Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity

Abstract

Although trastuzumab‐induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab‐induced cardiotoxicity, we carried out whole exome sequencing of germline DNA samples from 9 patients with trastuzumab‐induced cardiotoxicity, and conducted a case‐control association study of 2258 genetic variants between 9 cases (with trastuzumab‐induced cardiotoxicity) and general Japanese population controls registered in the Human Genetic Variation Database (HGVD). The top variant which showed the lowest P‐value in the screening study was rs139503277 in PHD Finger Protein 3 (P min = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing P min < .001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab‐induced cardiotoxicity). In the replication study, we observed that three variants had an effect in the same direction as in the screening study (rs78272919 in exon 2 of Keratin 15, rs5762940 in exon 2 of zinc and ring finger 3, and rs139944387 in exon 44 of Eyes shut homologs [EYS]). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab‐induced cardiotoxicity (rs139944387 in EYS, combined P min = .00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for patients with human epidermal growth factor receptor 2 (HER2)‐positive cancer.

The pan-cancer landscape of prognostic germline variants in 10,582 patients

“…In line with the heritability of some cancers, several germline variants predict a patient's risk for developing cancer and are useful for individualizing cancer screening guidelines [4][5][6][7][8][9][10][11][12][13]. Germline variation can affect drug sensitivity, predict drug toxicity, and could help select therapy to minimize side-effects [14][15][16][17][18][19][20][21][22][23][24][25][26]. Some germline variants increase patient risk for specific somatic aberrations, suggesting that germline variation may impact disease course [27].…”

hiPSCs in cardio-oncology: deciphering the genomics

“…58 A whole-exome association study was conducted that found no significant associations but identified 10 variants below a Pvalue threshold that were then examined in a replication cohort. 59 None of the variants were significant in the replication cohort, though the authors note three variants showed an effect in the same direction as the discovery cohort. 59 Only one GWAS of trastuzumab-induced cardiotoxicity has been published.…”

Intra‐ and interspecies comparison of EYS transcripts highlights its characteristics in the eye

“…Currently, the biologic significance of the novel EYS tv, tv5, is uncertain. One report indicates that a single nucleotide polymorphism, rs139944387, in exon 43 is associated with heart disease (17); therefore, these novel transcripts may be involved in cardiac development or maintenance. Future studies that examine the translation of the putative EYS protein variants and subsequent differences of their functional roles will be necessary.…”