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Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC.
Clin Genet. 2007 Feb; 71(2):130-9.CG

Abstract

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.

Authors+Show Affiliations

Sezione di Genetica Medica, Dipartimento di Biomedicina dell'Età evolutiva, Università di Bari, Bari, Italy. alexst@medgene.uniba.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17250661

Citation

Stella, A, et al. "Germline Novel MSH2 Deletions and a Founder MSH2 Deletion Associated With Anticipation Effects in HNPCC." Clinical Genetics, vol. 71, no. 2, 2007, pp. 130-9.
Stella A, Surdo NC, Lastella P, et al. Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC. Clin Genet. 2007;71(2):130-9.
Stella, A., Surdo, N. C., Lastella, P., Barana, D., Oliani, C., Tibiletti, M. G., Viel, A., Natale, C., Piepoli, A., Marra, G., & Guanti, G. (2007). Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC. Clinical Genetics, 71(2), 130-9.
Stella A, et al. Germline Novel MSH2 Deletions and a Founder MSH2 Deletion Associated With Anticipation Effects in HNPCC. Clin Genet. 2007;71(2):130-9. PubMed PMID: 17250661.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC. AU - Stella,A, AU - Surdo,N C, AU - Lastella,P, AU - Barana,D, AU - Oliani,C, AU - Tibiletti,M G, AU - Viel,A, AU - Natale,C, AU - Piepoli,A, AU - Marra,G, AU - Guanti,G, PY - 2007/1/26/pubmed PY - 2007/4/12/medline PY - 2007/1/26/entrez SP - 130 EP - 9 JF - Clinical genetics JO - Clin Genet VL - 71 IS - 2 N2 - 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. SN - 0009-9163 UR - https://www.unboundmedicine.com/medline/citation/17250661/Germline_novel_MSH2_deletions_and_a_founder_MSH2_deletion_associated_with_anticipation_effects_in_HNPCC_ L2 - https://doi.org/10.1111/j.1399-0004.2007.00745.x DB - PRIME DP - Unbound Medicine ER -