Chek2 / Chek2
Cancer de Mama || Gen BRCA1 || Gen BRCA2
Genes de susceptibilidad al cancer de mama.
Med Clin (Barc). 2006 Mar 4;126(8):304-10. Diez O., Gutierrez-Enriquez S., Ramon. Servicio de Genética. Hospital de la Santa Creu i Sant Pau. Barcelona., Servicio de Oncología Médica. Hospital de la Santa Creu i Sant Pau. Barcelona. España.
El gen CHEK2 desempeña un papel crucial en la reparación del ADN, el mantenimiento de la integridad del genoma y la regulación del punto G2/M del ciclo celular. Se activa en respuesta a lesiones del ADN, mediante la fosforilación llevada a cabo por la proteína del gen ATM, y evita la entrada de la célula en mitosis. Interactúa con otras proteínas involucradas en la reparación del ADN, como BRCA1 y p53. Estos hallazgos sugieren que CHEK2 es un candidato como gen de susceptibilidad al cáncer
El papel de CHEK2 en la susceptibilidad al cáncer se basó en la identificación de la mutación 1100delC en familias con el síndrome de Li-Fraumeni, caracterizado por un aumento marcado de riesgo de CM, sarcomas, leucemias, tumores cerebrales y otros
Increased Risk of Breast Cancer Associated With CHEK2*1100delC
Maren Weischer, Stig Egil Bojesen, Anne Tybjærg-Hansen, Christen Kirk Axelsson, and Børge Grønne Nordestgaard. Journal of Clinical Oncology, 10.1200/JCO.2005.05.5160
- Purpose
- CHEK2*1100delC heterozygosity has been associated with increased risk of breast, prostate, and
colorectal cancer in case-control studies. We tested the hypothesis that CHEK2*1100delC
heterozygosity in the general population increases the risk of cancer in general, and breast,
prostate, and colorectal cancer in particular.
- CHEK2*1100delC heterozygosity has been associated with increased risk of breast, prostate, and
- Patients and Methods
- We performed a prospective study of 9,231 individuals from the Danish general population, who
were observed for 34 years, and we performed a case-control study including 1,101 cases of
breast cancer and 4,665 controls. - Results
- Of the general population, 0.5% were heterozygotes and 99.5% were noncarriers. In the
prospective study, multifactorially adjusted hazard ratios by CHEK2*1100delC heterozygosity
versus noncarriers were 1.2 (95% CI, 0.7 to 2.1) for all cancers, 3.2 (95% CI, 1.0 to 9.9) for breast
cancer, 2.3 (95% CI, 0.6 to 9.5) for prostate cancer, and 1.6 (95% CI, 0.4 to 6.5) for colorectal
cancer. In the case-control study, age-matched odds ratio for breast cancer by CHEK2*1100delC
heterozygosity versus noncarriers was 2.6 (95% CI, 1.3 to 5.4). The absolute 10-year risk of breast
cancer in CHEK2*1100delC heterozygotes amounted to 24% in women older than 60 years
undergoing hormone replacement therapy, with a body mass index of 25 kg/m2 or higher. - Conclusion
- CHEK2*1100delC heterozygosity is associated with a three-fold risk of breast cancer in women in
the general population.
The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Osorio A, Rodriguez-Lopez R, Diez O, de la Hoya M, Ignacio Martinez J, Vega A, Esteban-Cardenosa E, Alonso C, Caldes T, Benitez J. Department of Human Genetics, Spanish National Cancer Center, Madrid, Spain. Int J Cancer. 2004 Jan 1;108(1):54-6.
Searching for low-penetrance genes involved in breast cancer susceptibility has been a field of interest in the last few years. Recently, the CHEK 2 gene, involved in DNA damage and replication checkpoints, has been pointed out as a good candidate; moreover, a specific variant in this gene,1100delC, has been found to increase breast cancer susceptibility among familial breast cancer cases not attributable to mutations in BRCA1 or BRCA2 genes. In our present study, we evaluated the role of the 1100delC variant as a susceptibility allele in breast cancer in the Spanish population. However, our results suggest that this variant is absent or very infrequent in our population, making its screening irrelevant from the practical point of view.
