Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC)

Heleen Van Der Klift, Juul Wijnen, Anja Wagner, Paul Verkuilen, Carli Tops, Robyn Otway, Maija Kohonen-Corish, Hans Vasen, Cristina Oliani, Daniela Barana, Pal Moller, Celia DeLozier-Blanchet, Pierre Hutter, William Foulkes, Henry T. Lynch, John Burn, Gabriela Möslein, Riccardo Fodde

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Abstract

A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories.

Original languageEnglish
Pages (from-to)123-138
Number of pages16
JournalGenes Chromosomes and Cancer
Volume44
Issue number2
DOIs
StatePublished - Oct 2005

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Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Introns
Genes
Southern Blotting
Alu Elements
Genetic Recombination
Colorectal Neoplasms
Polymerase Chain Reaction
Incidence

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Genetics

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Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). / Van Der Klift, Heleen; Wijnen, Juul; Wagner, Anja; Verkuilen, Paul; Tops, Carli; Otway, Robyn; Kohonen-Corish, Maija; Vasen, Hans; Oliani, Cristina; Barana, Daniela; Moller, Pal; DeLozier-Blanchet, Celia; Hutter, Pierre; Foulkes, William; Lynch, Henry T.; Burn, John; Möslein, Gabriela; Fodde, Riccardo.

In: Genes Chromosomes and Cancer, Vol. 44, No. 2, 10.2005, p. 123-138.

Research output: Contribution to journalArticle

Van Der Klift, H, Wijnen, J, Wagner, A, Verkuilen, P, Tops, C, Otway, R, Kohonen-Corish, M, Vasen, H, Oliani, C, Barana, D, Moller, P, DeLozier-Blanchet, C, Hutter, P, Foulkes, W, Lynch, HT, Burn, J, Möslein, G & Fodde, R 2005, 'Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC)', Genes Chromosomes and Cancer, vol. 44, no. 2, pp. 123-138. https://doi.org/10.1002/gcc.20219
Van Der Klift, Heleen ; Wijnen, Juul ; Wagner, Anja ; Verkuilen, Paul ; Tops, Carli ; Otway, Robyn ; Kohonen-Corish, Maija ; Vasen, Hans ; Oliani, Cristina ; Barana, Daniela ; Moller, Pal ; DeLozier-Blanchet, Celia ; Hutter, Pierre ; Foulkes, William ; Lynch, Henry T. ; Burn, John ; Möslein, Gabriela ; Fodde, Riccardo. / Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). In: Genes Chromosomes and Cancer. 2005 ; Vol. 44, No. 2. pp. 123-138.
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abstract = "A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories.",
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AU - Van Der Klift, Heleen

AU - Wijnen, Juul

AU - Wagner, Anja

AU - Verkuilen, Paul

AU - Tops, Carli

AU - Otway, Robyn

AU - Kohonen-Corish, Maija

AU - Vasen, Hans

AU - Oliani, Cristina

AU - Barana, Daniela

AU - Moller, Pal

AU - DeLozier-Blanchet, Celia

AU - Hutter, Pierre

AU - Foulkes, William

AU - Lynch, Henry T.

AU - Burn, John

AU - Möslein, Gabriela

AU - Fodde, Riccardo

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