Meta-Analysis of Rare Cancers Leveraging Clinically Ascertained Cohorts Reveals Novel Germline Susceptibility Loci

Abstract

Genome-wide association studies (GWAS) have advanced the understanding of germline susceptibility in common cancers, yet rare malignancies remain underexplored due to limited sample sizes. To address this gap, we conducted large-scale GWAS across 20 rare cancer types and meta-analyzed results from three cohorts: two clinically sequenced cancer center cohorts and an independent population biobank, comprising over 480,000 individuals. We identified nine novel genome-wide significant susceptibility loci with moderate to large effect sizes that replicated across cohorts in eight rare malignancies, including myelodysplastic syndromes (MDS), germ cell tumors, gastrointestinal stromal tumor (GIST), gastrointestinal neuroendocrine tumors, anal cancer (ANSC), non-melanoma skin cancer, mesothelioma, and hepatobiliary cancer. Among the strongest associations were loci in MDS near API5 (OR = 2.21, p = 1.06x10-8), in GIST near SLC6A18 and TERT (OR = 1.91, p = 8.20x10-50), and in ANSC near HLA-DQA2 (OR = 1.58, p = 5.50x10-18). The GIST risk variant was enriched in tumors harboring somatic KIT mutations (OR = 2.21, p = 6.5x10-4) and was associated with worse survival among carriers with KIT-mutant tumors (hazard ratio = 4.06, p = 0.015), implicating germline-somatic interplay in tumor initiation and progression. The ANSC risk variant was associated with HPV infection (OR = 1.44, p = 3.19x10-5), supporting a host-viral interaction in HPV-driven tumorigenesis. The MDS risk variant at the API5 locus was associated with altered neutrophil counts, suggesting a role in hematopoietic dysregulation in disease pathogenesis. We further identified novel, independent associations with mesothelioma, GIST, and hepatobiliary cancer at the 5p15.33 locus encompassing TERT, consistent with pleiotropic genetic effects at a core telomere-maintenance gene. Collectively, these findings demonstrate that integrating clinically ascertained sequencing cohorts with population biobanks substantially enhances germline discovery in rare cancers, enabling identification of high-confidence susceptibility loci and facilitating downstream biological interpretation through linked somatic, viral, and clinical data. This framework provides a scalable approach for characterizing inherited susceptibility across diverse rare malignancies.