Gene-Specific Cancer Patterns Among Pathogenic Germline Variant Carriers

ABSTRACT Key Points Question What are the gene-specific cancer patterns and risks among carriers of pathogenic or likely pathogenic variants in cancer susceptibility genes in a population-based cohort? Findings In this cohort study of 287,076 participants, carriers of pathogenic or likely pathogenic variants in cancer susceptibility genes had markedly higher cancer prevalence compared to noncarriers (e.g., 80% for MEN1 carriers vs 18.6%), with additional risk observed among monoallelic MUTYH co-carriers. Analyses also identified novel gene-cancer associations. Meaning These findings highlight substantial heterogeneity in inherited cancer risk and support more individualized strategies for genetic testing, cancer screening, and risk assessment. Importance We previously reported that >5% of the population carries pathogenic or likely pathogenic variants (P/LPVs) in key cancer susceptibility genes (CSGs). However, gene-specific cancer prevalence, spectrum, burden, lifetime risk, comorbidity, and the risk associated with autosomal recessive (AR) genes among carriers remain incompletely defined. Objective To investigate cancer prevalence, spectrum, burden, lifetime risk, comorbidity, and the uncover novel associations between cancer susceptibility genes and cancer occurrence in a gene-specific manner. Design A total of 72 cancer susceptibility genes was analyzed. Cancer diagnoses were identified using SNOMED codes and grouped into 35 categories. Setting This study utilized short-read whole genome sequencing data and electronic health record (EHR) data from the All of Us controlled-tier database v8. Participants A total of 287,076 participants with both genomic and EHR data were included in the analysis. Main Outcomes and Measures The primary outcome was an occurrence of a P/LPV in key CSGs. The other outcome is the incidence of cancer diagnosis. Associations between P/LPVs and overall and site-specific cancer risk were evaluated using regression models adjusted for age, sex, race, and ethnicity. Results Among genes with ≥10 unique carriers, cancer prevalence was highest for MEN1 (80%), followed by TP53 (57.7%), MLH1 (48.4%), and MSH2 (47.2%), compared to 18.6% among non-carriers. Carriers of P/LPVs in BRCA1, BRCA2, MLH1, APC, NF1, PTEN, and PALB2 had significantly earlier cancer diagnosis compared to non-carriers. Cancer prevalence was markedly higher in BRCA1 and BRCA2 carriers who are also mono-allelic MUTYH carriers (75% and 45.5%, respectively) compared with BRCA1 and BRCA2 alone (43.2% and 36.5%). Similar enrichment was observed for CHEK2 and PALB2 monoallelic MUTYH co-carriers. Adjusted survival analysis showed increased cancer risk for MLH1 (OR=6.08), PTEN (OR=5.80), and MSH2 (OR=5.19). Cancer specific analysis reveals significant novel associations including MITF with anal/perianal and prostate cancer; BLM with ovarian and soft tissue/sarcoma; WRN with gynecologic cancer (NOS); and FH with hematologic malignancy, alongside well-established gene-cancer relationships. Conclusions and Relevance This population-based analysis defines gene-specific cancer prevalence, spectrum, and risk, including contributions from AR variants. These findings support more precise genetic testing, screening, and risk stratification for individuals carrying inherited P/LPVs.