Abstract
The prevalence of pathological germline mutations in colorectal cancer has been widely studied, as germline mutations in the DNA mismatch repair genes hMLH1 and hMSH2 confer a high risk of colorectal cancer. However, because the sample size and population of previous studies are very different from each other, the conclusions still remain controversial. In this paper, Databases such as PubMed were applied to search for related papers. The data were imported into Comprehensive Meta-Analysis V2, which was used to estimate the weighted prevalence of hMLH1 and hMSH2 pathological mutations and compare the differences of prevalence among different family histories, ethnicities and related factors. This study collected and utilized data from 102 papers. In the Amsterdam-criteria positive group, the prevalence of pathological germline mutations of the hMLH1 and hMSH2 genes was 28.55% (95%CI 26.04%–31.19%) and 19.41% (95%CI 15.88%–23.51%), respectively, and the prevalence of germline mutations in hMLH1/hMSH2 was 15.44%/10.02%, 20.43%/13.26% and 15.43%/11.70% in Asian, American multiethnic and European/Australian populations, respectively. Substitution mutations accounted for the largest proportion of germline mutations (hMLH1: 52.34%, hMSH2: 43.25%). The total prevalence of mutations of hMLH1 and hMSH2 in Amsterdam-criteria positive, Amsterdam-criteria negative and sporadic colorectal cancers was around 45%, 25% and 15%, respectively, and there were no obvious differences in the prevalence of germline mutations among different ethnicities.
Highlights
Colorectal cancer (CRC) is a major worldwide public health problem [1], and is the second leading cause of cancer death in developed countries
Chosen papers were limited to those that were published in English and fulfilled the following selection criteria: 1) paper assessing only a specific type of mutation or only specific regions of genes were excluded; 2) the mutations had to be germline mutations with pathological features but not somatic, studies that revealed somatic alteration of the mismatch repair (MMR) genes presence were excluded; 3) case reports were excluded; 4) repetitive reports were unified by using the latest or the largest edition; 5) research on polymorphism was excluded; 6) Lynch syndrome patients with known MMR gene mutations were excluded; 7) the detection patient was limited to a diagnosis of colorectal cancer rather than other Lynch syndrome related cancer such as endometrial cancer
A total of 279 articles on hMLH1 and hMSH2 germline mutations in colorectal cancer were searched in an electronic database
Summary
Colorectal cancer (CRC) is a major worldwide public health problem [1], and is the second leading cause of cancer death in developed countries. CRC represents the sixth or seventh leading cause of cancer death [2]. It is estimated that hereditary nonpolyposis colorectal cancer (HNPCC) accounts for somewhere between less than 1% to 13% [3,4] of colorectal cancers, which make it the most common inherited CRC syndrome [5,6]. HNPCC is characterized by an autosomal dominant inheritance pattern of early onset colorectal cancer, which is associated with extra colonic malignancies, such as endometrial, urological and upper gastrointestinal cancers [7]. HNPCC, known as Lynch syndrome (LS), is caused by a germline mutation in the DNA mismatch repair (MMR) genes [9,10]. A normal functioning MMR system can recognize and correct the base-pair mismatches and small nucleotide (1–4 base pair) insertion/deletion mutations, which is essential for the maintenance of genomic stability [11]
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