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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 (Pmin = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing Pmin < .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 Pmin = .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.

SUBMITTER: Udagawa C

PROVIDER: S-EPMC5797809 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Family studies have shown a strong heritability component for venous thromboembolism (VTE), but established genetic risk factors are present in only half of VTE patients. AIM:To identify genetic risk factors in two large families with unexplained hereditary VTE. METHODS:We performed whole exome sequencing in 10 affected relatives of two unrelated families with an unexplained tendency for VTE. We prioritized variants shared by all affected relatives from both families, and evaluated these in the remaining affected and unaffected individuals. We prioritized variants based on 3 different filter strategies: variants within candidate genes, rare variants across the exome, and SNPs present in patients with familial VTE and with low frequency in the general population. We used whole exome sequencing data available from 96 unrelated VTE cases with a positive family history of VTE from an affected sib study (the GIFT study) to identify additional carriers and compared the risk-allele frequencies with the general population. Variants found in only one individual were also retained for further analysis. Finally, we assessed the association of these variants with VTE in a population-based case-control study (the MEGA study) with 4,291 cases and 4,866 controls. RESULTS:Six variants remained as putative disease-risk candidates. These variants are located in 6 genes spread among 3 different loci: 2p21 (PLEKHH2 NM_172069:c.3105T>C, LRPPRC rs372371276, SRBD1 rs34959371), 5q35.2 (UNC5A NM_133369.2:c.1869+23C>A), and 17q25.1 (GPRC5C rs142232982, RAB37 rs556450784). In GIFT, additional carriers were identified only for the variants located in the 2p21 locus. In MEGA, additional carriers for several of these variants were identified in both cases and controls, without a difference in prevalence; no carrier of the UNC5A variant was present. CONCLUSION:Despite sequencing of several individuals from two thrombophilic families resulting in 6 candidate variants, we were unable to confirm their relevance as novel thrombophilic defects.

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Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity.

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