Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Abstract

Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression.Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis.Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients' myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P ¼ 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P ¼ 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia.Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/carboplatin chemotherapy. Clin Cancer Res; 22(2); 366-73.Ó2015 AACR.

Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer

“…Even if the cohort was small, the results were consistent showing the same trend in most patients and, hence, small variations. Myelosuppression is a well-known side effect of chemotherapies [ 20 ]. Thus, also we observed that myeloid cells including MDSCs were reduced by gemcitabine treatment.…”

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

“…Unlike the dichotomized classification by the occurrence of grade 3–4 myelosuppression in previous studies, the GWAS used ordinal logistic regression to analyze the association of the myelosuppression grade with SNPs. Another study used whole‐exome sequencing to identify genetic markers for grade 3–4 neutropenia and thrombocytopenia in gemcitabine/carboplatin chemotherapy . The two studies identified several genetic markers related with myelosuppression risk, but there is a lack of functional studies and the results have not be analyzed or replicated in other studies.…”

Genetic Polymorphisms and Platinum-Based Chemotherapy-Induced Toxicities in Patients With Lung Cancer: A Systematic Review and Meta-Analysis

“…Therefore, determining the association between polymorphisms and platinum-related toxicities will be beneficial for individualized chemotherapy. Previously, two genome-wide association studies and one wholeexome sequencing study were conducted to identify the genetic markers for platinum-induced toxicities (9)(10)(11). In addition, Yin et al aimed to establish models to explain and predict platinum toxicity interindividual difference by simultaneously incorporating multiple genetic and clinical factors to explore the association of their interactions with platinum-induced toxicities (12,13).…”