Tyrosine Protein Kinase SYK-Related Gene Signature in Baseline Immune Cells Associated with Adjuvant Immunotherapy-Induced Immune-Related Adverse Events in Melanoma.

Purpose: Immune checkpoint inhibition (ICI) shows benefits in adjuvant (AT) and neoadjuvant melanoma treatments. However, ICI frequently induces severe immune-related adverse events (irAE). Unlike metastatic disease, in which irAEs are a clinical trade-off for treatment that improves survival, the toxicity burden from ICI in the AT setting is a substantial clinical problem urging for irAE-predictive biomarkers.

Germline immunomodulatory expression quantitative trait loci (ieQTLs) associated with immune-related toxicity from checkpoint inhibition.

Background: Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI).

Methods: We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes.

A genome-wide association study of germline variation and melanoma prognosis.

Background: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers.

Ultra Low-Coverage Whole-Genome Sequencing as an Alternative to Genotyping Arrays in Genome-Wide Association Studies.

An array-based genotyping approach has been the standard practice for genome-wide association studies (GWASs); however, as sequencing costs plummet over the past years, ultra low-coverage whole-genome sequencing (ulcWGS <0.5× coverage) has emerged as a promising alternative that provides superior genomic coverage with substantial reduction of genotyping cost. To evaluate the potential utility of ulcWGS, we performed a whole-genome sequencing (WGS) of 72 European individuals to a target coverage of 0.

Tumor immunogenomic signatures improve a prognostic model of melanoma survival.

Background: Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT.

Methods: Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT.

Germline genetic host factors as predictive biomarkers in immuno-oncology.

In immuno-oncology (IO), the baseline host factors attract significant clinical interest as promising predictive biomarker candidates. Growing evidence from experimental or population-based studies suggests that the host genetic factors contribute to the immunological status of a patient as it plays out at the multiple rate-limiting steps of the cancer immunity cycle. Recent observations suggest that germline genetics may be associated with tumor microenvironment phenotypes, autoimmune toxicities and/or efficacy of immunotherapy regimens and overall cancer survival.

Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM).

Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3-8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls.

Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition.

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy.

Association between number of children and carotid intima-media thickness in Bangladesh.

Previous studies on the association between number of children and carotid intima-media thickness (cIMT) were limited to Western populations. Pregnancy in women is associated with physiologic changes that may influence the risk of cardiovascular disease. Comparing the association between number of children and cIMT in men and women can provide insights on whether the association may be due to pregnancy.