Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young-and older-onset breast tumours.Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages "deconstructSigs" and "SomaticSignatures" to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset.Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while youngonset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for youngonset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. Signatures resembling COSMIC signatures 2 and 13 were observed among both age groups. We identified a class of tumours with a unique combination of signatures that may be associated with young age of onset. Conclusions:The results of this exploratory study provide some evidence that the mutational landscape and mutational signatures among young-onset breast cancer are different from those of older-onset patients. The characterization of young-onset tumours could provide clues to their etiology which may inform future prevention. Further studies are required to confirm our findings.

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Purpose: Breast cancer incidence among younger women (under age 50) has increased over the past 25 years, yet little is known about the etiology among this age group. The objective of this study was to investigate relationships between modi able and non-modi able risk factors and early-onset breast cancer among three prospective Canadian cohorts.Methods: A matched case-control study was conducted using data from Alberta's Tomorrow Project, BC Generations Project, and the Ontario Health Study. Participants diagnosed with breast cancer before age 50 were identi ed through provincial registries and matched to three control participants of similar age and follow-up. Conditional logistic regression was used to examine the association between factors and risk of early-onset breast cancer.Results: In total, 609 cases and 1,827 controls were included. A body mass index ≥30kg/m 2 was associated with a lower risk of early-onset breast cancer (OR=0.65; 95% CI: 0.47-0.90), while a waist circumference ≥88 cm was associated with an increased risk (OR=1.40; 95% CI: 1.06-1.84). A reduced risk was found for women with ≥2 pregnancies (OR=0.80; 95% CI: 0.64-1.00) and a rst-degree family history of breast cancer was associated with an increased risk (OR=2.06; 95% CI: 1.54-2.75).Conclusions: In this study, measures of adiposity, pregnancy history, and familial history of breast cancer are important risk factors for early-onset breast cancer. Evidence was insu cient to conclude if smoking, alcohol intake, fruit and vegetable consumption, and physical activity are meaningful risk factors. The results of this study could inform targeted primary and secondary prevention for early-onset breast cancer.

Background Incidence of testicular cancer is highest among young adults and has been increasing dramatically for men born since 1945. This study aimed to elucidate the factors driving this trend by investigating differences in mutational signatures by age of onset. Methods We retrieved somatic variant and clinical data pertaining to 135 testicular tumors from The Cancer Genome Atlas. We compared mutational load, prevalence of specific mutated genes, mutation types, and mutational signatures between age of onset groups (< 30 years, 30–39 years, ≥ 40 years) after adjusting for subtype. A recursively partitioned mixture model was utilized to characterize combinations of signatures among the young-onset cases. Results Mutational load was significantly higher among older-onset tumors (p < 0.05). There were no highly prevalent driver mutations among young-onset tumors. Mutated genes and types of nucleotide mutations were not significantly different by age group (p > 0.05). Signatures 1, 8 and 29 were more common among young-onset tumors, while signatures 11 and 16 had higher prevalence among older-onset tumors (p < 0.05). Among young-onset tumors, clustering of signatures resulted in four distinct tumor classes. Conclusions Signature contributions differ by age with signatures 1, 8 and 29 were more common among younger-onset tumors. While these signatures are connected with endogenous deamination of 5-methylcytosine, late replication errors and chewing tobacco, respectively, additional research is needed to further elucidate the etiology of young-onset testicular cancer. Large studies of mutational signatures among young-onset patients are required to understand epidemiologic trends as well as inform targeted prevention and treatment strategies.

Purpose: Breast cancer incidence among younger women (under age 50) has increased over the past 25 years, yet little is known about the etiology among this age group. The objective of this study was to investigate relationships between modifiable and non-modifiable risk factors and early-onset breast cancer among three prospective Canadian cohorts.Methods: A matched case-control study was conducted using data from Alberta’s Tomorrow Project, BC Generations Project, and the Ontario Health Study. Participants diagnosed with breast cancer before age 50 were identified through provincial registries and matched to three control participants of similar age and follow-up. Conditional logistic regression was used to examine the association between factors and risk of early-onset breast cancer. Results: In total, 609 cases and 1,827 controls were included. A body mass index ≥30kg/m2 was associated with a lower risk of early-onset breast cancer (OR=0.65; 95% CI: 0.47-0.90), while a waist circumference ≥88 cm was associated with an increased risk (OR=1.40; 95% CI: 1.06-1.84). A reduced risk was found for women with ≥2 pregnancies (OR=0.80; 95% CI: 0.64-1.00) and a first-degree family history of breast cancer was associated with an increased risk (OR=2.06; 95% CI: 1.54-2.75).Conclusions: In this study, measures of adiposity, pregnancy history, and familial history of breast cancer are important risk factors for early-onset breast cancer. Evidence was insufficient to conclude if smoking, alcohol intake, fruit and vegetable consumption, and physical activity are meaningful risk factors. The results of this study could inform targeted primary and secondary prevention for early-onset breast cancer.