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Clinicopathological and Molecular Genetic Study of Chinese Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Author: LiuFangQi
Tutor: CaiSanJun；ZhouXiaoYan；XuZuo；NanPeng
School: Fudan University
Course: Oncology
Keywords: Hereditary non -polyposis colorectal cancer Mismatch repair genes hMLH1 hMSH2 Clinical criteria Clinical and pathological features
CLC: R735.3
Type: Master's thesis
Year: 2009
Downloads: 70
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Abstract

Objective: To understand the characteristics of the Chinese HNPCC families hMLH1 and hMSH2 gene germ cell mutations, mutations in the difference between positive and negative aspects of the clinical and pathological features, comparison of different clinical diagnostic criteria to analyze the relationship between mutant genotype and clinical phenotype , from the molecular level to judge the clinical value of various clinical diagnostic criteria. Materials and methods: collect our hospital comply with relevant standards of HNPCC families 116 Li, 116 cases meet the Bethesda Guidelines, which meet the Amsterdam criteria 32 cases (the AC group), the remaining 84 cases, in line with Fudan recommended standard of 28 Li (FD group) The remaining 56 cases (BG Group). The clinical and pathological features of their proband by direct DNA sequencing method hMLH1 (19 exons) and hMSH2 genes (exon 16 outside) germline mutation detection, according to the mutation results in different packet analysis. Results: (1) .116 probands mutation positive accounted for 32 cases (mutation rate of 27.6%), 16 cases of MLH1 and MSH2 have their own AC group, 16 patients, FD 8 patients, BG group of 8 cases. Missense mutations in 14 cases, a nonsense mutation in seven cases, and splice site mutations in four cases, mutations within the framework of the two cases, the frameshift mutation in five cases. Mutations in hMLH1 gene in 16 cases, exon12 and exon15 each of three cases, exon7 accounted for the six cases, exon14 the total four cases; in 16 cases hMLH2 gene mutations. (2). Meet the Amsterdam standard (referred to as AC standard) of 32 pedigrees patients (the AC group) and in line with Fudan recommended standard (referred to as FD standards) of 28 pedigrees patients (FD group) compare results: between the two groups only at the same time or metachronous multiple primary fat-related malignancies proportion (21.6% vs.6%, P = 0.001) and parenteral tumor (18.3% vs.55.8%, P = 0.000) significant difference in age of onset in colorectal cancer tumor onset age, the proportion of right colon, synchronous or metachronous multiple primary colorectal ratio, the proportion of mucinous adenocarcinoma Ⅲ Ⅳ of proportion was no significant difference. AC sensitivity 50%, specificity 81%, about Teng index 31%: the FD standard sensitivity 75%, specificity of 58% and 33% of the Youden index. (3). Pedigree in the AC group mutation or divided into AC1 and AC2 comparative clinical case characteristics: age of onset in colorectal cancer, the tumor onset age, the proportion of right colon, at the same time or different the multiple primary colorectal ratio, simultaneously or metachronous multiple primary proportion of associated malignancies, parenteral tumor ratio, the proportion of mucinous adenocarcinoma was no significant difference in Ⅲ Ⅳ of proportion. (4) in the FD group pedigree mutation or FD1 and FD2, its characteristics of clinical cases for comparison: its clinical cases feature comparison: between the two groups at the same time or metachronous multiple primary hair related malignancy proportion (15.8% vs.1%, P = 0.05), there are significant differences, no statistically significant difference in other areas. (5) BG group, according to the mutation or not its in line with the terms of different multi-factor analysis: Condition 2 has a very significant statistical significance (P = 0.014), and whether the gene mutation is closely related to. (6). HMLH1 and hMSH2 mutation-positive family divided into two groups, their clinical cases feature comparison: synchronous or metachronous multiple primary Colorectal proportion (6% vs.33%, P = 0.04) significantly differences in other respects no significant difference. Conclusion: (1) The group of HNPCC families hMLH1 and hMSH2 mutation spectrum widely diverse type of mutation, hMLH1 in exon12 and exon15, mainly; hMLH2 from places exon7 and exon14 main. (2) the Fudan recommended standards to improve the sensitivity of the Amsterdam criteria the authenticity than Amsterdam criteria slightly higher; family with similar clinical and pathological features in line with the the Fudan recommendation pedigree and meet the Amsterdam criteria (only in multi-synchronous or metachronous The primary differences on the proportion of associated malignancies and parenteral tumor proportion, which may be associated with an increase in tumors of gastric cancer and liver cancer parenteral). These are the the Fudan recommended standard in the diagnosis of the important role of the Chinese HNPCC family. In addition, if any, in the family meet the of Fudan recommended standard related primary tumors indicates the mutation positive possibilities. (3) the Amsterdam criteria mutation negative group pedigrees patients with similar clinical and pathological features with mutation-positive group, suggesting that this part of the patient need for further testing (hMSH6, large deletions, etc.) and follow the same follow-up and treatment measures, but also The new type of mutation or gene may be found from these pedigrees. (4) of Bethesda Guidelines, five conditions, the condition 2 is a strong correlation with the mutation positive, prompting the the Bethesda Guidelines five conditions should be the respective weights, requiring further refinement. (5) of hMSH2 mutation-positive family at the same time or metachronous multiple primary colorectal proportion higher, suggesting that the clinical criteria of HNPCC pedigrees if synchronous or metachronous multiple primary colorectal patients, they will first hMSH2 detection .

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