Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer
Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-19-0899
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发表时间：
2019-10-01
影响因子：
11.5
通讯作者：
Meyer, Joshua E.
中科院分区：
文献类型：
--
作者：
Lieu, Christopher H.;Golemis, Erica A.;Meyer, Joshua E.
目的：青年结直肠癌的发病率呈上升趋势。实验设计：从18218例临床标本中提取DNA，然后杂交捕获403个肿瘤相关基因的3769个外显子和19个常见重排基因的47个内含子。确定基因组改变(GA)，并建立与患者年龄和微卫星稳定/微卫星不稳定性高(MSS/MSIH)状态的关联。结果：在所分析的大多数基因中，年轻(=50)队列中的总体基因组变异率相似。微卫星稳定(MSS)年轻和年长队列中的基因变异率基本相似，但有几个显著差异。特别是，TP53(FDR<；0.01)和CTNNB1(FDR=0.01)改变在年轻的结直肠癌患者中更常见，而APC(FDR<；0.01)、KRAS(FDR<；0.01)、BRAF(FDR<；0.01)和FAM123B(FDR<；0.01)的改变在老年结直肠癌患者中更常见。在MSI-H队列中，大多数基因在所有年龄组中的变化率相似，但在APC(FDR<；0.01)、BRAF(FDR<；0.01)和KRAS(FDR<；0.01)中有显著差异。结论：年轻和老年结直肠癌患者的肿瘤总体上表现出相似的基因组变化率。然而，在与生物学和治疗反应相关的几个基因上注意到了差异。还需要进行进一步的研究，以确定是否可以利用基因变异率的差异来为早发性散发性结直肠癌的年轻患者提供个性化治疗。
Purpose: The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.Experimental Design: DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSIH) status established.Results: Overall genomic alteration rates in the younger (= 50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53 (FDR < 0.01) and CTNNB1 (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and APC(FDR < 0.01), KRAS(FDR < 0.01), BRAF (FDR < 0.01), and FAM123B (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR < 0.01), BRAF (FDR < 0.01), and KRAS (FDR < 0.01).Conclusions: Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.