Bibliografía en Core Clinical Journals
Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells.
Circulation. 2004 Nov 9;110(19):3136-42. Epub 2004 Nov 1. Spyridopoulos I., Haendeler J., Urbich C., Brummendorf T.H., Oh H., Schneider M.D., Zeiher A.M., Dimmeler S.
Tumor suppressor genes in breast cancer: the gatekeepers and the caretakers.
Am J Clin Pathol. 2005 Dec;124 Suppl:S16-28. Oliveira A.M., Ross J.S., Fletcher J.A.
TLR9 engagement on CD4 T lymphocytes represses gamma-radiation-induced apoptosis through activation of checkpoint kinase response elements.
Blood. 2008 Mar 1;111(5):2704-13. Epub 2007 Dec 17. Zheng L., Asprodites N., Keene A.H., Rodriguez P., Brown K.D., Davila E.
Reduced p53 in peripheral blood mononuclear cells from patients with rheumatoid arthritis is associated with loss of radiation-induced apoptosis.
Arthritis Rheum. 2005 Apr;52(4):1047-57. Maas K., Westfall M., Pietenpol J., Olsen N.J., Aune T.
Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia.
Blood. 2006 Jul 15;108(2):638-44. Epub 2006 Mar 30. Rudd M.F., Sellick G.S., Webb E.L., Catovsky D., Houlston R.S.
Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study.
Lancet. 2005 Oct 29-Nov 4;366(9496):1554-7. Johnson N., Fletcher O., Naceur-Lombardelli C., dos S., Ashworth A., Peto J.
Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation.
Blood. 2005 Nov 1;106(9):3191-9. Epub 2005 Jul 12. Turner J., Koumenis C., Kute T.E., Planalp R.P., Brechbiel M.W., Beardsley D., Cody B., Brown K.D., Torti F.M., Torti S.V.
Breast-cancer genomics.
N Engl J Med. 2003 Aug 28;349(9):910-1; author reply 910-1. Friedenson B.
Hereditary breast cancer: from molecular pathology to tailored therapies.
J Clin Pathol. 2008 Oct;61(10):1073-82. Epub 2008 Aug 4. Tan D.S., Marchio C., Reis-Filho J.S.
CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin lymphomas.
Blood. 2002 Dec 15;100(13):4602-8. Epub 2002 Aug 1. Tort F., Hernandez S., Bea S., Martinez A., Esteller M., Herman J.G., Puig X., Camacho E., Sanchez M., Nayach I., Lopez-Guillermo A., Fernandez P.L., Colomer D., Hernandez L., Campo E.
Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.
JAMA. 2006 Mar 22;295(12):1379-88. Walsh T., Casadei S., Coats K.H., Swisher E., Stray S.M., Higgins J., Roach K.C., Mandell J., Lee M.K., Ciernikova S., Foretova L., Soucek P., King M.C.
Differential response of human acute myeloid leukemia cells to gemtuzumab ozogamicin in vitro: role of Chk1 and Chk2 phosphorylation and caspase 3.
Blood. 2003 Jun 1;101(11):4589-97. Epub 2003 Feb 6. Amico D., Barbui A.M., Erba E., Rambaldi A., Introna M., Golay J.
Mutations of Chk2 in primary hematopoietic neoplasms.
Blood. 2002 Apr 15;99(8):3075-7. Hangaishi A., Ogawa S., Qiao Y., Wang L., Hosoya N., Yuji K., Imai Y., Takeuchi K., Miyawaki S., Hirai H.
DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes.
J Clin Invest. 2003 Mar;111(6):877-85. Pippin J.W., Durvasula R., Petermann A., Hiromura K., Couser W.G., Shankland S.J.