Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer

K. Pylkäs, J. Tommiska, K. Syrjäkoski, J. Kere, M. Gatei, N. Waddell, M. Allinen, S. M. Karppinen, K. Rapakko, H. Kääriäinen, K. Aittomäki, C. Blomqvist, A. Mustonen, K. Holli, K. K. Khanna, Olli Kallioniemi, H. Nevanlinna, R. Winqvist (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

15 Citations (Scopus)

Abstract

Biallelic mutations in the ATM gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germline mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared to 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) previously associated with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial (P=0.006, OR 12.4, 95% CI 1.5-103.3) and 7/1124 unselected cases (P=0.07, OR 6.9, 95% CI 0.9-56.4), compared to 1/1107 in controls, suggesting an apparent, yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.
Original languageEnglish
Pages (from-to)1040-1045
JournalCarcinogenesis
Volume28
Issue number5
DOIs
Publication statusPublished - 2007
MoE publication typeA1 Journal article-refereed

Fingerprint

Ataxia Telangiectasia
Breast Neoplasms
Mutation
Alleles
Founder Effect
Population Control
Germ-Line Mutation
Neoplasms
Phosphotransferases
Phosphorylation
Genes
Proteins

Keywords

  • ataxia-telangiectasia
  • breast cancer
  • breast cancer risk
  • hereditary predisposition

Cite this

Pylkäs, K., Tommiska, J., Syrjäkoski, K., Kere, J., Gatei, M., Waddell, N., ... Winqvist, R. (2007). Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer. Carcinogenesis, 28(5), 1040-1045. https://doi.org/10.1093/carcin/bgl237
Pylkäs, K. ; Tommiska, J. ; Syrjäkoski, K. ; Kere, J. ; Gatei, M. ; Waddell, N. ; Allinen, M. ; Karppinen, S. M. ; Rapakko, K. ; Kääriäinen, H. ; Aittomäki, K. ; Blomqvist, C. ; Mustonen, A. ; Holli, K. ; Khanna, K. K. ; Kallioniemi, Olli ; Nevanlinna, H. ; Winqvist, R. / Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer. In: Carcinogenesis. 2007 ; Vol. 28, No. 5. pp. 1040-1045.
@article{4f087dcd253e41d3b8cf946878496c5d,
title = "Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer",
abstract = "Biallelic mutations in the ATM gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germline mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared to 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) previously associated with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial (P=0.006, OR 12.4, 95{\%} CI 1.5-103.3) and 7/1124 unselected cases (P=0.07, OR 6.9, 95{\%} CI 0.9-56.4), compared to 1/1107 in controls, suggesting an apparent, yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.",
keywords = "ataxia-telangiectasia, breast cancer, breast cancer risk, hereditary predisposition",
author = "K. Pylk{\"a}s and J. Tommiska and K. Syrj{\"a}koski and J. Kere and M. Gatei and N. Waddell and M. Allinen and Karppinen, {S. M.} and K. Rapakko and H. K{\"a}{\"a}ri{\"a}inen and K. Aittom{\"a}ki and C. Blomqvist and A. Mustonen and K. Holli and Khanna, {K. K.} and Olli Kallioniemi and H. Nevanlinna and R. Winqvist",
year = "2007",
doi = "10.1093/carcin/bgl237",
language = "English",
volume = "28",
pages = "1040--1045",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "5",

}

Pylkäs, K, Tommiska, J, Syrjäkoski, K, Kere, J, Gatei, M, Waddell, N, Allinen, M, Karppinen, SM, Rapakko, K, Kääriäinen, H, Aittomäki, K, Blomqvist, C, Mustonen, A, Holli, K, Khanna, KK, Kallioniemi, O, Nevanlinna, H & Winqvist, R 2007, 'Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer', Carcinogenesis, vol. 28, no. 5, pp. 1040-1045. https://doi.org/10.1093/carcin/bgl237

Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer. / Pylkäs, K.; Tommiska, J.; Syrjäkoski, K.; Kere, J.; Gatei, M.; Waddell, N.; Allinen, M.; Karppinen, S. M.; Rapakko, K.; Kääriäinen, H.; Aittomäki, K.; Blomqvist, C.; Mustonen, A.; Holli, K.; Khanna, K. K.; Kallioniemi, Olli; Nevanlinna, H.; Winqvist, R. (Corresponding Author).

In: Carcinogenesis, Vol. 28, No. 5, 2007, p. 1040-1045.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer

AU - Pylkäs, K.

AU - Tommiska, J.

AU - Syrjäkoski, K.

AU - Kere, J.

AU - Gatei, M.

AU - Waddell, N.

AU - Allinen, M.

AU - Karppinen, S. M.

AU - Rapakko, K.

AU - Kääriäinen, H.

AU - Aittomäki, K.

AU - Blomqvist, C.

AU - Mustonen, A.

AU - Holli, K.

AU - Khanna, K. K.

AU - Kallioniemi, Olli

AU - Nevanlinna, H.

AU - Winqvist, R.

PY - 2007

Y1 - 2007

N2 - Biallelic mutations in the ATM gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germline mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared to 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) previously associated with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial (P=0.006, OR 12.4, 95% CI 1.5-103.3) and 7/1124 unselected cases (P=0.07, OR 6.9, 95% CI 0.9-56.4), compared to 1/1107 in controls, suggesting an apparent, yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.

AB - Biallelic mutations in the ATM gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germline mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared to 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) previously associated with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial (P=0.006, OR 12.4, 95% CI 1.5-103.3) and 7/1124 unselected cases (P=0.07, OR 6.9, 95% CI 0.9-56.4), compared to 1/1107 in controls, suggesting an apparent, yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.

KW - ataxia-telangiectasia

KW - breast cancer

KW - breast cancer risk

KW - hereditary predisposition

U2 - 10.1093/carcin/bgl237

DO - 10.1093/carcin/bgl237

M3 - Article

VL - 28

SP - 1040

EP - 1045

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 5

ER -