Differential rates of frameshift alterations in four repeat sequences of hereditary nonpolyposis colorectal cancer tumors

• Published in: Human genetics 2002-09, Vol.111 (3), p.284-289
• Main Authors: PAOLONI-GIACOBINO, Ariane, REY-BERTHOD, Claudine, COUTURIER, Alexia, ANTONARAKIS, Stylianos E, HUTTER, Pierre
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Amyloid beta-Protein Precursor - genetics; Apoptosis - genetics; Base Pair Mismatch - genetics; bcl-2-Associated X Protein; Biological and medical sciences; Carrier Proteins; Caspase 1 - genetics; Cell Division - genetics; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Repair - genetics; DNA, Neoplasm - genetics; Frameshift Mutation; Fundamental and applied biological sciences. Psychology; Germ-Line Mutation; Humans; Microsatellite Repeats; Molecular and cellular biology; Molecular genetics; Mutagenesis. Repair; MutL Protein Homolog 1; Neoplasm Proteins - genetics; Nuclear Proteins; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcl-2; Receptors, Transforming Growth Factor beta - genetics
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-002-0789-0

DNA sequences of mono-, di-, and trinucleotide repeats are prone to replication errors and thus constitute mutational hot spots. This is well illustrated by the occurrence of DNA microsatellite instability in tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) resulting from a defect in a gene that participates in postreplicative DNA mismatch repair (MMR). We selected repeat sequences present within coding regions of four genes involved in either cell proliferation or promotion of apoptosis. These repeats consisted of (A)10 in the TGF beta RII, (G)8 in the BAX, (A)8 in the CASP1, and (CCA)7 in the APP genes. These repeats were analyzed in ten tumors from HNPCC patients carrying a germline pathogenic mutation in the MMR gene MLH1. For each tumor the rate of somatic replication errors was measured by sequencing 20-50 cloned PCR-amplified fragments. Substantial intertumor variations were observed in the pattern of repeat alterations, with error rates varying between 12% and 80% for TGF beta RII, 2% and 84% for BAX, 0% and 30% for CASP1, and 0% to 18% for APP. The BAX repeat error rate did not exceed 20% in nine of the ten tumors, in contrast to results from previous studies. High error rates in more than one gene in a same tumor suggested additive selective effects from inactivation of different pathways influencing tumorigenesis. Our methodology can contribute to define tumor characteristics and may, if applied to genes strongly involved in tumorigenesis, improve tumor classification and outcome prediction.