2026 Sequencing Strategies for Population and Cancer Epidemiology Studies (SeqSPACE) : Submission #4

Submission information
Submission Number: 4
Submission ID: 180692
Submission UUID: 36a28f05-5c80-43ed-b7bb-7fd8c98e46e9
Submission URI: /egrp/seqspaceabstracts

Created: Fri, 05/22/2026 - 13:47
Completed: Fri, 05/22/2026 - 13:47
Changed: Fri, 05/22/2026 - 13:47

Remote IP address: 10.208.28.95
Submitted by: Anonymous
Language: English

Is draft: No
First Name Ryan
Middle Initial L
Last Name Collins
Degree(s) PhD
Position/Title/Career Status Instructor
Organization Dana-Farber Cancer Institute
Email ryan_collins@dfci.harvard.edu
Abstract Title Diverse mediators of cancer predisposition uncovered by germline whole genome sequencing of unexplained familial cancers
Abstract Summary 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 MSH2 in individuals with phenotypes consistent with Lynch syndrome and BRCA1 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 TSTD2 and BRAT1 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.