Identification of germline hereditary cancer syndrome variants and associated cancers in a healthcare biobank population.

Abstract

10581 Background: Identification of pathogenic/likely pathogenic variants (P/LPV) in hereditary cancer syndrome (HCS) genes enables surveillance and prevention. Population genomic screening can complement traditional ascertainment of at-risk individuals based on personal or family history. But lack of data on cancer risks in unselected individuals with a HCS P/LPV challenges clinical decision making in these cohorts. We summarize a biobank’s population screening for HCS variants and a case-control assessment of reported relevant cancers. Methods: MyCode is a health system biobank with >357,000 patients consented to research leveraging exome and electronic health record (EHR) data and to the receipt of medically relevant P/LPV. Available exomes were evaluated for P/LPV in 27 HCS genes based on predicted molecular consequence and ClinVar status. Clinically confirmed P/LPV were disclosed to eligible patients (cases). Patients’ prior knowledge of their result was determined using EHR data and patient report. Relevant cancer diagnoses were extracted from the EHR using validated methods in cases and variant-negative controls (n=169,099) with available EHR data. Associations between P/LPV and relevant cancers were assessed using a Firth logistic regression in 9 genes with >30 cases. Ages of diagnoses were compared using Wilcoxon rank sum test. Results: 183,822 patients’ exomes have been evaluated; 2,035 P/LPV in 27 HCS have been disclosed to 2,027 patients. 80% (n=1,625) of patients were previously unaware of their result. Increased odds and earlier ages of diagnosis for a subset of relevant cancers were observed in patients with P/LPV (Table). Conclusions: HCS P/LPV were disclosed to 1.1% of biobank patients, most of whom were unaware of their result. P/LPV were associated with a higher odds and earlier age of diagnosis of some relevant cancers compared to controls, indicating that genomic screening facilitates ascertainment of at-risk individuals. To guide clinical recommendations, research on cumulative cancer risks in broader populations will be needed. Associations (OR and 95% CI) between P/LPV and relevant cancers. Gene Breast Ovarian Pancreatic Prostate Colorectal Endometrial Thyroid (Medullary) Renal APC n=61 15.8 (6.5-33.5) *,a BRCA1 n=308 13.4 (9.6-18.5) *,a 28.6 (18.5-42.8) *,a 2.4 (0.5-6.7) 1.5 (0.8-2.6) BRCA2 n=599 6.0 (4.6-7.7) *,a 7.6 (4.6-11.9) * 2.1 (0.7-4.7) 2.4 (1.6-3.5) * PALB2 n=133 2.5 (1.2-4.7) * 2.5 (0.3-9.2) 6.0 (1.2-17.3) * 2.7 (1.0-6.4) * MLH1 n=48 2.2 (0.02-15.5) 3.4 (0.02-24.2) 0.5 (0.03-4.1) 59.6 (31.0-111.8) *,a 26.5 (11.6-56.3) *,a MSH6 n=212 0.6 (0.01-4.3) 2.1 (0.2-7.6) 1.7 (0.8-3.2) 5.2 (2.8-8.8) *,a 14.0 (8.3-22.5) *,a PMS2 n=194 1.9 (0.2-7.0) 0.7 (0.01-5.1) 1.0 (0.4-2.3) a 4.7 (2.4-8.2) * 4.3 (1.8-8.5) * RET n=105 2690.6 (1593.8-4580.1) * SDHB n=45 11.4 (3.1-30.5) * *denotes significant OR α = 0.05, a age of diagnosis significantly lower in cases.