Association between family history and mismatch repair in colorectal cancer

BACKGROUND AND AIMS: Germline mutations in mismatch repair (MMR) genes cause a greatly increased risk of cancer of the gastrointestinal and female reproductive tracts (hereditary non-polyposis colorectal cancer (HNPCC)). Loss of MMR expression is common in colorectal cancer (CRC) overall. Such loss is assumed to be acquired predominantly, although a population of CRC cases will include individuals with unrecognised MMR mutations. This study examines the association between MMR gene expression and family history of cancer among the CRC population. METHODS: Individuals with CRC were identified from two well characterised populations: (1) consecutive hospital patients (n = 644) and (2) a population based cases series (n = 249). CRC was examined for expression of hMLH1 and hMSH2 using immunohistochemistry, and expression was related to family history using logistic regression. RESULTS: hMLH1 and hMSH2 expression was assessed in 732 CRCs with 8% showing loss of expression. No association was seen overall for hMLH1 or hMSH2 expression and family history of CRC. Loss of hMSH2 was predicted by family history of extracolonic cancer (odds ratio (OR) 5.78 (95% confidence interval (CI) 0.95–35.18)) and family history suggestive of HNPCC (OR 27.84 (95% CI 4.37–177.56)). Loss of hMLH1 was not predicted by family history of extracolonic cancer or a family history suggestive of HNPCC but was for a family history of at least two affected relatives (OR 4.88 (95% CI 1.25–19.03)). CONCLUSIONS: Individuals with hMSH2 deficient CRC in the general population exhibit a family history and other characteristics suggestive of HNPCC, and may carry germline MMR mutations. Loss of hMLH1 is only associated with a strong family history of extracolonic cancer at older ages, suggesting a novel mechanism of susceptibility

Bcl-2 expression predicts radiotherapy failure in laryngeal cancer

Early stage laryngeal cancer can be effectively cured by radiotherapy or conservative laryngeal surgery. In the UK, radiotherapy is the preferred first line treatment. However, up to 25% of patients with T2 tumours will demonstrate locally persistent or recurrent disease at the original site, requiring salvage surgery to achieve a definitive cure. Patients experiencing treatment failure have a relatively poor prognosis. A retrospective analysis was conducted consisting of 124 patients with early stage (T1–T2, N0) laryngeal squamous cell carcinoma. In total, 62 patients who failed radiotherapy were matched for T stage, laryngeal subsite and smoking history to a group of 62 patients successfully cured by radiotherapy. Using immunohistochemistry the groups were compared for expression of apoptotic proteins: bcl-2, bcl-XL, bax, bak and survivin. Radioresistant laryngeal cancer was associated with bcl-2 (P<0.001) and bcl-XL (P=0.005) expression and loss of bax expression (P=0.012) in pretreatment biopsies. Bcl-2 has an accuracy of 71% in predicting radiotherapy outcome. The association between expression of bcl-2, bcl-XL and bax with radioresistant cancer suggests a potential mechanism by which cancer cells avoid the destructive effects of radiotherapy. Predicting radioresistance, using bcl-2, would allow the clinician to recommend conservative laryngeal surgery as an alternative first line treatment to radiotherapy

A comparison of microsatellite instability in early onset gastric carcinomas from relatively low and high incidence European populations.

We have investigated the genetic basis of gastric carcinomas occurring in patients aged under 40 years from a Portuguese population with a relatively high incidence of gastric cancer. We analysed a panel of 12 microsatellite loci in DNA extracted from gastric carcinomas arising in 16 patients aged 24-39 years from Braga, Portugal. Overall, microsatellite instability (MI) in at least 1 locus was detected in 44% (7 of 16) of carcinomas. A single patient demonstrated a mutator phenotype suggestive of the hereditary nonpolyposis colorectal cancer syndrome with instability in 82% of loci. This carcinoma showed loss of expression of the hMLH1 mismatch repair protein. In a previous study, we found no evidence of MI among 10 cases of early onset gastric carcinomas from an English population, which has a relatively low incidence of gastric cancer. Comparing the 2 series, we found that there was a significant difference (p = 0.04) in the prevalence of MI (at least 1 marker affected). This geographical difference in low-level MI may be related to a significantly higher prevalence of background chronic atrophic gastritis (8 of 16 vs. 0 of 8) and Helicobacter pylori infection (15 of 16 vs. 2 of 8) in Portuguese carcinomas compared with English cases. Genetic mechanisms underlying the hereditary non-polyposis colorectal cancer syndrome may play a role in a small number of early onset gastric carcinomas. The difference in prevalence of low-level MI between these relatively high and low incidence European populations requires further investigation

Rapid detection of allele loss in colorectal tumours using microsatellites and fluorescent DNA technology.

In order to investigate allele loss in colorectal tumours we have developed a rapid technique which overcomes most of the problems associated with radioactive Restriction Fragment Length Polymorphism (RFLP) analysis of allele loss. We utilise microsatellite length polymorphisms which are highly informative and are closely linked to loci of interest. Sequences containing microsatellites can be amplified from normal and tumour DNA pairs by a polymerase chain reaction (PCR) in which one of the primers is fluorescently labelled. This enables us to detect the products on polyacrylamide gels run on an automated DNA sequencer using dedicated software, by which results are automatically quantitated in terms of peak size, height, and area. Using this technique we have analysed 26 normal tissue: cancer pairs for allele loss at two loci linked to the adenomatous polyposis coli (APC) gene on chromosome 5q. Repeated assays yielded identical results for each pair. Allele loss was found in 10 out of 25 informative samples (40%)