Determining colorectal cancer features using a Rwandan population to lay a foundation and inform precise colorectal cancer clinical management

Background and study aims
Genetics aspects of colorectal cancer throughout the world are gaining considerable scientific attention due to their impact on surveillance and management, including targeted therapy. Microsatellites are short tandem repeat DNA sequences distributed throughout the human genome. Secondary to their repeated structure, microsatellites are disposed to errors that are ordinarily fixed by the mismatch repair system (MMR), which when faulty, leads to a strong mutator phenotype known as microsatellite instability (MSI). MSI is one of the major pathways causing colorectal cancer, as it accounts for 15% of all colorectal cancer cases in Caucasian populations.
Several clinical trials have demonstrated that MSI-high colorectal cancer is significantly responsive to immunotherapy using immune checkpoint inhibitors. In Africa, there is a dearth of data on the subject, and in Rwanda specifically, there is presently no reported data on this subject. To our knowledge, this is the largest MSI status study on CRC in an African population.
There are mismatch repair (MMR) genes that are responsible for correcting errors that arise during DNA replication. Proteins within the MMR system are MLH1, PMS2, MSH2, MSH6, MLH3, MSH3, PMS1, and Exo1. When the repair system is ineffective, it results in a strong mutator phenotype called microsatellite instability (MSI). MSI is one of the major carcinogenic (cancer-causing) pathways of colorectal cancer, and there are usually two mechanisms:
1. Hereditary nonpolyposis colorectal cancer, commonly known as Lynch Syndrome, where a mutation in one of the MMR genes is inherited from a parent
2. Sporadic mutation (a mutation that occurs throughout the course of a person's lifetime and is not inherited), which accounts for 15% of colorectal cancers, mostly occurring in the MLH1 gene
Who can participate?
Colorectal cancer patients who have been diagnosed either at King Faisal Hospital (KFH) or at Rwanda Military Hospital (RMH) between 01/01/2019 and 31/12/2021.
What does the study involve?
This study will look at the medical records of all colorectal cancer patients meeting the selection criteria during the study period. Data will be entered directly into a Microsoft Excel data collection tool and stored on a password-protected laptop. Colorectal cancer tissue or blood collected as part of routine medical care will be used for DNA analysis to identify microsatellite instability (MSI). A commercial kit from Promega (MSI Analysis System, Version 1.2) will be used to categorise MSI in one of three categories: MSI-H, MSI-L, or MSS.

研究背景与研究目的
结直肠癌（colorectal cancer）的全球遗传学特征因其对包括靶向治疗在内的监测与管理工作具有重要影响，正受到科学界的广泛关注。微卫星（microsatellites）是分布于整个人类基因组中的短串联重复DNA序列。由于其重复序列的结构特性，微卫星易发生复制错误，这类错误通常可由错配修复系统（mismatch repair system, MMR）修复；若该系统功能缺陷，则会引发强烈的突变表型，即微卫星不稳定性（microsatellite instability, MSI）。MSI是导致结直肠癌的主要分子通路之一，在高加索人群中，其占所有结直肠癌病例的15%。
多项临床试验已证实，微卫星高度不稳定（MSI-H）型结直肠癌对免疫检查点抑制剂免疫治疗具有显著响应性。在非洲地区，相关研究数据较为匮乏，而卢旺达目前尚无相关报道。据我们所知，本研究是非洲人群中规模最大的结直肠癌MSI状态分析研究。
错配修复（MMR）基因负责校正DNA复制过程中产生的错误。MMR系统包含的蛋白有MLH1、PMS2、MSH2、MSH6、MLH3、MSH3、PMS1以及Exo1。当修复系统功能失效时，会引发被称为微卫星不稳定性（MSI）的强突变表型。MSI是结直肠癌的主要致癌通路之一，其主要存在两种机制：
1. 遗传性非息肉病性结直肠癌，即常说的林奇综合征（Lynch Syndrome）：患者从父母处遗传了某一MMR基因的突变；
2. 散发性突变：指在个体生命周期中自发产生且不具有遗传性的突变，该类突变引发的结直肠癌占所有结直肠癌病例的15%，且多数突变发生于MLH1基因。

入组人群
2019年1月1日至2021年12月31日期间，在费萨尔国王医院（King Faisal Hospital, KFH）或卢旺达军事医院（Rwanda Military Hospital, RMH）确诊的结直肠癌患者。

研究内容
本研究将回顾分析研究周期内符合入组标准的所有结直肠癌患者的病历资料。数据将直接录入微软Excel（Microsoft Excel）数据采集工具，并存储于密码保护的笔记本电脑中。将使用常规诊疗过程中留存的结直肠癌组织或血液样本进行DNA分析，以检测微卫星不稳定性（MSI）。本研究将采用普洛麦格（Promega）公司的MSI分析系统（MSI Analysis System, Version 1.2）商品化试剂盒，将MSI状态分为三类：微卫星高度不稳定（MSI-H）、微卫星低度不稳定（MSI-L）以及微卫星稳定（MSS）。