青少年和青年结直肠癌左右侧肿瘤的分子分析。
Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer.
机构信息
Department of Medical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina, USA.
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
出版信息
Oncologist. 2020 May;25(5):404-413. doi: 10.1634/theoncologist.2019-0552. Epub 2019 Dec 17.
BACKGROUND
The incidence of colorectal cancer (CRC), particularly left-sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA.
MATERIALS AND METHODS
A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next-generation sequencing (NGS), protein expression, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data.
RESULTS
RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%), KRAS (64.1% vs. 45.5%), PIK3CA (27% vs. 11.2%), and RNF43 (24.2% vs. 2.9%). Notably, additional mutations in distinct genes involved in histone modification and chromatin remodeling, as well as genes associated with DNA repair and cancer-predisposing syndromes, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%), ARID1A (53.3% vs. 21.4%), MSH6 (11.1% vs. 2.3%), MLH1 (10.5% vs. 2.3%), MSH2 (10.5% vs. 1.2%), POLE (5.9% vs. 0.6%), PTEN (10.8% vs. 2.3%), and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB-high regardless of MSI status.
CONCLUSION
Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA.
IMPLICATIONS FOR PRACTICE
Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right- and left-sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right- and left-sided CRC show distinct molecular features in AYA, overall and in subgroups based on microsatellite instability status. Alterations in DNA double-strand break repair and homologous recombination repair, as well as epigenetic mechanisms, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population.
背景
青少年和年轻成年人（AYA）的结直肠癌（CRC）发病率，尤其是左侧肿瘤（LT），正在上升。表观遗传事件似乎在肿瘤发生和癌症进展中起着重要作用，尤其是在年轻患者中。我们比较了 AYA 中 LT 和右侧肿瘤（RT）的分子特征。
材料和方法
在 612 例原发性 CRC 的 AYA 队列中，共确定了 246 例 LT 和 56 例 RT。通过下一代测序（NGS）、蛋白表达和基因扩增对肿瘤进行检查。根据 NGS 数据确定肿瘤突变负担（TMB）和微卫星不稳定性（MSI）。
结果
与 LT 相比，RT 在几个基因中显示出更高的突变率，包括 BRAF（10.3%比 2.8%）、KRAS（64.1%比 45.5%）、PIK3CA（27%比 11.2%）和 RNF43（24.2%比 2.9%）。值得注意的是，RT 还具有独特的组蛋白修饰和染色质重塑相关基因以及与 DNA 修复和癌症易感综合征相关的基因的额外突变，最常见的是 KMT2D（27.8%比 3.4%）、ARID1A（53.3%比 21.4%）、MSH6（11.1%比 2.3%）、MLH1（10.5%比 2.3%）、MSH2（10.5%比 1.2%）、POLE（5.9%比 0.6%）、PTEN（10.8%比 2.3%）和 BRCA1（5.4%比 0.6%）。MSI 在 20.8%的 RT 中可见，而在 4.8%的 LT 中可见。无论 MSI 状态如何，RT 均具有更高的 TMB-高频率。
结论
AYA CRC 的分子谱分析显示 RT 与 LT 之间存在不同的分子特征。表观遗传机制和 DNA 修复基因的改变需要进一步研究，这可能是 AYA CRC 的一个有前途的治疗靶点。
意义
与年长患者相比，青少年和年轻成年人（AYA）的结直肠癌（CRC）具有不同的临床病理特征和预后，构成了一个独特的实体。需要对 AYA 的右左肿瘤进行分子谱分析，以深入了解 CRC 的生物学，并为该年龄组量身定制靶向治疗。本研究发现，AYA 的右左 CRC 显示出不同的分子特征，总体上以及基于微卫星不稳定性状态的亚组中均如此。DNA 双链断裂修复和同源重组修复以及表观遗传机制的改变似乎起着关键作用。目前的分子谱数据可能支持在 AYA 人群中制定个性化的治疗策略。
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