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)

    Research output: Contribution to journalArticleScientificpeer-review

    108 Citations (Scopus)

    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

    Fingerprint

    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.
    @article{0e13668ab3484a05b0f939ba6a8c75ab,
    title = "CHEK2 variant I157T may be associated with increased breast cancer risk",
    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