were performed to analyze the risk survival by sex. Among the 1,274,118 patients included [median (range) age, 65 year (18-85+) years; 688,481 (54.9%) male]. The median follow-up was 21 months (0-191). Substantial improvements in survival were observed for both sexes during the years of inclusion analyzed, with no difference between them, reaching a reduction of almost 17% of deaths in 2010, and of almost 28% in 2015, compared to 2004. The women had a median survival of 74 months and overall mortality of 48.7%. Males had a median survival of 30 months (29.67-30.33) with an overall mortality of 56.2%. The PSM showed a reduced difference (6 months shorter median survival and 2.3% more death in men), but no change in hazards was observed compared to the unmatched analysis [adjusted HR: 0.888 (0.864-0.912) vs. 0.876 (0.866-0.886) in unmatched]. The discrepancy in survival between men and women is not explained only by the incidence of more aggressive and more advanced cancers in the former.

DISP-10. A SYSTEMATIC REVIEW OF SEX DIFFERENCES OF INCIDENCE AND OVERALL SURVIVAL IN 15 NON-REPRODUCTIVE CANCERS

Abstract Sex is an important factor that influences disease development, progression, and treatment. In multiple non-reproductive cancers, sex differences in incidence, progression, treatment response, survival, and other clinical outcomes are observed. Overall, males have a 20% higher chance of developing cancer over their lifetime, and experience worse clinical outcomes when compared with females. The NIH recognizes the importance of sex as a biologic variable and addressing sex as a biological variable is now required for all researchers submitting NIH grants. While more researchers are investigating the role of sex differences in cancer, a systematic review that examines the patterns of sex differences in incidence and survival across 15 non-reproductive cancers has not yet been published. We performed a systematic review by searching five databases using keywords and controlled vocabulary terms for each concept of interest and limited to English language. Records were included if it reported sex differences in human adults (18+), addressed incidence, mortality, or survival, at least one of the 15 cancers of interest, and were a cohort, cross-sectional, RCT, or case control study. Covidence was used for screening and two reviewers independently screened each record at title/abstract and then full text. Two reviewers independently completed data extraction using Microsoft Excel and the Cochrane RoB 2.0, and JBI tools were used for risk of bias assessment. The searches and pilot of the methods are underway. Understanding the role sex-differences play on incidence and survival are important for adding to our understanding of advances in diagnosis and treatment of individuals with cancer.

LGBTQI cancer patients' quality of life and distress: A comparison by gender, sexuality, age, cancer type and geographical remoteness.

BackgroundThere is growing acknowledgement of the psycho-social vulnerability of lesbian, gay, bisexual, transgender, queer and/or intersex (LGBTQI) people with cancer. The majority of research to date has focused on cisgender adults with breast or prostate cancer.Study AimThis study examined psycho-social factors associated with distress and quality of life for LGBTQI cancer patients and survivors, across a range of sexualities and gender identities, intersex status, tumor types, ages and urban/rural/remote location using an intersectional theoretical framework.Method430 LGBTQI people with cancer completed an online survey, measuring distress, quality of life (QOL), and a range of psycho-social variables. Participants included 216 (50.2%) cisgender women, 145 (33.7%) cisgender men, and 63 (14.7%) transgender and gender diverse (TGD) people. Thirty-one (7.2%) participants reported intersex variation and 90 (20%) were adolescents or young adults (AYA), aged 15-39. The majority lived in urban areas (54.4%) and identified as lesbian, gay or bisexual (73.7%), with 10.9% identifying as bisexual, and 10.5% as queer, including reproductive (32.4%) and non-reproductive (67.6%) cancers.ResultsForty-one percent of participants reported high or very high distress levels, 3-6 times higher than previous non-LGBTQI cancer studies. Higher rates of distress and lower QOL were identified in TGD compared to cisgender people, AYAs compared to older people, those who identify as bisexual or queer, compared to those who identify as lesbian, gay or homosexual, and those who live in rural or regional areas, compared to urban areas. Elevated distress and lower QOL was associated with greater minority stress (discrimination in life and in cancer care, discomfort being LGBTQI, lower outness) and lower social support, in these subgroups. There were no differences between reproductive and non-reproductive cancers. For the whole sample, distress and poor QOL were associated with physical and sexual concerns, the impact of cancer on gender and LGBTQI identities, minority stress, and lack of social support.ConclusionLGBTQI people with cancer are at high risk of distress and impaired QOL. Research and oncology healthcare practice needs to recognize the diversity of LGBTQI communities, and the ways in which minority stress and lack of social support may affect wellbeing.

