1. ¹Laboratoire de Génétique Moléculaire, Signalisation et Cancer UMR5201 CNRS, Université Claude Bernard Lyon I, Lyon cedex, France
2. ²International Agency for Research on Cancer, Lyon cedex, France
3. ³Plate-forme Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon cedex, France
4. ⁴Service de Génétique Oncologique, Institut Curie, Paris cedex, France

Correspondence: Dr S Mazoyer, Laboratoire de Génétique Moléculaire, Signalisation, et Cancer, CNRS UMR5201, Faculté de Médecine Rockefeller, Université Claude Bernard – Lyon 1, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France. E-mail: sylvie.mazoyer@sante.univ-lyon1.fr

Received 11 April 2005; Revised 11 July 2005; Accepted 12 July 2005; Published online 19 September 2005.

Abstract

BRCA2 (BReast CAncer susceptibility gene 2) germline mutation carriers are at increased risk for breast and ovarian cancers. Mutations occurring in the ovarian cancer cluster region (OCCR) are linked to higher ovarian cancer and/or lower breast cancer risk(s) than mutations occurring elsewhere in BRCA2. Most BRCA2 germline mutations introduce premature termination codons (PTCs), making their mRNAs likely targets of nonsense-mediated mRNA decay (NMD), a mechanism that eliminates PTC-bearing transcripts to prevent expression of truncated proteins. Contradictory evidence exists regarding whether NMD can be triggered by PTCs located far upstream of the nearest exon–exon junction (EEJ). Since the OCCR comprises a major portion of the 4.9 kb exon 11 of BRCA2, we investigated if transcripts bearing PTCs in this large exon are unable to trigger NMD, and if this might contribute to the phenotypic difference associated with the OCCR. We examined cDNA from 18 carriers of PTC-introducing germline mutations located throughout BRCA2, and found that PTC-bearing transcripts were 1.4–3.3-fold less prevalent than their nonmutated counterparts irregardless of PTC position. We conclude that NMD can recognize PTCs up to 4.5 kb upstream of the nearest EEJ, demonstrating that a general inability of NMD to recognize PTCs in exon 11 is unlikely to explain the genotype–phenotype correlation associated with the OCCR.