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Hereditary non-polyposis colorectal cancer (HNPCC) is caused by inactivating mutations of DNA mismatch repair genes. Large genomic rearrangements in these genes have been increasingly recognized as important causes of HNPCC. Using multiplex ligation-dependent probe amplification, we identified three MSH2 deletions in Italian patients with HNPCC (proband A: exons 1–3, proband M: exon 8, and proband C: exons 1–6). Deletion breakpoint sequencing allowed us to develop rapid polymerase chain reaction-based mutation screening, which confirmed the presence of the deletions in affected and asymptomatic individuals of families A, C, and M. While the exon 8 and exon 1–3 deletions appear to be novel, the MSH2 1–6 deletion found in family C is identical to the one recently documented in two branches of another unrelated Italian family (family V+Va). Haplotype analysis showed that the kindreds C and V+Va (both from northeastern Italy, both displaying clinical features of the Muir–Torre syndrome) shared a seven-locus haplotype, indicating that the MSH2 1–6 deletion is probably a founder mutation. Families A, C, M, and V+Va all showed progressively earlier cancer-onset ages in successive generations. Analysis of 23 affected parent–child pairs in the four kindreds showed median anticipation of 12 years in offsprings’ onset of cancer (p = 0.0001). No birth cohort effect was found. This is the first significant evidence of anticipation effects in HNPCC families carrying MSH2 deletions. [ABSTRACT FROM AUTHOR]

Mutation-predicting models can be useful when deciding on the genetic testing of individuals at risk and in determining the cost effectiveness of screening strategies at the population level. The aim of this study was to evaluate the performance of a newly developed genetic model that incorporates tumor microsatellite instability (MSI) information, called the AIFEG model, and in predicting the presence of mutations in MSH2 and MLH1 in probands with suspected hereditary non-polyposis colorectal cancer. The AIFEG model is based on published estimates of mutation frequencies and cancer penetrances in carriers and non-carriers and employs the program MLINK of the FASTLINK package to calculate the proband's carrier probability. Model performance is evaluated in a series of 219 families screened for mutations in both MSH2 and MLH1, in which 68 disease-causing mutations were identified. Predictions are first obtained using family history only and then converted into posterior probabilities using information on MSI. This improves predictions substantially. Using a probability threshold of 10% for mutation analysis, the AIFEG model applied to our series has 100% sensitivity and 71% specificity. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated the clinical activity and toxicity of combination chemotherapy with irinotecan and oxaliplatin in patients with advanced pancreatic cancer that had progressed despite ≥1 course of a gemcitabine-containing regimen. Methods: Thirty patients with metastatic pancreatic cancer and Karnofsky performance status ≥70 received oxaliplatin 60 mg/m2 on days 1 + 15 and irinotecan 60 mg/m2 on days 1 + 8 + 15 every 4 weeks. Patients were assessed on the basis of clinical benefit response, changes in serum tumour marker CA 19-9, objective tumour response, time to progressive disease (TTP), and survival. Results: Six patients (20%) had clinical benefit response (median duration of 7.2 months). CA 19-9 levels were reduced ≥50% from baseline in 8 patients (26%) and remained stable in 8 patients. CT scans revealed that 3 patients (10%) had a partial response and 7 (23%) had stable disease. Two patients (7%) were down-staged and underwent surgery. Median TTP was 4.1 months, median survival was 5.9 months and the 1-year survival rate was 23.3%. The most serious adverse events were grade 3–4 leukopenia in 2 patients (6%), grade 3 neuropathy in 2 (6%) and grade 3 diarrhoea in 1 (3%). Conclusion: Chemotherapy with irinotecan and oxaliplatin is an active and well-tolerated combination in patients with advanced pre-treated pancreatic cancer. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2–5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining. [ABSTRACT FROM AUTHOR]

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