Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer
Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer
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DOI：
10.1634/theoncologist.2019-0552
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发表时间：
2019-12-17
期刊：
影响因子：
5.8
通讯作者：
Lenz, Heinz-Josef
中科院分区：
文献类型：
--
作者：
Salem, Mohamed E.;Battaglin, Francesca;Lenz, Heinz-Josef
结直肠癌（CRC），特别是左侧肿瘤（LT）在青少年和年轻人（AYA）中的发病率正在上升。表观遗传事件似乎在肿瘤发生和癌症进展中起重要作用，特别是在年轻患者中。我们比较了LT的分子特征，右侧肿瘤（RT）在AYA。材料与方法在612例原发性结直肠癌患者中，共发现246例LT和56例RT。通过下一代测序（NGS）、蛋白质表达和基因扩增检查肿瘤。基于NGS数据确定肿瘤突变负荷（TMB）和微卫星不稳定性（MSI）。结果RT组BRAF、KRAS、PIK 3CA、RNF 43基因突变率分别为10.3%、64.1%、24.2%和2.9%; LT组BRAF、KRAS、PIK 3CA、RNF 43基因突变率分别为2.8%、45.5%、27%和11.2%。值得注意的是，参与组蛋白修饰和染色质重塑的不同基因以及与DNA修复和癌症易感综合征相关的基因的额外突变是RT的特征;最常见的KMT 2D（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%）和BRCA1（5.4% vs. 0.6%）。MSI见于RT的20.8%与LT的4.8%。无论MSI状态如何，RT具有更高的TMB-高频率。结论AYA结直肠癌的分子生物学特征显示RT与LT具有不同的分子生物学特征，其表观遗传学机制和DNA修复基因的改变值得进一步研究，可能成为AYA结直肠癌治疗的新靶点。实践的意义青少年和年轻人（AYA）的结直肠癌（CRC）包括一个独特的实体，与老年患者相比，具有不同的临床病理特征和预后。需要对AYA患者的右侧和左侧肿瘤进行分子分析，以获得对CRC生物学的新见解，并在该年龄组中定制靶向治疗。这项研究发现，总体而言，右侧和左侧CRC在AYA中表现出不同的分子特征，并且在基于微卫星不稳定状态的亚组中表现出不同的分子特征。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。目前的分子分析数据可能支持AYA人群个性化治疗策略的发展。
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.