Aging is a complex biological process characterized by hallmark features accumulating over the life course, shaping the individual's aging trajectory and subsequent disease risks. There is substantial individual variability in the aging process between men and women. In general, women live longer than men, consistent with lower biological ages as assessed by molecular biomarkers, but there is a paradox. Women are frailer and have worse health at the end of life, while men still perform better in physical function examinations. Moreover, many age-related diseases show sex-specific patterns. In this review, we aim to summarize the current knowledge on sexual dimorphism in human studies, with support from animal research, on biological aging and illnesses. We also attempt to place it in the context of the theories of aging, as well as discuss the explanations for the sex differences, for example, the sex-chromosome linked mechanisms and hormonally driven differences.

Sex differences in biological aging with a focus on human studies.

The coming decade in precision oncology: six riddles

Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.

/pdf/divergent-mutational-processes-distinguish-hypoxic-and-4d2e7cwovt.pdf

Divergent mutational processes distinguish hypoxic and normoxic tumours.

Cancer incidence is higher in men than in women at most shared anatomic sites for currently unknown reasons. The authors quantified the extent to which behaviors (smoking and alcohol use), anthropometrics (body mass index and height), lifestyles (physical activity, diet, medications), and medical history collectively explain the male predominance of risk at 21 shared cancer sites.

Sex disparities in the incidence of 21 cancer types: Quantification of the contribution of risk factors

Although all cancers share common hallmarks, we have long realized that there is no silver-bullet treatment for the disease. Many clinical oncologists specialize in a single cancer type, based predominantly on the tissue of origin. With advances brought by genetics and cancer genomic research, we now know that cancers are profoundly different, both in origins and in genetic alterations. At the same time, commonalities such as key driver mutations, altered pathways, mutational, immune and microbial signatures and other areas (many revealed by pan-cancer studies) point to the intriguing possibility of targeting common traits across diverse cancer types with the same therapeutic strategies. Studies designed to delineate differences and similarities across cancer types are thus critical in discerning the basic dynamics of oncogenesis, as well as informing diagnoses, prognoses and therapies. We anticipate growing emphases on the development and application of therapies targeting underlying commonalities of different cancer types, while tailoring to the unique tissue environment and intrinsic molecular fingerprints of each cancer type and subtype. Here we summarize the facets of pan-cancer research and how they are pushing progress toward personalized medicine. Ding and colleagues discuss the era of pan-cancer analysis, covering the fundamental insights gained, unique opportunities and challenges, and the future of such approaches in the basic and clinical space.

Moving pan-cancer studies from basic research toward the clinic

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here, we describe the first pan-cancer analysis of sex differences in whole genomes of 1,983 tumours of 28 subtypes from the ICGC Pan-Cancer Analysis of Whole Genomes project. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in cancer research.

/pdf/sex-differences-in-mutational-processes-10vxqdcis6.pdf

Sex Differences in Mutational Processes

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here, we describe the first pan-cancer analysis of sex differences in whole genomes of 1,983 tumours of 28 subtypes from the ICGC Pan-Cancer Analysis of Whole Genomes project. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in cancer research. Sex disparities in cancer epidemiology include an increased overall cancer risk in males corresponding with higher incidence in most tumor types, even after adjusting for known risk factors1,2. Cancer mortality is also higher in males, due in part to better survival for female patients in many cancer types, including those of the colon and head & neck3. Interestingly, female colorectal cancer patients respond better to surgery4 and adjuvant chemotherapy, though this is partially due to biases in tumour location and microsatellite instability5. Similarly, premenopausal female nasopharyngeal cancer patients have improved survival regardless of tumour stage, radiation or chemotherapy regimen6. There is a growing body of evidence for sex differences in cancer genomics7-13, but their molecular origins and clinical implications remain largely elusive. Previous studies have mostly focused on protein coding regions, leaving the vast majority of the genome unexplored. We hypothesized that there are uncharacterized sex differences in the non-coding regions of the genome. Using whole genome sequencing data from the Pan-cancer Analysis of Whole Genomes (PCAWG) project14, we performed a survey of sex-biased mutations in 1,983 samples (1,213 male, 770 female) from 28 tumour subtypes, excluding those of the sex organs (Supplementary Table 1). We also excluded the X and Y chromosomes to focus on autosomal sex differences in cancers affecting both men and women, but there are known to be significant X-chromosome mutational differences between tumours arising in men and women15. Our analysis revealed sex differences in both genome-wide phenomena and in specific genes. These sex-biases occur not only at the pan-cancer level across all 1,983 samples, but also in individual tumour subtypes.

/pdf/sex-differences-in-oncogenic-mutational-processes-38872w3uan.pdf

Sex Differences in Oncogenic Mutational Processes

Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited understanding of its associations with specific mutational processes, non-coding driver genes and evolutionary features. To fill this gap, we quantified hypoxia in 1,188 tumours spanning 27 cancer types. We show that elevated hypoxia is associated with increased mutational load across cancers, irrespective of the underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology are directly associated with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in tumours with high hypoxia, and mutations in PTEN interact with hypoxia to direct the evolutionary trajectory of tumours. Overall, this work demonstrates that hypoxia plays a critical role in shaping the genomic landscape of cancer.

/pdf/divergent-mutational-processes-distinguish-hypoxic-and-2lbmwu1eo7.pdf

Divergent mutational processes distinguish hypoxic and normoxic tumours

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Sex Differences in Mutational Processes

Sex Differences in Oncogenic Mutational Processes

Divergent mutational processes distinguish hypoxic and normoxic tumours