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Clinical features and hMSH2/hMLH1 germ-line mutations in Chinese patients with hereditary nonpolyposis colorectal cancer

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Chinese Medical Journal 2008年第14期121卷 1265-1268页

作者： SHEN Xuan-san ZHAO Bo WANG Zhen-jun Department of General Surgery Beijing Chaoyang Hospital Capital Medical University Beijing 100020 China

Background At least five mismatch repair （MMR） genes, including hMSH2, hMLH1, hPMS, hPMS2, and hMSH6/GTBP, are associated with hereditary nonpolyposis colorectal cancer （HNPCC）. More than 90% of families with HNPCC harbor the hMSH2and hMLH1 gene mutations. We have analyzed the clinical features of HNPCC among Chinese patients and report the results of screening for mutations in the hMSH2 and hMLH1 genes. Methods The data concerning gender, site of colorectal cancer （CRC）, age at diagnosis, history of synchronous and/or metachronous colorectal cancer, instance of extracolonic cancers, and histopathology of tumors for 126 patients from 28 independent families with HNPCC were collected. Fifteen of the families met the Amsterdam I criteria, and 13 met the Japanese clinical criteria for diagnosis. Genomic DNA was extracted from the peripheral lymphocytes. Polymerase chain reaction （PCR） and denaturing high-performance liquid chromatography （DHPLC） were used to screen the coding region of the hMSH2 and hMLH1 genes. Samples showing abnormal DHPLC profiles were sequenced. Results One hundred and seventy malignant neoplasms were found in the 126 patients, of whom 23 had multiple cancers. Ninety-eight of the patients （77.8%） had colorectal cancers, with an average age at onset of 45.9 years and a right-sided predominance. Eight hMSH2 or hMLH1 gene sequence variations were found in 12 families, and a germ-line G204X nonsense mutation in the third exon of hMSH2 was found, representing the first mutation in an MMR gene ever found in people of Chinese Mongolian ethnicity. Conclusions HNPCC is a typical autosomally dominant hereditary disease, characterized by early onset, a predominance of proximal colorectal cancer, and multiple synchronous and metachronous colorectal cancers. DHPLC is a powerful tool for detecting mutations in the hMSH2 and hMLH1 genes, Mutations in the first nine exons of the hMLH1 gene were more common in Chinese patients.

关键词： colorectal neoplasms hereditary nonpolyposis mutation multiphasic screen denaturing high-performance liquid chromatography

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Clinical and genetic characteristics of Chinese hereditary nonpolyposis colorectal cancer families

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World Journal of Gastroenterology 2006年第25期12卷 4074-4077页

作者： Xu-Lin Wang Ying Yuan Su-Zhan Zhang Shan-Rong Cai Yan-Qin Huang Qiang Jiang Shu Zheng Cancer Institute the 2nd Affiliated Hospital College of Medicine Zhejiang University 88 Jie-Fang Road Hangzhou 310009 Zhejiang Province China

AIM： To analyze the clinical characteristics of Chinese hereditary nonpolyposis colorectal cancer （HNPCC） families and to screen the germline mutations of human mismatch repair genes hMLH1 and hMSH2 in the probands. METHODS： Thirty-one independent Chinese HNPCC families were collected in Zhejiang Province. All of them met Chinese HNPCC criteria. Clinical data about patient gender, site of colorectal cancer, age of onset, history of multiple colorectal cancer, associated extracolonic cancer were recorded. PCR and denaturing high performance liquid chromatography （DHPLC） were employed to screen the mutations. Sequencing analysis was used to find out the exact mutation site and characteristics of the samples showing abnormal DHPLC profiles. RESULTS： One hundred and thirty-six malignant neoplasms were found in 107 patients including 14 multiple cancers. One hundred and six of the 136 neoplasms （77.9%） were diagnosed as colorectal cancer, with an average age of onset at 48.57 ±29.00 years. Gastric cancer was the most common extracolonic cancer （10.3%） in these families. Twenty-three different sequence variations in hMLHI and hMSH2 genes were detected in these 17 families. Fifteen sequence variations were located in the exons, including 5 SNPs, 3 silent mutations, 3 missense mutations, 2 nonsense mutations and 2 frameshift mutations. The latter seven mutations seemed to be pathogenic. CONCLUSION： Germline mutations of hMLH1 and hMSH2 genes are identified in about one-third HNPCC kindreds fulfilling Chinese HNPCC criteria. Chinese HNPCC families have some particular clinical characteristics, such as a left-sided predominance, less synchronous or metachronous colorectal cancer, and frequent occurrence of gastric cancer.

关键词： Colorectal cancer hereditary nonpolyposis DNA mutation analysis High pressure liquid Chromatography Oncogenes

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Clinicopathological and molecular genetic analysis of HNPCC in China

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World Journal of Gastroenterology 2005年第11期11卷 1673-1679页

作者： Ding-CunLuo QiCai Meng-HongSun Yao-ZhongNi Shi-ChangNi Zhe-JingChen Xiao-YangLi Chong-WeiTao Xue-MiaoZhang Da-RenShi DepartmentofSurgicalOncology SecondPeople'sHospitalofWenzhouWenzhou325028ZhejiangProvinceChina DepartmentofPathology CancerHospital/CancerInstituteFudanUniversityShanghai200032China DepartmentofSurgery TheFirstAffiliatedHospitalWenzhouMedicalCollegeWenzhou325000ZhejiangProvinceChina

AIM: To explore the clinicopathological and molecular genetic features of hereditary nonpolyposis colorectal cancer (HNPCC) in Chinese population. METHODS: We collected 16 Chinese HNPCC families from Wenzhou, Zhejiang Province, China. Tumor tissues and peripheral white blood cells were studied using microdissection, microsatellite analysis, immunostaining of hMSH2 and hMLH1 proteins and direct DNA sequencing of hMSH2 and hMLH1 genes. RESULTS: (1) A total of 50 patients had CRC. Average age at diagnosis of the first CRC was 45.7 years; 40.9% and 28.7% of the CRCs were located proximal to the splenic flexure and in the rectum, respectively. Thirty-eight percent of the colorectal cancer patients had synchronous and metachronous CRC. 34.4% and 25% of the CRCs were poor differentiation cancer and mucinous adenocarcinoma, respectively. Fourteen extracoloni tumors were found, and the hepatic cancer was the most common tumor type. Twenty-one patients whose median survival time was 5.7 years died during 1-23 years. Twenty-nine patients have survived for 1-28 years, 58.6%, 41.4% and 24.1% patients have survived for more than 5, 10 and 15 years, respectively; (2) All nine tumor-tissues showed microsatellite instability (MSI) at more than two loci. Four tumor-tissues lost hMSH2 protein expression and one lost hMLH1 protein expression. Three pathological germline mutations were identified from five genetically analyzed families; two of three mutations had not been reported previously as they were a transition from C to A in exon 14 (codon 743) of hMSH2 and a TIC deletion in exon 14 (codon 530)of hMLH1. CONCLUSION: Chinese HNPCC have specific clinicopathological features, such as early onset, propensity to involve the proximal colon, and high frequency of multiple CRCs, liver cancer more frequent than endometrial cancer. Chinese HNPCC showed relatively frequent germline mutation of mismatch repair (MMR) genes that correlated closely with high-level MSI and loss of expression of M

关键词： Colorectal neoplasms hereditary nonpolyposis Sequence analysis Microsatellite instability Mutation Immunohistochemistry

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