Rectal cancer profiling identifies distinct subtypes in India based on age at onset, genetic, epigenetic and clinicopathological characteristics
Rectal cancer profiling identifies distinct subtypes in India based on age at onset, genetic, epigenetic and clinicopathological characteristics
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DOI：
10.1002/mc.22250
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发表时间：
2015-12-01
影响因子：
4.6
通讯作者：
Talukdar, Fazlur Rahman
中科院分区：
文献类型：
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作者：
Laskar, Ruhina Shirin;Ghosh, Sankar Kumar;Talukdar, Fazlur Rahman
直肠癌是一种异质性疾病，其通过以遗传和表观遗传改变为特征的多种途径发展。印度的直肠癌和早发病例比例相对较高。我们分析了来自印度的80例原发性直肠癌患者的遗传学（KRAS、TP 53和BRAF突变和MSI）、表观遗传学改变（10个肿瘤相关基因/位点的CpG岛甲基化检测）、相关临床病理特征和生存趋势。采用BAT 25和BAT 26单核苷酸标记检测MSI，直接测序检测KRAS、TP 53和BRAF V600 E突变。甲基特异性聚合酶链反应用于确定经典CIMP组标志物（P16、hMLH 1、MINT 1、MINT 2和MINT 31）以及其他肿瘤特异性基因（DAPK、RASSF 1、BRCA 1和GST P1）的启动子甲基化状态。MSI和BRAF突变不常见，但总体KRAS突变频率较高（67.5%）;在早发病例中，低KRAS密码子12和新KRAS G15 S突变伴RASSF 1甲基化是显著的。分层聚类以及主成分分析确定了具有离散的发病年龄、临床病理学、分子学和生存特征的三个不同的患者亚组：（i）KRAS相关的CIMP-高亚组;（ii）具有不同KRAS突变模式的显著年轻的MSS、CIMP低、TP 53突变组，和（iii）CIMP阴性、TP 53突变组。与其他亚组相比，早发亚组表现出最不利的疾病特征，具有晚期、低分化肿瘤，并且具有最差的生存率。印度人群中直肠癌患者的遗传和表观遗传分析确定了不同的亚型。(c)2014 Wiley Periodicals，Inc.
Rectal cancer is a heterogeneous disease that develops through multiple pathways characterized by genetic and epigenetic alterations. India has a comparatively higher proportion of rectal cancers and early-onset cases. We analyzed genetic (KRAS, TP53 and BRAF mutations, and MSI), epigenetic alterations (CpG island methylation detection of 10 tumor-related genes/loci), the associated clinicopathological features and survival trend in 80 primary rectal cancer patients from India. MSI was detected using BAT 25 and BAT 26 mononucleotide markers and mutation of KRAS, TP53, and BRAF V600E was detected by direct sequencing. Methyl specific polymerase chain reaction was used to determine promoter methylation status of the classic CIMP panel markers (P16, hMLH1, MINT1, MINT2, and MINT31) as well as other tumor specific genes (DAPK, RASSF1, BRCA1, and GSTP1). MSI and BRAF mutations were uncommon but high frequencies of overall KRAS mutations (67.5%); low KRAS codon 12 and a novel KRAS G15S mutation with concomitant RASSF1 methylation in early onset cases were remarkable. Hierarchical clustering as well as principal component analysis identified three distinct subgroups of patients having discrete age at onset, clinicopathological, molecular and survival characteristics: (i) a KRAS associated CIMP-high subgroup; (ii) a significantly younger MSS, CIMP low, TP53 mutant group having differential KRAS mutation patterns, and (iii) a CIMP-negative, TP53 mutated group. The early onset subgroup exhibited the most unfavorable disease characteristics with advanced stage, poorly differentiated tumors and had the poorest survival compared to the other subgroups. Genetic and epigenetic profiling of rectal cancer patients identified distinct subtypes in Indian population. (c) 2014 Wiley Periodicals, Inc.