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.
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We thank Colette Bonnardel for her expert family data management, Nathalie Foray and Susanne Pauly for their excellent technical assistance, the Genethon (France) for the establishment of lymphoblastoid cell lines and HT Lynch for his long-term collaboration in this study. This work was supported by la Ligue Nationale Contre le Cancer – Comité du Rhône and the Interdisciplinary Health Research International Team on Breast Cancer Susceptibility (INHERIT BRCA) Research Program. MDW was funded by the Ministère de la Recherche and l'Association pour la Recherche sur le Cancer.
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Ware, M., DeSilva, D., Sinilnikova, O. et al. Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene?. Oncogene 25, 323–328 (2006). https://doi.org/10.1038/sj.onc.1209033
- ovarian cancer cluster region
- nonsense-mediated mRNA decay
- genotype–phenotype correlation
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