Abstract 3393: A pan-cancer analysis of cancer-predisposition germline pathogenic variants (gPVs) utilizing the cancer genome atlas (TCGA) reveals distinct survival trends associated with immune response pathways

Abstract A family history of cancer has previously been shown to positively impact survival outcomes in various cancers. Additionally, specific cancer-predisposition germline pathogenic variants (gPVs) have also been shown to have a beneficial effect on survival across multiple cancers including colorectal cancer, ovarian cancer and melanoma. However, the impact on survival of commonly accepted cancer-predisposition gPVs across cancers has not been widely studied. Here, we examine the effect of 85 common cancer-predisposition gPVs on survival outcomes across all cancer types in the Cancer Genome Atlas (TCGA). When examining survival trends, we observed that cancers with a greater proportion of gPVs generally had improved survival (p = 0.0088). When examining each cancer indication separately, those with significantly improved survival amongst gPV positive patients included bladder [HR = 0.35, p = 0.01] and ovarian cancer [HR = 0.55, p = 0.0003], whereas head and neck squamous cell carcinoma had significantly worse survival [HR = 1.43, p = 0.04]. Interestingly, bladder and ovarian cancer gPV positive patients had significant upregulations in immune-stimulatory transcriptomic pathways with the majority of gPVs in the homologous recombination deficient (HRD) variant category, whereas the opposite was observed in head and neck squamous cell carcinoma. Thus, by examining a large array of cancer-predisposition gPVs in all cancer subtypes included in TCGA, we not only demonstrate the prevalence of a wider variety of gPVs across cancer indications but that specific categories of gPVs can influence survival across cancers in a beneficial manner, potentially by creating a pro-inflammatory immune response. Citation Format: Alan Shen, Lin Li, Joshua Arbesman, Ying Ni, Pauline Funchain. A pan-cancer analysis of cancer-predisposition germline pathogenic variants (gPVs) utilizing the cancer genome atlas (TCGA) reveals distinct survival trends associated with immune response pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3393.