Prevalence and risk factors for sexual dysfunction in young women following a cancer diagnosis – a population-based study

Background Self-reported sex problems among women diagnosed with reproductive and nonreproductive cancers before the age of 40 are not fully understood. This study aimed to determine sexual dysfunction in young women following a cancer diagnosis in relation to women of the general population. Furthermore, to identify factors associated with sexual dysfunction in women diagnosed with cancer. Materials and Methods A population-based cross-sectional study with 694 young women was conducted 1.5 years after being diagnosed with cancer (response rate 72%). Potential participants were identified in national quality registries covering breast and gynecological cancer, lymphoma and brain tumors. The women with cancer were compared to a group of women drawn from the general population (N = 493). Sexual activity and function were assessed with the PROMIS® SexFS. Logistic regression was used to assess differences between women with cancer and the comparison group, and to identify factors associated with sexual dysfunction. Results The majority of the women with cancer (83%) as well as the women from the comparison group (87%) reported having had sex the last month (partner sex and/or masturbation). More than 60% of the women with cancer (all diagnoses) reported sexual dysfunction in at least one of the measured domains. The women with cancer reported statistically significantly more problems than women of the comparison group across domains such as decreased interest in having sex, and vaginal and vulvar discomfort. Women with gynecological or breast cancer and those receiving more intense treatment were at particular high risk of sexual dysfunction (≥2 domains). Concurrent emotional distress and body image disturbance were associated with more dysfunction. Conclusion The results underscore the need to routinely assess sexual health in clinical care and follow-up. Based on the results, development of interventions to support women to cope with cancer-related sexual dysfunction is recommended.

Rapid Actions of the Nuclear Progesterone Receptor through cSrc in Cancer

The nuclear progesterone receptor (PR) is mainly known for its role as a ligand-regulated transcription factor. However, in the last ten years, this receptor’s extranuclear or rapid actions have gained importance in the context of physiological and pathophysiological conditions such as cancer. The PR’s polyproline (PXPP) motif allows protein–protein interaction through SH3 domains of several cytoplasmatic proteins, including the Src family kinases (SFKs). Among members of this family, cSrc is the most well-characterized protein in the scenario of rapid actions of the PR in cancer. Studies in breast cancer have provided the most detailed information on the signaling and effects triggered by the cSrc–PR interaction. Nevertheless, the study of this phenomenon and its consequences has been underestimated in other types of malignancies, especially those not associated with the reproductive system, such as glioblastomas (GBs). This review will provide a detailed analysis of the impact of the PR–cSrc interplay in the progression of some non-reproductive cancers, particularly, in GBs.

Unexplored Functions of Sex Hormones in Glioblastoma Cancer Stem Cells.

Biological sex impacts a wide array of molecular and cellular functions that impact organismal development and can influence disease trajectory in a variety of pathophysiological states. In nonreproductive cancers, epidemiological sex differences have been observed in a series of tumors, and recent work has identified previously unappreciated sex differences in molecular genetics and immune response. However, the extent of these sex differences in terms of drivers of tumor growth and therapeutic response is less clear. In glioblastoma (GBM), the most common primary malignant brain tumor, there is a male bias in incidence and outcome, and key genetic and epigenetic differences, as well as differences in immune response driven by immune-suppressive myeloid populations, have recently been revealed. GBM is a prototypic tumor in which cellular heterogeneity is driven by populations of therapeutically resistant cancer stem cells (CSCs) that underlie tumor growth and recurrence. There is emerging evidence that GBM CSCs may show a sex difference, with male tumor cells showing enhanced self-renewal, but how sex differences impact CSC function is not clear. In this mini-review, we focus on how sex hormones may impact CSCs in GBM and implications for other cancers with a pronounced CSC population. We also explore opportunities to leverage new models to better understand the contribution of sex hormones vs sex chromosomes to CSC function. With the rising interest in sex differences in cancer, there is an immediate need to understand the extent to which sex differences impact tumor growth, including effects on CSC function.

Sex Differences in Differentiated Thyroid Cancer.

