CHEK2 variant I157T may be associated with increased breast cancer risk

Outi Kilpivaara, Pia Vahteristo, Jacob Falck, Kirsi Syrjäkoski, Hannaleena Eerola, Douglas Easton, Jirina Bartkova, Jiri Lukas, Päivi Heikkilä, Kristiina Aittomäki, Kaija Holli, Carl Blomqvist, Olli Kallioniemi, Jiri Bartek, Heli Nevanlinna (Corresponding Author)

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Abstract

Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low‐penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population‐based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06–1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68–1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild‐type CHEK2 co‐expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild‐type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC.
Original languageEnglish
Pages (from-to)543 - 547
Number of pages5
JournalInternational Journal of Cancer
Volume111
Issue number4
DOIs
Publication statusPublished - 2004
MoE publication typeA1 Journal article-refereed

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Checkpoint Kinase 2
Breast Neoplasms
Proteins
Odds Ratio
Confidence Intervals
Population Control
Cell Cycle Checkpoints
Ionizing Radiation
Transducers
DNA Damage
Cultured Cells
Alleles

Keywords

  • CHEK2
  • germ line
  • mutation
  • susceptibility
  • population

Cite this

Kilpivaara, O., Vahteristo, P., Falck, J., Syrjäkoski, K., Eerola, H., Easton, D., ... Nevanlinna, H. (2004). CHEK2 variant I157T may be associated with increased breast cancer risk. International Journal of Cancer, 111(4), 543 - 547. https://doi.org/10.1002/ijc.20299
Kilpivaara, Outi ; Vahteristo, Pia ; Falck, Jacob ; Syrjäkoski, Kirsi ; Eerola, Hannaleena ; Easton, Douglas ; Bartkova, Jirina ; Lukas, Jiri ; Heikkilä, Päivi ; Aittomäki, Kristiina ; Holli, Kaija ; Blomqvist, Carl ; Kallioniemi, Olli ; Bartek, Jiri ; Nevanlinna, Heli. / CHEK2 variant I157T may be associated with increased breast cancer risk. In: International Journal of Cancer. 2004 ; Vol. 111, No. 4. pp. 543 - 547.
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abstract = "Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low‐penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population‐based series of breast cancer patients (77/1035, 7.4{\%}, odds ratio [OR] = 1.43, 95{\%} confidence interval [CI] = 1.06–1.95, p = 0.021) than among population controls (100/1885, 5.3{\%}). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5{\%}, OR = 1.04, 95{\%} CI = 0.68–1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild‐type CHEK2 co‐expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild‐type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC.",
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Kilpivaara, O, Vahteristo, P, Falck, J, Syrjäkoski, K, Eerola, H, Easton, D, Bartkova, J, Lukas, J, Heikkilä, P, Aittomäki, K, Holli, K, Blomqvist, C, Kallioniemi, O, Bartek, J & Nevanlinna, H 2004, 'CHEK2 variant I157T may be associated with increased breast cancer risk', International Journal of Cancer, vol. 111, no. 4, pp. 543 - 547. https://doi.org/10.1002/ijc.20299

CHEK2 variant I157T may be associated with increased breast cancer risk. / Kilpivaara, Outi; Vahteristo, Pia; Falck, Jacob; Syrjäkoski, Kirsi; Eerola, Hannaleena; Easton, Douglas; Bartkova, Jirina; Lukas, Jiri; Heikkilä, Päivi; Aittomäki, Kristiina; Holli, Kaija; Blomqvist, Carl; Kallioniemi, Olli; Bartek, Jiri; Nevanlinna, Heli (Corresponding Author).

In: International Journal of Cancer, Vol. 111, No. 4, 2004, p. 543 - 547.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - CHEK2 variant I157T may be associated with increased breast cancer risk

AU - Kilpivaara, Outi

AU - Vahteristo, Pia

AU - Falck, Jacob

AU - Syrjäkoski, Kirsi

AU - Eerola, Hannaleena

AU - Easton, Douglas

AU - Bartkova, Jirina

AU - Lukas, Jiri

AU - Heikkilä, Päivi

AU - Aittomäki, Kristiina

AU - Holli, Kaija

AU - Blomqvist, Carl

AU - Kallioniemi, Olli

AU - Bartek, Jiri

AU - Nevanlinna, Heli

PY - 2004

Y1 - 2004

N2 - Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low‐penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population‐based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06–1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68–1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild‐type CHEK2 co‐expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild‐type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC.

AB - Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low‐penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population‐based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06–1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68–1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild‐type CHEK2 co‐expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild‐type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC.

KW - CHEK2

KW - germ line

KW - mutation

KW - susceptibility

KW - population

U2 - 10.1002/ijc.20299

DO - 10.1002/ijc.20299

M3 - Article

VL - 111

SP - 543

EP - 547

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 4

ER -

Kilpivaara O, Vahteristo P, Falck J, Syrjäkoski K, Eerola H, Easton D et al. CHEK2 variant I157T may be associated with increased breast cancer risk. International Journal of Cancer. 2004;111(4):543 - 547. https://doi.org/10.1002/ijc.20299