微卫星稳定型(MSS)结直肠癌的高肿瘤突变负荷(TMB):不同的分子关联指向可变的病理生理

Q3 Medicine
Ioannis A. Voutsadakis
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引用次数: 1

摘要

背景具有错配修复(MMR)系统缺陷的结直肠癌是该疾病的少数。MMR缺陷癌症的特征是高肿瘤突变负担(TMB),并且对免疫检查点抑制剂的免疫疗法敏感。相反,大多数结直肠癌精通MMR(微卫星稳定型,MSS),TMB较低。然而,这些MSS癌症中有一些具有高TMB。方法对已发表的结直肠癌基因组研究进行检查,以确定TMB超过10个突变/Mb的MSS病例。研究了癌症基因组学cBioportal网站上详细介绍的四项研究的数据,并提供了MSI状态的数据。结果在转移性结直肠癌的MSK研究中,7.5%的MSS肿瘤患者的TMB高于10个突变/Mb。MSK对局限性直肠癌的研究表明,9.5%的MSS肿瘤患者TMB较高。DFCI队列包括10名TMB超过10个突变/Mb的患者,其特征为MSS,并且没有MMR或校对聚合酶突变。编码KRAS途径蛋白质的基因突变在具有高TMB的MSS肿瘤中比在具有低TMB的对应肿瘤中更频繁。此外,参与DNA损伤反应和表观遗传学调控的基因在高TMB的MSS结直肠癌中更频繁地发生突变。结论KRAS信号转导途径、DDR基因突变和表观遗传修饰基因突变可能会增加MSS结直肠癌亚群的突变负担。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology

Background

Colorectal cancers with defects in the Mismatch Repair (MMR) system represent a minority of the disease. MMR defective cancers are characterized by high Tumor Mutation Burden (TMB) and are sensitive to immunotherapy with immune checkpoint inhibitors. In contrast, the majority of colorectal cancers are MMR proficient (Microsatellite Stable, MSS) and display a low TMB. However, a few of these MSS cancers have high TMB.

Methods

Published genomic studies of colorectal cancers were examined to identify cases profiled as MSS and having a TMB above 10 mutations / Mb. Data from four studies detailed in the cBioportal for cancer genomics site and providing data on MSI status were examined.

Results

In the MSK study of metastatic colorectal cancers, 7.5% of patients with MSS tumors had a high TMB of more than 10 mutations/ Mb. The MSK study of localized rectal cancers showed that 9.5% of patients with MSS tumors had a high TMB. The DFCI cohort included 10 patients with TMB above 10 mutations/ Mb characterized as MSS and not having MMR or proofreading polymerases mutations. Mutations in genes encoding for proteins of the KRAS pathways were more frequent in MSS tumors with high TMB than in counterparts with low TMB. Moreover, genes involved in DNA damage response and in epigenetic regulations were more frequently mutated in MSS colorectal cancers with high TMB.

Conclusion

Alterations of the KRAS signal transduction pathways, DDR gene mutations and epigenetic modifier mutations may contribute to increase mutation burden in subsets of MSS colorectal cancers.

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来源期刊
CiteScore
4.30
自引率
0.00%
发文量
148
审稿时长
56 days
期刊介绍: Cancer Treatment and Research Communications is an international peer-reviewed publication dedicated to providing comprehensive basic, translational, and clinical oncology research. The journal is devoted to articles on detection, diagnosis, prevention, policy, and treatment of cancer and provides a global forum for the nurturing and development of future generations of oncology scientists. Cancer Treatment and Research Communications publishes comprehensive reviews and original studies describing various aspects of basic through clinical research of all tumor types. The journal also accepts clinical studies in oncology, with an emphasis on prospective early phase clinical trials. Specific areas of interest include basic, translational, and clinical research and mechanistic approaches; cancer biology; molecular carcinogenesis; genetics and genomics; stem cell and developmental biology; immunology; molecular and cellular oncology; systems biology; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; cancer policy; and integration of various approaches. Our mission is to be the premier source of relevant information through promoting excellence in research and facilitating the timely translation of that science to health care and clinical practice.
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