LAUSR

Clonal hematopoiesis (CH) is an age-related phenomenon where hematopoietic stem cells and their progeny acquire specific somatic mutations in a small, well-defined set of leukemogenic genes conferring them with fitness advantage leading to clonal proliferation. Mosaic chromosomal alterations (mCAs) are somatic structural variants that are manifestations of genomic instability and a sign of CH when they occur in blood. The recent availability of large-scale cohorts with blood exome sequence and genotype data has powered genome-wide association studies (GWAS) investigating the germline genetic contribution to CH and mCA risk. However, phenotypes of somatic mutation acquisition in driver genes, clonal selection and expansion, and chromosomal mosaicism are processes that are not confined to blood and contribute to neoplastic transformation across tissue types. GWAS of solid tumor susceptibility have so far identified hundreds of germline variants associated with cancer risk and it is likely that a subset of these variants contributes to solid tumor risk by affecting these somatic phenotypes in the corresponding tissues of origin and that some of the variants exert these somatic effects across tissues. We aimed to identify this subset of solid tumor risk variants by undertaking fixed effects inverse-variance weighted meta-analyses combining breast, prostate, ovarian, and endometrial cancer GWAS (total n = 237,483 cases/317,006 controls; no UK Biobank samples included) with UK Biobank-based CH (10,203 “cases”/173,918 controls) and mCA (66,011 “cases”/378,188 controls) risk GWAS in pairs where each pair involved one solid tumor type and one of either CH or mCA (for example, breast cancer and mCA constituted a pair). These analyses collectively identified 61 independent (r2<0.05) lead variants at combined cross-trait genome-wide significance (P<5 × 10−8) across 22 genomic loci where each lead variant was associated with each trait individually at P<10−3, had the same direction of allelic effect across traits, and little evidence of heterogeneity in effect (I2<40%). New loci (>1 Mb away from previously reported risk loci for a given trait) counts were: 14 new loci in the context of mCA risk, 6 new loci for CH risk, 2 for breast cancer risk, and one each for prostate, ovarian, and endometrial cancer risks. In silico functional annotation of these loci suggested lead variant-target genes that could be assigned to the discrete pathways of mitotic spindle assembly (INCENP, CENPN, ZWILCH, MAD1L1), p53 signaling (TP53, MDM4, SPI1), DNA damage repair (ATM, RAD51C, CHEK2, USP28, PARP8), and myeloid oncogenesis (WT1, HOXA9, L3MBTL3). Our novel approach combining the latest and largest blood somatic genomic trait GWAS with large-scale solid tumor risk GWAS thus yielded clear mechanistic insights into the shared inherited genetic basis of solid tumor risk and somatic genomic traits. Citation Format: Victoria Gray, George Richenberg, Pedro Quirós, Matthew Freedman, Paul Pharoah, Simon Gayther, Michelle Jones, George Vassiliou, Kate Lawrenson, Siddhartha Kar. Cross-trait genome-wide association meta-analyses of clonal hematopoiesis and solid tumor risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5227.