Background: Sex dimorphism strongly impacts tumor biology, with most cancers having a male predominance. Uniquely, thyroid cancer (TC) is the only nonreproductive cancer with striking female predominance with three- to four-fold higher incidence among females, although males generally have more aggressive disease. The molecular basis for this observation is not known, and current approaches in treatment and surveillance are not sex specific. Summary: Although TC has overall good prognosis, 6-20% of patients develop regional or distant metastasis, one third of whom are not responsive to conventional treatment approaches and suffer a 10-year survival rate of only 10%. More efficacious treatment strategies are needed for these aggressive TCs, as tyrosine kinase inhibitors and immunotherapy have major toxicities without demonstrable overall survival benefit. Emerging evidence indicates a role of sex hormones, genetics, and the immune system in modulation of both risk for TC and its progression in a sex-specific manner. Conclusion: Greater understanding of the molecular mechanisms underlying sex differences in TC pathogenesis could provide insights into the development of sex-specific, targeted, and effective strategies for prevention, diagnosis, and management. This review summarizes emerging evidence for the importance of sex in the pathogenesis, progression, and response to treatment in differentiated TC with emphasis on the role of sex hormones, genetics, and the immune system.

Profound synchrony of age-specific incidence rates and tumor suppression for different cancer types as revealed by the multistage-senescence model of carcinogenesis.

The age-specific trend of cancer incidence rates, but not its magnitude, is well described employing the multistage theory of carcinogenesis by Armitage and Doll in combination with the senescence model of Pompei and Wilson. We derived empirical parameters of the multistage-senescence model from U.S. Surveillance, Epidemiology, and End Results (SEER) incidence data from 2000–2003 and 2010–2013 for The Cancer Genome Atlas (TCGA) cancer types. Under the assumption of a constant tumor-specific transition rate between stages, there is an extremely strong linear relationship (P < 0.0001) between the number of stages and the stage transition rate. The senescence tumor suppression factor for 20 non-reproductive cancers is remarkably consistent (0.0099±0.0005); however, five female reproductive cancers have significantly higher tumor suppression. The peak incidence rate for non-reproductive cancers occurs at a younger age for cancers with fewer stages and their carcinogenic stages are of longer duration. Driver gene mutations are shown to contribute on average only about a third of the carcinogenic stages of different tumor types. A tumor’s accumulated incidence, calculated using a two-variable (age, stage) model, is strongly associated with intrinsic cancer risk. During both early adulthood and senescence, the pace of tumor suppression appears to be synchronized across most cancer types, suggesting the presence of overlapping evolutionary processes.

Sex and Gender Differences in Kidney Cancer: Clinical and Experimental Evidence.

Simple SummaryKidney cancer is a frequent malignant tumor that accounts for approximately 5% of all cancer incidences. It affects both males and females, but males are twice as likely to develop kidney cancer than females. Evidence shows that this discrepancy takes root in individual differences, such as genetics or pathologies that affect the patient. It is then reflected in the clinical characteristics of the tumors, as males have larger and more aggressive tumors. Understanding the sex- and gender-based differences in kidney cancer is essential to be able to offer patients individualized medicine that would better cover their needs in terms of prevention, diagnosis and treatment.Sex and gender disparities have been reported for different types of non-reproductive cancers. Males are two times more likely to develop kidney cancer than females and have a higher death rate. These differences can be explained by looking at genetics and genomics, as well as other risk factors such as hypertension and obesity, lifestyle, and female sex hormones. Examination of the hormonal signaling pathways bring further insights into sex-related differences. Sex and gender-based disparities can be observed at the diagnostic, histological and treatment levels, leading to significant outcome difference. This review summarizes the current knowledge about sex and gender-related differences in the clinical presentation of patients with kidney cancer and the possible biological mechanisms that could explain these observations. Underlying sex-based differences may contribute to the development of sex-specific prognostic and diagnostic tools and the improvement of personalized therapies.

Sex disparities matter in cancer development and therapy.

Curing cancer through precision medicine is the paramount aim of the new wave of molecular and genomic therapies. Currently, whether patients with non-reproductive cancers are male or female according to their sex chromosomes is not adequately considered in patient standard of care. This is a matter of consequence because there is growing evidence that these cancer types generally initiate earlier and are associated with higher overall incidence and rates of death in males compared with females. Gender, in contrast to sex, refers to a chosen sexual identity. Hazardous lifestyle choices (notably tobacco smoking) differ in prevalence between genders, aligned with disproportionate cancer risk. These add to underlying genetic predisposition and influences of sex steroid hormones. Together, these factors affect metabolism, immunity and inflammation, and ultimately the fidelity of the genetic code. To accurately understand how human defences against cancer erode, it is crucial to establish the influence of sex. Our Perspective highlights evidence from basic and translational research indicating that including genetic sex considerations in treatments for patients with cancer will improve outcomes. It is now time to adopt the challenge of overhauling cancer medicine based on optimized treatment strategies for females and males.