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NCI CANCERLIT^® Search: Non-polyposis Colon Cancer, Hereditary - June 2002

National Cancer Institute^®
Last Modified: June 1, 2002

Clinicopathological and molecular genetic analysis of 4 typical Chinese HNPCC families.
High frequency of microsatellite instability and loss of mismatch-repair protein expression in patients with double primary tumors of the
Evolution of colorectal cancer: change of pace and change of direction.

Table of Contents

1
UI - 11854906
AU - Cai Q; Sun MH; Lu HF; Zhang TM; Mo SJ; Xu Y; Cai SJ; Zhu XZ; Shi DR
TI - Clinicopathological and molecular genetic analysis of 4 typical Chinese HNPCC families.
SO - World J Gastroenterol 2001 Dec;7(6):805-10
AD - Department of Pathology, Cancer Hospital/Cancer Institute, Fudan University, Shanghai 200032, China.
AIM: To study the clinicopathological and molecular genetic characteristics of typical Chinese hereditary nonpolyposis cotorectal cancer (HNPCC) families. METHODS: Four typical Chinese HNPCC families were analyzed using microdissection, microsatellite instability analysis, immunostaining of hMSH2 and hMLH1 proteins and direct DNA sequencing of hMSH2 and hMLH1 genes. RESULTS: All five tumor tissues of 4 probands from the 4 typical Chinese HNPCC families showed microsatellite instability at more than two loci (MSI-H or RER+ phenotype). Three out of the 4 cases lost hMSH2 protein expression and the other case showed no hMLH1 protein expression. Three pathological germline mutations (2 in hMSH2 and 1 in hMLH1), which had not been reported previously, were identified. The same mutations were also found in other affected members of two HNPCC families,respectively. CONCLUSION: Typical Chinese HNPCC families showed relatively frequent germline mutation of mismatch repair genes. High-level microsatellite instability and loss of expression of mismatch repair genes correlated closely with germline mutation of mismatch repair genes. Microsatellite instability analysis and immunostaining of mismatch repair gene might serve as effective screening methods before direct DNA sequencing. It is necessary to establish clinical criteria and molecular diagnostic strategies more suitable for Chinese HNPCC families.

2
UI - 12015776
AU - Planck M; Rambech E; Moslein G; Muller W; Olsson H; Nilbert M
TI - High frequency of microsatellite instability and loss of mismatch-repair protein expression in patients with double primary tumors of the endometrium and colorectum.
SO - Cancer 2002 May 1;94(9):2502-10
AD - Department of Oncology, the Jubileum Institution, University Hospital, Lund, Sweden. maria.planck@onk.lu.se
BACKGROUND: Patients with the familial syndrome hereditary nonpolyposis colorectal carcinoma (HNPCC) exhibit an increased risk for several tumor types, of which the greatest lifetime risk is for colorectal and endometrial carcinoma. HNPCC is caused by a germline mutation in one of several identified mismatch repair (MMR) genes and typically presents with microsatellite instability (MSI) and frequent loss of MMR protein expression in the tumor tissue. The objective of this study was to estimate the proportion of double primary tumors of the endometrium and colorectum that displays tumor characteristics suggestive of MMR deficiency. METHODS: The authors used the southern Sweden regional population-based Cancer Registry to identify women who developed double primary tumors of the endometrium and colorectum. Of the 256 women who were diagnosed with carcinoma at both of these sites during the period 1958-1998, 39 women had developed their first tumor before age 50 years. The authors successfully retrieved 67 tumors from 36 of these patients and analyzed them for MSI and immunohistochemical expression of the MMR genes, MLH1, MSH2, and MSH6. RESULTS: The MSI status of the 67 tumors was high MSI in 37 tumors, low MSI in 13 tumors, and microsatellite stable (MSS) in 17 tumors. Immunohistochemical loss of MMR protein expression was correlated with MSI status and was demonstrated in 29 high MSI tumors, in 1 low MSI tumor, and in 1 MSS tumor. A concordant loss of the same MMR protein in both tumors was found in 12 of 27 patients. CONCLUSIONS : The authors demonstrated a high frequency of MSI (75%) in tumors from women with endometrial and colorectal carcinoma who had their first tumor diagnosed before age 50 years and observed concordant immunohistochemical loss of MMR protein expression, suggestive of a possible underlying germline mutation, in 12 of 27 patients (44%). They concluded that double primary malignancies of the colorectum and endometrium at a young age should make the clinician suspect HNPCC. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10501

3
UI - 11987262
AU - Jass JR; Young J; Leggett BA
TI - Evolution of colorectal cancer: change of pace and change of direction.
SO - J Gastroenterol Hepatol 2002 Jan;17(1):17-26
AD - Department of Pathology, School of Medicine, University of Queensland, Herston, Australia. j.jass@mailbox.uq.edu.au
This review compiles evidence for an alternative to the classical adenoma-carcinoma sequence in the evolution of colorectal cancer. It is suggested that between 30 and 50 of colorectal cancers are not initiated by mutation of the tumor suppressor gene APC, but through the epigenetic silencing of genes implicated in the control of differentiation, cell cycle control and DNA repair proficiency. The precursor polyps are often characterized by a serrated architecture, and include hyperplastic polyps, admixed polyps and serrated adenomas. The alternative pathway is heterogeneous and may culminate in cancers showing low or high level DNA microsatellite instability (MSI-L and MSI-H, respectively), and in cancers that are microsatellite stable (MSS). Cancers showing DNA MSI may be characterized by an accelerated evolution. Cancers in hereditary non-polyposis colorectal cancer show features of both classical (adenoma and APC mutation) and alternative pathways (rapid evolution, MSI-H and lack of chromosomal instability).

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