Boora Ganesh K, Kanwar Rahul, Kulkarni Amit A, Abyzov Alexej, Sloan Jeff, Ruddy Kathryn J, Banck Michaela S, Loprinzi Charles L, Beutler Andreas S
Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
Department of Health Sciences Research (Biostatistics and Informatics), Mayo Clinic, Rochester, Minnesota.
Cancer Med. 2016 Apr;5(4):631-9. doi: 10.1002/cam4.625. Epub 2016 Jan 14.
Paclitaxel-induced peripheral neuropathy (PIPN) cannot be predicted from clinical parameters and might have a pharmacogenomic basis. Previous studies identified single nucleotide variants (SNV) associated with PIPN. However, only a subset of findings has been confirmed to date in more than one study, suggesting a need for further re-testing and validation in additional clinical cohorts. Candidate PIPN-associated SNVs were identified from the literature. SNVs were retested in 119 patients selected by extreme phenotyping from 269 in NCCTG N08C1 (Alliance) as previously reported. SNV genotyping was performed by a combination of short-read sequencing analysis and Taqman PCR. These 22 candidate PIPN SNVs were genotyped. Two of these, rs7349683 in the EPHA5 and rs3213619 in ABCB1 were found to be significantly associated with PIPN with an Odds ratios OR = 2.07 (P = 0.02) and OR = 0.12 (P = 0.03), respectively. In addition, three SNVs showed a trend toward a risk- or protective effect that was consistent with previous reports. The rs10509681 and rs11572080 in the gene CYP2C8*3 showed risk effect with an OR = 1.49 and rs1056836 in CYP1B1 showed a protective effect with an OR = 0.66. None of the other results supported the previously reported associations, including some SNVs displaying an opposite direction of effect from previous reports, including rs1058930 in CYP2C8, rs17222723 and rs8187710 in ABCC2, rs10771973 in FGD4, rs16916932 in CACNB2 and rs16948748 in PITPNA. Alliance N08C1 validated or supported a minority of previously reported SNV-PIPN associations. Associations previously reported by multiple studies appeared to have a higher likelihood to be validated by Alliance N08C1.
紫杉醇引起的周围神经病变（PIPN）无法通过临床参数预测，可能具有药物基因组学基础。先前的研究确定了与PIPN相关的单核苷酸变异（SNV）。然而，迄今为止，只有一部分研究结果在不止一项研究中得到了证实，这表明需要在更多临床队列中进行进一步的重新测试和验证。从文献中确定了候选的PIPN相关SNV。如先前报道，通过极端表型从NCCTG N08C1（联盟）的269名患者中选择了119名患者对SNV进行重新测试。通过短读测序分析和Taqman PCR相结合的方法进行SNV基因分型。对这22个候选PIPN SNV进行了基因分型。其中两个，EPHA5中的rs7349683和ABCB1中的rs3213619被发现与PIPN显著相关，优势比分别为OR = 2.07（P = 0.02）和OR = 0.12（P = 0.03）。此外，三个SNV显示出与先前报道一致的风险或保护作用趋势。CYP2C8*3基因中的rs10509681和rs11572080显示出风险作用，OR = 1.49，而CYP1B1中的rs1056836显示出保护作用，OR = 0.66。其他结果均不支持先前报道的关联，包括一些SNV显示出与先前报道相反的作用方向，如CYP2C8中的rs1058930、ABCC2中的rs17222723和rs8187710、FGD4中的rs10771973、CACNB2中的rs16916932以及PITPNA中的rs16948748。联盟N08C1验证或支持了少数先前报道的SNV - PIPN关联。先前多项研究报道的关联似乎更有可能被联盟N08C1验证。
