Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus

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 Cannon-Albright, Catharina Larsson, David E. Goldgar, Steven A. Narod

Research output: Contribution to journalArticle

190 Citations (Scopus)

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 cancer. 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 cancers. 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.

Original languageEnglish
Pages (from-to)309-311
Number of pages3
JournalNature Genetics
Volume12
Issue number3
DOIs
StatePublished - Mar 1996

Fingerprint

Minisatellite Repeats
Ovarian Neoplasms
Alleles
Penetrance
Breast Neoplasms
Chromosomes
BRCA1 Gene
Proto-Oncogenes
Neoplasms
Polymerase Chain Reaction
Mutation
Genes

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics

Cite this

Phelan, C. M., Rebbeck, T. R., Weber, B. L., Devilee, P., Ruttledge, M. H., Lynch, H. T., ... Narod, S. A. (1996). Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nature Genetics, 12(3), 309-311. https://doi.org/10.1038/ng0396-309

Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. / Phelan, Catherine M.; Rebbeck, Timothy R.; Weber, Barbara L.; Devilee, Peter; Ruttledge, Martin H.; Lynch, Henry T.; Lenoir, Gilbert M.; Stratton, Michael R.; Easton, Douglas F.; Ponder, Bruce A J; Cannon-Albright, Lisa; Larsson, Catharina; Goldgar, David E.; Narod, Steven A.

In: Nature Genetics, Vol. 12, No. 3, 03.1996, p. 309-311.

Research output: Contribution to journalArticle

Phelan, CM, Rebbeck, TR, Weber, BL, Devilee, P, Ruttledge, MH, Lynch, HT, Lenoir, GM, Stratton, MR, Easton, DF, Ponder, BAJ, Cannon-Albright, L, Larsson, C, Goldgar, DE & Narod, SA 1996, 'Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus', Nature Genetics, vol. 12, no. 3, pp. 309-311. https://doi.org/10.1038/ng0396-309
Phelan, Catherine M. ; Rebbeck, Timothy R. ; Weber, Barbara L. ; Devilee, Peter ; Ruttledge, Martin H. ; Lynch, Henry T. ; Lenoir, Gilbert M. ; Stratton, Michael R. ; Easton, Douglas F. ; Ponder, Bruce A J ; Cannon-Albright, Lisa ; Larsson, Catharina ; Goldgar, David E. ; Narod, Steven A. / Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. In: Nature Genetics. 1996 ; Vol. 12, No. 3. pp. 309-311.
@article{82cde3d57f454170aa40343548b2c2b7,
title = "Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus",
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 cancer. 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 cancers. 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.",
author = "Phelan, {Catherine M.} and Rebbeck, {Timothy R.} and Weber, {Barbara L.} and Peter Devilee and Ruttledge, {Martin H.} and Lynch, {Henry T.} and Lenoir, {Gilbert M.} and Stratton, {Michael R.} and Easton, {Douglas F.} and Ponder, {Bruce A J} and Lisa Cannon-Albright and Catharina Larsson and Goldgar, {David E.} and Narod, {Steven A.}",
year = "1996",
month = "3",
doi = "10.1038/ng0396-309",
language = "English",
volume = "12",
pages = "309--311",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus

AU - Phelan, Catherine M.

AU - Rebbeck, Timothy R.

AU - Weber, Barbara L.

AU - Devilee, Peter

AU - Ruttledge, Martin H.

AU - Lynch, Henry T.

AU - Lenoir, Gilbert M.

AU - Stratton, Michael R.

AU - Easton, Douglas F.

AU - Ponder, Bruce A J

AU - Cannon-Albright, Lisa

AU - Larsson, Catharina

AU - Goldgar, David E.

AU - Narod, Steven A.

PY - 1996/3

Y1 - 1996/3

N2 - 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 cancer. 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 cancers. 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.

AB - 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 cancer. 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 cancers. 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.

UR - http://www.scopus.com/inward/record.url?scp=13344268996&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13344268996&partnerID=8YFLogxK

U2 - 10.1038/ng0396-309

DO - 10.1038/ng0396-309

M3 - Article

VL - 12

SP - 309

EP - 311

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -