Rare Germline Variants in Immune and Drug Target Genes Among Cancer Exceptional Responders

Background Cancer treatment response is highly variable, even among patients with the same tumor type and treatment. Exceptional responders (ERs), who are individuals who experience unusually favorable outcomes, provide critical insights into the biological factors driving treatment success. While prior studies have highlighted the role of somatic changes, the contribution of germline rare variants remains underexplored. This study aimed to uncover the genetic underpinnings of exceptional responses by identifying rare, non-silent and predicted deleterious germline mutations enriched among ERs compared to typical cancer patients. Methods The Network of Enigmatic Exceptional Responders (NEER) project collected clinical and germline whole-genome sequencing (WGS) data from 53 ERs. After quality control procedures and ancestry background checks, 51 ERs were left for final analysis. While non-silent mutations were identified based on allele frequencies and mutation types, multiple pathogenicity predictors were applied for predicted deleterious variants. These were compared to a harmonized and comparable subset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort (n=414) using Fisher's exact tests. Kaplan-Meier survival analysis applied to evaluate prognostic associations in PCAWG patients. Additionally, Fisher's exact tests were conducted stratified by cancer type and treatment regimen to identify potential associations between rare germline variants and therapeutic responses. Results Variants in immune-related genes such as CCL26 and GPRC5D were prevalent, suggesting enhanced immune regulation among ERs. Fourteen genes with non-silent and eight with predicted deleterious mutations showed significantly different frequencies between NEER and PCAWG cohorts (FDR < 0.05). IRX3 emerged as a protective gene enriched in ERs, whereas OR6B2 was associated with poor survival in PCAWG lung cancer patients. Moreover, rare non-silent germline variants in drug target genes were enriched among ERs treated with cisplatin and doxorubicin, implicating altered DNA repair and drug-binding mechanisms in their remarkable outcomes. Conclusions This study reveals a distinctive germline mutation landscape in exceptional cancer responders, marked by immune-related and drug-target-associated variants that may enhance therapy response and prolong survival. The findings highlight potential novel prognostic biomarkers, such as IRX3 and OR6B2, providing a foundation for developing personalized cancer treatments informed by rare genetic variation.