レ点腫瘍学ノート

Top / 日記 / 2022年 / 2月8日

MSI-HとBRAF変異が合併しやすいことに関するメモ

大腸癌 MSI

MSI-H大腸癌は、大腸癌のうちの5%程度を占めるマイノリティではありますが疫学的にも治療薬の選択や治療効果・予後の面でも大腸癌の多くを占めるMSS大腸癌とはかなり異なる挙動を閉めるので治療の個別化において非常に重要なサブグループになっています。

MSI固形がんに関するレビュー

Microsatellite instability: a review of what the oncologist should know

Microsatellite instability: a review of what the oncologist should know - Cancer Cell International
The patients with high microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) tumors recently have been reported that can benefit from immunotherapy, and MSI can be used as a genetic instability of a tumor detection index. However, many studies have shown that there are many heterogeneous phenomena in patients with MSI tumors in terms of immunotherapy, prognosis and chemotherapy sensitivity. Here we mainly review the research results of MSI detection methods, the mechanisms of MSI occurrence and its relationship with related tumors, aiming to make a brief analysis of the current research status of MSI and provide comparable reference and guidance value for further research in this field.
https://cancerci.biomedcentral.com/articles/10.1186/s12935-019-1091-8

MSI-H大腸癌はゲノム変化の様相がかなり異なる

高変異量(TMB-High)大腸癌の多くはMSI-Hですが(その他はPOLEやPOLD1機能欠失)、このMSI-Hの中にもMSH2・MSH6などの機能が先天的に欠失したものとMLH1がエピジェネティックにサイレンス化されているものがあります。

MLH1-Silenced and Non-Silenced Subgroups of Hypermutated Colorectal Carcinomas Have Distinct Mutational Landscapes

MLH1-Silenced and Non-Silenced Subgroups of Hypermutated Colorectal Carcinomas Have Distinct Mutational Landscapes
Approximately 15% of colorectal carcinomas (CRC) exhibit a hypermutated genotype accompanied by high levels of microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumors, unlike the majority of colorectal carcinomas, are often ...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926301/
Redefining Colorectal Cancer by Tumor Biology | American Society of Clinical Oncology Educational Book
Colorectal cancer treatment has undergone a paradigm shift. We no longer see this disease as a singular, anatomic tumor type but rather a set of disease subgroups. Largely because of a better understanding of cancer biology and the introduction and integration of molecular biomarkers—the premise of precision therapy—we are beginning to direct treatments toward the right tumor target(s) in the right patients. The field of molecular profiling is continually evolving, and new biomarkers are constantly being discovered that have investigational, therapeutic, and/or prognostic implications—negative or positive. To date, only a few biomarkers have sufficient actionable, clinical implication to earn international guideline-recommended routine testing. Hence, it is vital that the treating oncologist should know which biomarkers to assess, when in the treatment course to test for them, and how the test is to be done. Correct interpretation of profiling results is imperative. Herein, we focus on international guideline-recommended mutation testing for patients prior to their colorectal cancer treatment initiation. The clinical applications of circulating tumor DNA (ctDNA) in patients with metastatic disease, based on our current knowledge and capabilities, are also addressed.
https://ascopubs.org/doi/10.1200/EDBK_279867

なお、転移を有する大腸癌の場合で原発巣と転移巣で遺伝子変異が乖離するのではないかという懸念もあります。しかし、現状では原発巣と転移巣のどちらかで遺伝子検査を行うことができればある程度の実用性はあると考えられます。

High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases
The prevalence and clinical implications of genetic heterogeneity in patients with multiple colorectal liver metastases remain largely unknown. In a p…
https://www.sciencedirect.com/science/article/pii/S1533002819304475
High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases
Genetic testing is needed for the treatment of colorectal cancer (CRC), especially molecular-targeted therapy. The effects of anti-EGFR therapy and prognosis are affected by the presence of KRAS mutations. However, whether primary CRC or metastatic tissues are appropriate in the analysis is still unclear. In the present study, we assessed the concordance of KRAS/BRAF mutation status and microsatellite instability (MSI) in primary CRC and corresponding metastases. This study enrolled 457 patients with surgically resected primary and corresponding metastatic CRC (499 synchronous metastases and 57 metachronous metastases) and seven local recurrences, and KRAS/BRAF mutation and MSI status were analysed for these tumours. The concordance rates of KRAS mutation, BRAF mutation, wild-type, MSI-H and MSS between primary CRC and corresponding metastases were 93.9% (214/228), 100% (30/30), 99.3% (304/306), 87.5% (21/24) and 100% (137/137), respectively. These high concordance rates were not different between synchronous and metachronous metastases. In conclusion, a high concordance of KRAS/BRAF mutation status and MSI status was observed between primary CRC and corresponding metastases in this study. Either primary CRC or metastatic tissues can be used for testing KRAS/BRAF mutation status and MSI status.
https://www.spandidos-publications.com/10.3892/or.2016.5323

また、MLH1欠失を有する大腸癌では治療標的となる遺伝子再構成があるという報告もあります。

MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories
Targetable kinase fusions are extremely rare (<1%) in colorectal cancers (CRCs), making their diagnosis challenging and often underinvestigated. They …
https://www.sciencedirect.com/science/article/abs/pii/S0046817721000897?via%3Dihub

なぜBRAF変異とMSI-Hが合併して起こりやすいかに関しては、リンチ症候群ではほとんどBRAF変異が見られないことからBRAF→MSI-H方向の変異の伝播があると考えられます。またBRAF変異とMSI-Hが合併する場合のMSIはほとんどがMLH1 silencingによってもたらされることから、エピジェネティックな機序が働いているものと考えられます。

BRAFが転写制御因子MAFGを介してCIMP関連遺伝子をサイレンシングする

in vitroではBRAFがMAFGとかいう転写制御因子を操ってMLH1や他のCIMP関連遺伝子のサイレンシングしてるとかいう話があるようです。

The BRAF Oncoprotein Functions through the Transcriptional Repressor MAFG to Mediate the CpG Island Methylator Phenotype
Most colorectal cancers containing oncogenic BRAF have a CpG island methylator phenotype (CIMP) characterized by aberrant hypermethylation and transcriptional silencing of many genes. Fang et al. show that oncogenic BRAF promotes increased levels of the transcriptional repressor MAFG, leading to binding of MAFG on CIMP gene promoters and transcriptional silencing.
https://www.cell.com/molecular-cell/fulltext/S1097-2765(14)00643-1

ただし、シングルセルで前向きにこういう事象が起こるのかというような検証がされている報告は今のところ見つけられませんでした。


この記事に対するコメント

このページには、まだコメントはありません。

お名前:

更新日:2022-02-08 閲覧数:817 views.