Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study

S L Neuhausen, A K Godwin, R Gershoni-Baruch, E Schubert, J Garber, D Stoppa-Lyonnet, E Olah, B Csokay, O Serova, F Lalloo, A Osorio, M Stratton, K Offit, J Boyd, M A Caligo, R J Scott, Andrew Craig Schofield, E Teugels, M Schwab, L Cannon-Albright & 10 others T Bishop, D Easton, J Benitez, M C King, B A Ponder, B Weber, P Devilee, A Borg, S A Narod, D Goldgar

Research output: Contribution to journalArticle

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Abstract

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P
Original languageEnglish
Pages (from-to)1381-1388
Number of pages8
JournalAmerican Journal of Human Genetics
Volume62
Issue number6
DOIs
Publication statusPublished - 1 Jun 1998

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Haplotypes
Phenotype
Mutation
Ovarian Neoplasms
Breast Neoplasms
Incidence
Microsatellite Repeats
Exons
Breast

Keywords

  • Adult
  • BRCA2 Protein
  • Breast Neoplasms
  • Breast Neoplasms, Male
  • Evolution, Molecular
  • Female
  • Genetic Markers
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Mutation
  • Neoplasm Proteins
  • Ovarian Neoplasms
  • Phenotype
  • Polymorphism, Genetic
  • Repetitive Sequences, Nucleic Acid
  • Transcription Factors
  • BRCA2
  • Breast cancer
  • Ovarian cancer
  • Mutation origin
  • Cancer, breast
  • Cancer, Ovarian

Cite this

Neuhausen, S. L., Godwin, A. K., Gershoni-Baruch, R., Schubert, E., Garber, J., Stoppa-Lyonnet, D., ... Goldgar, D. (1998). Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. American Journal of Human Genetics, 62(6), 1381-1388. https://doi.org/10.1086/301885

Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. / Neuhausen, S L; Godwin, A K; Gershoni-Baruch, R; Schubert, E; Garber, J; Stoppa-Lyonnet, D; Olah, E; Csokay, B; Serova, O; Lalloo, F; Osorio, A; Stratton, M; Offit, K; Boyd, J; Caligo, M A; Scott, R J; Schofield, Andrew Craig; Teugels, E; Schwab, M; Cannon-Albright, L; Bishop, T; Easton, D; Benitez, J; King, M C; Ponder, B A; Weber, B; Devilee, P; Borg, A; Narod, S A; Goldgar, D.

In: American Journal of Human Genetics, Vol. 62, No. 6, 01.06.1998, p. 1381-1388.

Research output: Contribution to journalArticle

Neuhausen, SL, Godwin, AK, Gershoni-Baruch, R, Schubert, E, Garber, J, Stoppa-Lyonnet, D, Olah, E, Csokay, B, Serova, O, Lalloo, F, Osorio, A, Stratton, M, Offit, K, Boyd, J, Caligo, MA, Scott, RJ, Schofield, AC, Teugels, E, Schwab, M, Cannon-Albright, L, Bishop, T, Easton, D, Benitez, J, King, MC, Ponder, BA, Weber, B, Devilee, P, Borg, A, Narod, SA & Goldgar, D 1998, 'Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study', American Journal of Human Genetics, vol. 62, no. 6, pp. 1381-1388. https://doi.org/10.1086/301885
Neuhausen SL, Godwin AK, Gershoni-Baruch R, Schubert E, Garber J, Stoppa-Lyonnet D et al. Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. American Journal of Human Genetics. 1998 Jun 1;62(6):1381-1388. https://doi.org/10.1086/301885
Neuhausen, S L ; Godwin, A K ; Gershoni-Baruch, R ; Schubert, E ; Garber, J ; Stoppa-Lyonnet, D ; Olah, E ; Csokay, B ; Serova, O ; Lalloo, F ; Osorio, A ; Stratton, M ; Offit, K ; Boyd, J ; Caligo, M A ; Scott, R J ; Schofield, Andrew Craig ; Teugels, E ; Schwab, M ; Cannon-Albright, L ; Bishop, T ; Easton, D ; Benitez, J ; King, M C ; Ponder, B A ; Weber, B ; Devilee, P ; Borg, A ; Narod, S A ; Goldgar, D. / Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. In: American Journal of Human Genetics. 1998 ; Vol. 62, No. 6. pp. 1381-1388.
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AU - Neuhausen, S L

AU - Godwin, A K

AU - Gershoni-Baruch, R

AU - Schubert, E

AU - Garber, J

AU - Stoppa-Lyonnet, D

AU - Olah, E

AU - Csokay, B

AU - Serova, O

AU - Lalloo, F

AU - Osorio, A

AU - Stratton, M

AU - Offit, K

AU - Boyd, J

AU - Caligo, M A

AU - Scott, R J

AU - Schofield, Andrew Craig

AU - Teugels, E

AU - Schwab, M

AU - Cannon-Albright, L

AU - Bishop, T

AU - Easton, D

AU - Benitez, J

AU - King, M C

AU - Ponder, B A

AU - Weber, B

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AU - Borg, A

AU - Narod, S A

AU - Goldgar, D

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N2 - Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P

AB - Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P

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KW - Breast Neoplasms, Male

KW - Evolution, Molecular

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KW - Genetic Markers

KW - Genotype

KW - Haplotypes

KW - Humans

KW - Male

KW - Mutation

KW - Neoplasm Proteins

KW - Ovarian Neoplasms

KW - Phenotype

KW - Polymorphism, Genetic

KW - Repetitive Sequences, Nucleic Acid

KW - Transcription Factors

KW - BRCA2

KW - Breast cancer

KW - Ovarian cancer

KW - Mutation origin

KW - Cancer, breast

KW - Cancer, Ovarian

U2 - 10.1086/301885

DO - 10.1086/301885

M3 - Article

VL - 62

SP - 1381

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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