Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC

Authors: Stella; Surdo¹; Lastella¹; Barana²; Oliani²; Tibiletti³; Viel⁴; Natale⁵; Piepoli⁶; Marra⁷; Guanti¹

Source: Clinical Genetics, Volume 71, Number 2, February 2007 , pp. 130-139(10)

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Abstract:

Stella A, Surdo NC, Lastella P, Barana D, Oliani C, Tibiletti MG, Viel A, Natale C, Piepoli A, Marra G, Guanti G. Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC.

Clin Genet 2007. © Blackwell Munksgaard, 2007

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.

Keywords: anticipation; founder effects; HNPCC; MSH2 deletions

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1399-0004.2007.00745.x

Affiliations: 1: Sezione di Genetica Medica, Dipartimento di Biomedicina dell'Età evolutiva, Università di Bari, Bari, Italy 2: UOA di Oncologia, ULSS 5 Ovest Vicentino, Vicenza, Italy 3: U.O. Anatomia Patologica, Ospedale di Circolo, Varese, Italy 4: Oncologia Sperimentale 1, Centro Riferimento Oncologico, IRCCS, Aviano (PN), Italy 5: UO Chirurgia Generale Ospedaliera, OORR, Foggia, Italy 6: Laboratory Research Department of Gastroenterology, IRCCS “Casa Sollievo della Sofferenza” San Giovanni Rotondo (FG), Italy 7: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

Publication date: 2007-02-01

Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC

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