Background: The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left-sided CRC between younger (≤45 years) and older patients (≥65).
Subjects, materials, and methods: In total, 1,126 CRC tumor samples from the splenic flexure to (and including) the rectum were examined by next-generation sequencing (NGS), immunohistochemistry, and in situ hybridization. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed by NGS.
Results: Younger patients (n = 350), when compared with older patients (n = 776), showed higher mutation rates in genes associated with cancer-predisposing syndromes (e.g., Lynch syndrome), such as MSH6 (4.8% vs. 1.2%, p = .005), MSH2 (2.7% vs. 0.0%, p = .004), POLE (1.6% vs. 0.0%, p = .008), NF1 (5.9% vs. 0.5%, p < .001), SMAD4 (14.3% vs. 8.3%, p = .024), and BRCA2 (3.7% vs. 0.5%, p = .002). Genes involved in histone modification were also significantly more mutated: KDM5C (1.9% vs. 0%, p = .036), KMT2A (1.1% vs. 0%, p = .033), KMT2C (1.6% vs. 0%, p = .031), KMT2D (3.8% vs. 0.7%, p = .005), and SETD2 (3.2% vs. 0.9%, p = .039). Finally, TMB-high (9.7% vs. 2.8%, p < .001) and MSI-high (MSI-H; 8.1% vs. 1.9%, p = .009) were more frequent in younger patients.
Conclusion: Our findings highlight the importance of genetic counseling and screening in younger CRC patients. MSI-H and TMB-high tumors could benefit from immune-checkpoint inhibitors, now approved for the treatment of MSI-H/deficient mismatch repair metastatic CRC patients. Finally, histone modifiers could serve as a new promising therapeutic target. With confirmatory studies, these results may influence our approach to younger adults with CRC.
Implications for practice: The increasing rate of colorectal cancers (CRC), primarily distal tumors, among young adults poses a global health issue. This study investigates the molecular differences between younger (≤45 years old) and older (≥65) adults with left-sided CRCs. Younger patients more frequently harbor mutations in genes associated with cancer-predisposing syndromes. Higher rates of microsatellite instability-high and tumor mutational burden-high tumors occur in younger patients, who could benefit from immune-checkpoint inhibitors. Finally, histone modifiers are more frequently mutated in younger patients and could serve as a new promising therapeutic target. This study provides new insights into mutations that may guide development of novel tailored therapy in younger CRC patients.
摘要
背景。结直肠癌 (CRC) 在年轻患者中的发病率呈上升趋势，这主要是由于降结肠和直肠中的肿瘤所导致。因此，我们旨在探讨年轻患者(≤45 岁)与年长患者(≥65 岁)之间的左侧 CRC 分子差异。
受试者、材料和方法。通过下一代测序 (NGS)、免疫组织化学和原位分子杂交的方法，一共对 1 126 个取样自结肠脾曲至(并包括)直肠的 CRC 肿瘤样本进行了检查。通过 NGS 对微卫星不稳定性 (MSI) 和肿瘤突变负荷 (TMB) 进行了评估。
结果。研究表明，年轻患者 (n = 350) 与年长患者 (n = 776) 相比，癌症易感综合征(例如林奇综合征)相关的基因突变率较高，如 MSH6(4.8% vs. 1.2%，p = 0.005)、MSH2(2.7% vs. 0.0%，p = 0.004)、POLE(1.6% vs. 0.0%，p = 0.008)、NF1(5.9% vs. 0.5%，p < 0.001)、SMAD4(14.3% vs. 8.3%，p = 0.024)以及 BRCA2(3.7% vs. 0.5%，p = 0.002)。参与组蛋白修饰的基因也发生了更为显著的突变:KDM5C(1.9% vs. 0%，p = 0.036)、KMT2A(1.1% vs. 0%，p = 0.033)、KMT2C(1.6% vs. 0%，p = 0.031)、KMT2D(3.8% vs. 0.7%，p = 0.005)以及 SETD2(3.2% vs. 0.9%，p = 0.039)。最后，年轻患者出现 TMB 高(9.7% vs. 2.8%，p < 0.001)和 MSI 高(MSI‐H；8.1% vs. 1.9%，p = 0.009)的频率更高。
结论。我们的研究结果强调了在 CRC 年轻患者中开展遗传咨询与筛查的重要性。MSI‐H 和 TMB 高的肿瘤可以得益于免疫检查点抑制剂，该抑制剂现已获准用于治疗 MSI‐H/缺失性错配修复转移性 CRC 患者。最后，组蛋白修饰基因可以作为一个有希望的全新治疗靶点。通过验证性研究，这些结果可能会影响我们对患CRC 的年轻成人的治疗方法。
对临床实践的提示:年轻成人罹患结直肠癌 (CRC)(主要是远端肿瘤)的增长率已构成全球性的健康问题。本研究调查了左侧 CRC 年轻患者(≤45 岁)和年长患者(≥65 岁)之间的分子差异。年轻患者发生与癌症易感综合征相关的基因突变的频率较高。年轻患者罹患微卫星不稳定性高和肿瘤突变负荷高的肿瘤的比率更高，他们可以受益于免疫检查点抑制剂。最后，组蛋白修饰基因在年轻患者中发生突变的频率更高，可以作为一个有希望的全新治疗靶点。本研究提出了有关基因突变的全新见解，可以为研发针对 CRC 年轻患者的新型定制治疗提供指导。
Keywords: Cancer syndromes; Colorectal cancer; Early‐onset; Histone modifiers; Microsatellite instability; Tumor mutational burden.
© AlphaMed Press 2018.