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ASSOCIATION OF SPORADIC MSI‐H COLORECTAL CANCER and SMOKING IN AN AUSTRALIAN POPULATION
Author(s) -
Chong AK,
Young JP,
Howlett M,
Leggett BA,
Jass JR
Publication year - 2001
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2001.ca01-12.x
Subject(s) - microsatellite instability , medicine , colorectal cancer , dna mismatch repair , population , cancer , oncology , germline mutation , gastroenterology , pathology , microsatellite , genetics , mutation , allele , biology , gene , environmental health
Background High level microsatellite instability (MSI‐H) is present in 15% of all colorectal cancers. Some of these occur in the setting of hereditary nonpolyposis colorectal cancer (HNPCC) and are due to the germline mutations in one of the mismatch repair (MMR) genes hMLH1 , hMSH 2 , hMSH6 or hPMS2 . The remainder comprise sporadic msi‐h tumours, largely attributable to hypermethylation of hMLH1 . A recent study has suggested an association between msi‐h tumours and smoking. However, familial and sporadic msi‐h tumours were not differentiated. Aims To explore the association between MSI‐H colorectal cancers and smoking in a well characterised cohort of sporadic colorectal cancer patients. Methods DNA was extracted from frozen tumour specimens obtained from three centres over an 11‐year period. Accurate family histories were obtained. Subjects with significant family histories, loss of hMSH2 or hMSH6 on immunohistochemistry, or patients under 55 years with loss of hMLH‐1 on immunohistochemistry were considered to have HNPCC and excluded from this study. MSI status was determined using a panel of six microsatellite markers consisting of mononucleotide (BAT26, BAT25, c‐myb T22) and higher order repeats (D5S346, D2S123, MYCL). MSI‐H was defined as instability at two or more markers including at least one mononucleotide repeat. Fifty‐two patients with MSI‐H tumours were identified. This study population was age and sex matched with a control group of 115 patients with microsatellite stable tumours (MSS). Smoking history was obtained from patient records and categorised into two groups (never smoked vs. current or ex‐smokers). Results Twenty‐five (48%) patients with MSI‐H cancers were current or ex‐smokers compared with 34 (30%) of patients with MSS cancers ( P = 0.014, χ 2 test). Conclusions In our population of patients with sporadic colorectal cancer, subjects with MSI‐H cancers were significantly more likely to be current or ex‐smokers than those with MSS cancers. Cigarette smoke may predispose to methylation of MMR genes in sporadic MSI‐H cancers.