Journal ArticleDOI
Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus
Catherine M. Phelan,Catherine M. Phelan,Timothy R. Rebbeck,Barbara L. Weber,Peter Devilee,Martin H. Ruttledge,Henry T. Lynch,Gilbert M. Lenoir,Michael R. Stratton,Douglas F. Easton,Bruce A.J. Ponder,Lisa A. Cannon-Albright,Catharina Larsson,David E. Goldgar,Steven A. Narod,Steven A. Narod +15 more
TLDR
This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome, and whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer.Abstract:
Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5 ) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of this VNTR have an increased risk of certain types of cancers, including breast cancer2–4. To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer5. Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.read more
Citations
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Journal ArticleDOI
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies
Antonis C. Antoniou,Paul D.P. Pharoah,Steven A. Narod,Harvey A. Risch,Jorunn E. Eyfjord,John L. Hopper,Niklas Loman,Håkan Olsson,Oskar T. Johannsson,Åke Borg,Barbara Pasini,Paolo Radice,Siranoush Manoukian,Diana Eccles,Nelson L.S. Tang,E. Olah,Hoda Anton-Culver,Ellen Warner,Jan Lubinski,Jacek Gronwald,Bohdan Górski,Hrafn Tulinius,Steinunn Thorlacius,Hannaleena Eerola,Heli Nevanlinna,Kirsi Syrjäkoski,Olli Kallioniemi,Deborah J. Thompson,Christopher H. Evans,Julian Peto,Julian Peto,Fiona Lalloo,D G R Evans,Douglas F. Easton +33 more
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
Journal ArticleDOI
Recommendations for follow-up care of individuals with an inherited predisposition to Cancer. II. BRCA1 and BRCA2
Wylie Burke,Mary B. Daly,Judy Garber,Jeffrey R. Botkin,Mary Jo Ellis Kahn,Patrick M. Lynch,Anne McTiernan,Kenneth Offit,Jeffrey M. Perlman,Gloria M. Petersen,Elizabeth J. Thomson,Claudette Varricchio +11 more
TL;DR: It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
Journal ArticleDOI
Breast cancer genetics: what we know and what we need
TL;DR: High- and low-penetrance breast-cancer-susceptibility alleles are reviewed and ongoing efforts to identify additional susceptibility genes are discussed, which will lead to individualized breast cancer risk assessment and a reduction in breast cancer incidence.
Journal ArticleDOI
Simple sequence repeats as a source of quantitative genetic variation
TL;DR: It is proposed that repeat-number variation in SSRs (simple sequence repeats) is a major source of quantitative mutation, which has broad implications for understanding molecular processes of evolutionary adaptation, including the evolutionary control of the mutation process itself.
Journal ArticleDOI
Decision analysis - Effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations
TL;DR: It is suggested that prophylactic mastectomy provides substantial gains in life expectancy and prophyllactic oophorectomy more limited gains for young women with BRCA1 or BRCa2 mutations.
References
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Book ChapterDOI
Regression Models and Life-Tables
TL;DR: The analysis of censored failure times is considered in this paper, where the hazard function is taken to be a function of the explanatory variables and unknown regression coefficients multiplied by an arbitrary and unknown function of time.
Journal Article
Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.
TL;DR: Data from families with evidence of linkage to BRCA1 is used to estimate the age-specific risks of breast and ovarian cancer in BRCa1-mutation carriers and to examine the variation in risk between and within families.
Journal ArticleDOI
Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue
TL;DR: DNA sequence analysis of the activated oncogene from the T24 human bladder carcinoma line and two alleles of its normal cellular progenitor (c-Ha-ras-1) indicates that the genes encompass at least four exons.
Journal ArticleDOI
Unusual case of Smith-Lemli-Opitz syndrome “type II”
TL;DR: The findings in this fetus extend the wide spectrum of abnormalities of the SLO phenotype, and emphasize that a genetic pathological examination and biochemical studies should always be undertaken on atypical cases, especially fetuses.
Journal ArticleDOI
A Collaborative Survey of 80 Mutations in the BRCA1 Breast and Ovarian Cancer Susceptibility Gene: Implications for Presymptomatic Testing and Screening
Donna Shattuck Eidens,Melody Mcclure,Jacques Simard,Fernand Labrie,Steve Narod,Fergus J. Couch,Kent Hoskins,Barbara L. Weber,Lucio H. Castilla,Mike Erdos,Lawrence C. Brody,Lori Friedman,Elizabeth A. Ostermeyer,Csilla Szabo,Mary-Claire King,Suresh C. Jhanwar,Kenneth Offit,Larry Norton,Teresa Gilewski,Mathew Lubin,Michael P. Osborne,Donald W. Black,Marie Boyd,Michael Steel,Sue A. Ingles,Robert W. Haile,Annika Lindblom,Håkan Olsson,Åke Borg,D. Timothy Bishop,Ellen Solomon,Paolo Radice,Giovanbattista Spatti,Simon A. Gayther,Bruce A.J. Ponder,William H. Warren,Michael R. Stratton,Qingyun Liu,Frank Fujimura,Cathryn M. Lewis,Mark H. Skolnick,David E. Goldgar +41 more
TL;DR: The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test for BRCA1 mutations.
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