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  • Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred

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Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred
  1. A H Prowse1,*,
  2. D C Schultz1,3,†,
  3. S Guo1,
  4. L Vanderveer1,
  5. J Dangel1,
  6. B Bove1,
  7. P Cairns1,
  8. M Daly2,
  9. A K Godwin1
  1. 1Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
  2. 2Department of Population Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
  3. 3Department of Chemistry, Lehigh University, Bethlehem, PA, USA
  1. Correspondence to:
 Dr A H Prowse, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK; 
 amanda.prowse{at}obstetrics-gynaecology.oxford.ac.uk

https://doi.org/10.1136/jmg.40.8.e102

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    Epidemiological studies estimate that at least 10% of all cancer cases, including breast cancer, can be attributed to inherited susceptibility. Two hereditary breast cancer genes, BRCA1 and BRCA2, have been identified and women who inherit a mutated copy of either gene have a raised lifetime risk of breast and ovarian cancer.1–4 More than 80% of families with multiple cases of breast cancer and ovarian cancer and most very large families with multiple cases of breast cancer carry mutations in either BRCA1 or BRCA2.5–7 However, only one third of families with only four or five cases of breast cancer and no cases of ovarian cancer carry mutations in either BRCA1 or BRCA2.6,8 Large scale screening studies for BRCA1 and BRCA2 mutations have shown that the percentage of high risk breast cancer families carrying a predisposing mutation in either gene is likely to be overestimated and depending on the criteria used to define the syndrome is likely to be greatly overestimated.6,9,10 Therefore, additional BRCA genes remain to be identified.

    Inactivation of the INK4a/ARF locus on human chromosome 9p21 by point mutation, deletion, or hypermethylation is observed in many cancers.11–17 Accumulating evidence now suggests that the frequency of involvement of the INK4a/ARF locus in human cancers may be second only to that of TP53, underscoring its broad importance in tumorigenesis. The INK4a/ARF locus encodes for two distinct tumour suppressor genes, p16INK4a and p14ARF, which have alternative first exons (1α or 1β) and common exons 2 and 3; p16INK4a is encoded by three exons (designated 1α, 2, and 3), whereas p14ARF is encoded by a unique first exon (exon 1β) which splices into the INK4A exon 2, but is translated into an alternative reading frame …

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    Footnotes

    • ↵* Present address: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

    • ↵† Present address: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA