Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies

Abstract

Background Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. Methods To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. Results We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Conclusions Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

“…However, pathogenic variants in these 83 genes were not observed in our patients with primary breast and lung cancer [ 8 ]. In a third study, gene-based burden testing showed that there was an increase in carriers with BRCA1 and BRCA2 loss of function variants for breast cancer patients with an additional lung cancer [ 9 ]. A pathogenic BRCA2 variant was also found in one of our 55 patients.…”

“…Pathogenic variants were identified in moderate- and high-risk cancer predisposition genes in 15.2% of probands (67/440), but none of these patients had been diagnosed with primary breast and lung cancer [ 8 ]. More recently, a study has assessed genetic susceptibility to MPCs (n = 6429) across 36 organ sites, through WES of two multi-ancestry study populations [ 9 ]. A total of 22 variant-phenotype associations were identified, which included rare and common variants.…”

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases

“…We identified rare protein-truncating variants in the DDR genes BRCA2 (OR = 3.23 [2.65-3.90], P = 7.5×10 -29 ) and ATM (OR = 2.92 [2.34-3.63], P = 1.17×10 -19 ), and additionally rare damaging variants in SAMHD1 (OR = 2.02 [1.65-2.45], P = 2.36×10 -11 ) as significantly associated with increased prostate cancer risk (Figures 1 & 2, Table 2 and Supplementary Table 3). Germline variants in SAMHD1 have recently been reported as associated with the risk of prostate cancer in an analysis of the UK Biobank only 24 , and additionally, there is evidence of association with breast cancer 25 and primary cancers collectively 26,27 . Here, we independently validate the SAMHD1 association with prostate cancer in the UK Biobank and replicate the finding in additional cohorts (Supplementary Table 3).…”

Susceptibility Genes Associated with Multiple Primary Cancers

“…Men diagnosed with prostate cancer exhibit an elevated risk of developing thyroid and colorectal cancers, among others [170,171]. Notably, the replicable discovery of variant rs6998061 in the 8q24 locus, associated with increased risk for both prostate and colorectal cancers, underscores the region's significance [172]. Among the genes in the 8q24 region, MYC is of particular significance.…”

“…Similar to the BRCA gene, individuals with NCBP1 mutations have an increased likelihood of developing a second tumor in breast cancer survivors. However, BRCA1/2 carriers predominantly develop ovarian cancer, while NCBP1 carriers are more predisposed to cervical cancer [172]. Tumor stem cells are always at the center of MPC research due to their inherent tumorigenicity.…”