Clinicopathological and molecular genetic analysis of HNPCC in China

Abstract

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 TTC 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 MMR genes protein.

Figure 1

MSI status of H1 proband. Microsatellite analysis of H1 proband with five microsatellite markers, MSI in 5/5 loci.

Figure 2

A: Immunohistochemical staining. Lack of hMSH2 protein expression in carcinoma area of H1 proband tumor section. ×400; B: Immunohistochemical staining. Normal expression of hMLH1 protein in tumor from H5 proband. ×200.

Figure 3

A: C-A transition (TCA-TAA) at codon 743 in exon 14 of hMSH2 gene in H7 proband; B: TTC deletion at codon 530 in exon 14 of hMLH1 gene in H5 proband; C: G-A transition (TCGgta→TCGata) at intron 15-exon 15 borders of hMLH1 gene in H6 proband.