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Human Genetics

, Volume 111, Issue 3, pp 284–289 | Cite as

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

  • Ariane Paoloni-Giacobino
  • Claudine Rey-Berthod
  • Alexia Couturier
  • Stylianos E. Antonarakis
  • Pierre Hutter
Original Investigation

Abstract.

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 β 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 β 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.

Keywords

Amyloid Precursor Protein Microsatellite Instability Hereditary Nonpolyposis Colorectal Cancer Amyloid Precursor Protein Gene Germline Pathogenic Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Ariane Paoloni-Giacobino
    • 1
  • Claudine Rey-Berthod
    • 2
  • Alexia Couturier
    • 2
  • Stylianos E. Antonarakis
    • 1
  • Pierre Hutter
    • 2
  1. 1.Division of Medical Genetics, Geneva University Medical School and Geneva University Hospitals, 1211 Geneva 4, SwitzerlandSwitzerland
  2. 2.Unit of Genetics, Institut Central des Hôpitaux Valaisans, Av. Grand-Champsec 86, 1951 Sion, SwitzerlandSwitzerland

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