Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development

SIMPLE SUMMARY: Women with a family history of cancer are at increased risk of cancer, including endometrial cancer (affecting the womb lining). In some of the women with such family history, the risk can be explained by deleterious changes in mismatch repair genes that cause Lynch syndrome. This study explored the role of other genes in risk of endometrial cancer, using several approaches. The number and type of changes in gene sequence information in women with endometrial cancer was compared to that from individuals in the general population. Gene sequence changes in endometrial cancer patients with a family history of cancer were also analyzed. Lastly, endometrial cancers from individuals with gene changes were examined for distinctive genomic patterns expected to be seen if a gene change was driving the cancer. This study has identified several additional genes for further exploration in relation to endometrial cancer risk and therapy. ABSTRACT: Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas (n = 539; 308 European ancestry), and germline data from 33 suspected familial European ancestry EC patients demonstrating immunohistochemistry-detected tumor MMR proficiency. Germline variants in MMR and 26 other known/candidate EC risk genes were annotated for pathogenicity in the two EC datasets, and also for European ancestry individuals from gnomAD as a population reference set (n = 59,095). Ancestry-matched case–control comparisons of germline variant frequency and/or sequence data from suspected familial EC cases highlighted ATM, PALB2, RAD51C, MUTYH and NBN as candidates for large-scale risk association studies. Tumor mutational signature analysis identified a microsatellite-high signature for all cases with a germline pathogenic MMR gene variant. Signature analysis also indicated that germline loss-of-function variants in homologous recombination (BRCA1, PALB2, RAD51C) or base excision (NTHL1, MUTYH) repair genes can contribute to EC development in some individuals with germline variants in these genes. These findings have implications for expanded therapeutic options for EC cases.