{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T13:11:40Z","timestamp":1778850700491,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,13]]},"group-title":"Genetic and Genomic Medicine","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Cancer frequently clusters in families due to shared environment and genetics. However, many familial cancer cases lack a clinically recognized pathogenic germline variant (PGV). We analyzed germline genomes and family history from 2,726 individuals without a PGV in the All of Us Research Program, including 1,496 cases across 18 cancer types with extensive family history and 1,230 family history-negative, cancer-free controls. We identified allelic series of rare structural variants inactivating\n                  <jats:italic>MSH2<\/jats:italic>\n                  in individuals with phenotypes consistent with Lynch syndrome and\n                  <jats:italic>BRCA1<\/jats:italic>\n                  in breast cancer. Cancer polygenic risk scores were enriched in cases and correlated with patterns of cancer diagnoses within families. Exome-wide rare variant analyses nominated six candidate predisposition genes, including\n                  <jats:italic>TSTD2<\/jats:italic>\n                  and\n                  <jats:italic>BRAT1<\/jats:italic>\n                  in thyroid and breast cancer, respectively. Overall, polygenic risk and rare variants impacting known genes explained a median of 5% of unexplained familial cancers, increasing to 11% when including newly nominated risk factors.\n                <\/jats:p>","DOI":"10.64898\/2026.05.08.26352653","type":"posted-content","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T15:55:12Z","timestamp":1778687712000},"source":"Crossref","is-referenced-by-count":0,"title":["Diverse mediators of cancer predisposition uncovered by germline whole genome sequencing of unexplained familial cancers"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7650-9117","authenticated-orcid":false,"given":"Noah","family":"Fields","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, 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