ImCORE Germline Genomics initiative - iGGi

This study examines how germline genetic variation influences clinical outcomes of immune checkpoint inhibitor (ICB) therapy. Although ICBs improve survival for many cancers, only some patients benefit, and nearly half develop unpredictable immune‑related adverse events (irAEs). Identifying biomarkers for for ICB efficacy and toxicity is essential.

We analyzed 992 cancer patients treated with ICBs at CHUV between 2013 and 2022, all with germline DNA and detailed clinical data. Using genome‑wide association studies, Human Leukocyte Antigen (HLA) typing and polygenic risk scores, the study assessed links between genetic variation and treatment efficacy or toxicity.

Overall, 46% of patients developed grade ≥2 irAEs—most commonly thyroiditis, colitis, and skin reactions. Clinical factors such as age, BMI, serum albumin, and treatment regimen were associated with both irAE risk and survival. No germline variants reached genome‑wide significance for treatment efficacy, but several HLA associations with irAEs were identified and replicated. Genome‑wide analyses of irAEs showed no significant associations after correction.

Our results contributed to the international Cancer Immunology Germline Genomics Initiative (CiGGi), supporting broader analyses of HLA and polygenic risk score associations with common irAEs and helping inform future personalized immunotherapy strategies.