Journal of the National Cancer Institute Advance Access originally published online on June 12, 2007
JNCI Journal of the National Cancer Institute 2007 99(12):929-935; doi:10.1093/jnci/djm005
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Prostate Cancer Progression and Survival in BRCA2 Mutation Carriers
Affiliations of authors: Icelandic Cancer Registry, Reykjavik, Iceland (LT, JGJ, EJO, GHO, HT); Molecular and Cell Biology Laboratory, University of Iceland and the Icelandic Cancer Society, Reykjavik, Iceland (LV, JEE); Department of Medicine, University of Iceland, Reykjavik, Iceland (LT, LV, TT, JGJ, JEE); Iceland Genomics Corporation, Reykjavik, Iceland (TR, ST); Department of Urology, Landspitali University Hospital, Reykjavik, Iceland (EJ)
Correspondence to: Laufey Tryggvadóttir, MSc, Icelandic Cancer Registry, Skógarhlíð 8, PO Box 5420, Iceland (e-mail: laufeyt{at}krabb.is).
Background: Mutations in the BRCA2 gene are associated with an increased risk of prostate cancer, but it is not known whether they are associated with progression of the disease. We compared prostate cancer–specific survival, disease stage, and tumor grade between prostate cancer patients carrying the Icelandic BRCA2 999del5 founder mutation and noncarriers.
Methods: Using population-based registries, we identified all 596 prostate cancer patients who were diagnosed in Iceland during 1955 through 2004 among 29603 male relatives of unselected breast cancer probands. BRCA2 mutation status could be determined for 527 patients (88.4%). Stage and grade were abstracted from original records, blindly with respect to mutation status, for a subgroup of 89 patients that included all mutation carriers and, for each carrier, two control patients without the BRCA2 999del5 mutation who were matched to the carrier on years of diagnosis and birth. Hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer–specific survival were estimated using multivariable regression models. All statistical tests were two-sided.
Results: The mutation was carried by 30 patients (5.7%). Compared with noncarriers, BRCA2 999del5 mutation carriers had a lower mean age at diagnosis (69.0 years versus 74.0 years; P = .002), more advanced tumor stage (stages 3 or 4, 79.3% versus 38.6%; P<.001), higher tumor grade (grades G3–4, 84.0% versus 52.7%, P = .007), and shorter median survival time (2.1 years, 95% CI = 1.4 to 3.6 years, versus 12.4 years, 95% CI = 9.9 to 19.7 years). Carrying the BRCA2 999del5 mutation was also associated with an increased risk of dying from prostate cancer (adjusting for year of diagnosis and birth, HR = 3.42, 95% CI = 2.12 to 5.51); the association remained after adjustment for stage and grade (HR = 2.35, 95% CI = 1.08 to 5.11). The prognosis of BRCA2 999del5 mutation carriers was not associated with period of diagnosis or with relatedness to breast cancer probands.
Conclusions: The Icelandic BRCA2 999del5 founder mutation was strongly associated with rapidly progressing lethal prostate cancer.
| CONTEXT AND CAVEATS Prior knowledge An association exists between BRCA2 gene mutations and risk for prostate cancer, but associations with disease progression are unknown. Study design Icelandic population–based study of Icelandic BRCA2 999del5 founder mutation status and prostate cancer–specific survival among relatives of breast cancer patients with prostate cancer. Contribution Carrying the Icelandic BRCA2 999del5 founder mutation was associated with younger diagnosis, higher grade and stage of disease, and higher rate of mortality from prostate cancer compared with carrying only the wild-type gene. Implications The Icelandic BRCA2 999del5 founder mutation is associated with an aggressive and lethal form of prostate cancer. Limitations The study was of a single protein-truncating BRCA2 mutation in a specific population, and thus, the data may not reflect a general association between BRCA2 mutations and aggressive prostate cancer.
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Manuscript received November 28, 2006; revised April 23, 2007; accepted May 4, 2007.
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J Natl Cancer Inst 2007 99: 908-909.
J Natl Cancer Inst 2007 99: 905.
J Natl Cancer Inst 2007 99: 905.
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