Characterization of Mutator Phenotype in Familial Colorectal Cancer Patients Not Fulfilling Amsterdam Criteria

• Published in: Clinical cancer research Vol. 10; no. 18; pp. 6159 - 6168
• Main Authors: KIM, Jin C, LEE, Kang H, KIM, Jung S, KA, In H, KOO, Kum H, ROH, Seon A, KIM, Hee C, YU, Chang S, KIM, Tae W, CHANG, Heung M, GONG, Gyeong Y
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2004
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Age of Onset; Aged; Aged, 80 and over; Alternative Splicing; Antineoplastic agents; Biological and medical sciences; Carrier Proteins; Cell Line, Tumor; Colonic Neoplasms - genetics; Colorectal Neoplasms - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Methylation; DNA Repair; Exons; Family Health; Female; Genotype; Humans; Immunohistochemistry; Introns; Male; Medical sciences; Microsatellite Repeats; Middle Aged; Mutation; MutL Protein Homolog 1; Neoplasm Proteins - genetics; Nuclear Proteins; Pharmacology. Drug treatments; Phenotype; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Tumors; Colonic disease; Human; Mutator gene; Phenotype; Rectal disease; Colorectal cancer; Digestive diseases; Intestinal disease; Familial cancer; Malignant tumor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0651

Purpose: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria. Experimental Design: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1 -promoter methylation, mutations at MMR genes ( hMLH1 , hMSH2 , hMSH6 , and hPMS2 ), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2). Results: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1 -promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer ( P < 0.001) and younger age at onset ( P = 0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission ( P = 0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors. Conclusion: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.