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The effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other deleterious CHEK2 or BRCA1 mutations
  1. Cezary Cybulski (cezarycy{at}sci.pam.szczecin.pl)
  1. Pomeranian Medical University, Poland
    1. Bohdan Górski (gorskib{at}sci.pam.szczecin.pl)
    1. Pomeranian Medical University, Poland
      1. Tomasz Huzarski (huzarski{at}sci.pam.szczecin.pl)
      1. Pomeranian Medical University, Poland
        1. Tomasz Byrski (tomekbyr{at}poczta.onet.pl)
        1. Pomeranian Medical University, Poland
          1. Jacek Gronwald (jgron{at}sci.pam.szczecin.pl)
          1. Pomeranian Medical University, Poland
            1. Tadeusz Debniak (debniak{at}wp.pl)
            1. Pomeranian Medical University, Poland
              1. Dominika Wokolorczyk (dominikawok{at}o2.pl)
              1. Pomeranian Medical University, Poland
                1. Anna Jakubowska (aniaj{at}sci.pam.szczecin.pl)
                1. Pomeranian Medical University, Poland
                  1. Pablo Serrano-Fernández (ihcc{at}pabloserrano.eu)
                  1. Pomeranian Medical University, Poland
                    1. Thilo Dork (doerk.thilo{at}mh-hannover.de)
                    1. Hannover Medical School, Germany
                      1. Steven A Narod (steven.narod{at}wchospital.ca)
                      1. Women's College Research Institute, Canada
                        1. Jan Lubinski (lubinski{at}sci.pam.szczecin.pl)
                        1. Pomeranian Medical University - International Hereditary Cancer Center, Poland

                          Abstract

                          Purpose: Carriers of heterozygous mutations in CHEK2 or BRCA1 are at increased risk of breast cancer. These mutations are rare and a very small number of women in a population will carry two mutations. However, it is of interest to estimate the breast cancer risks associated with carrying two mutations because this information may be informative for genetic counselors and may provide clues to the carcinogenic process.

                          Experimental Design: We genotyped 7,782 Polish breast cancer patients and 6,233 controls for seven founder mutations in BRCA1 and CHEK2. Odds ratios and 95% confidence limits were estimated for the mutations, singly and in combination.

                          Results: Of the 7,782 women with breast cancer, 1091 had one mutation (14.0%) and 37 had two mutations (0.5%). Compared to controls, the odds ratio for a BRCA1 mutation in isolation was 13.1 (95% CI 8.2 to 21). The odds ratio was smaller for BRCA1 mutation carriers who also carried a CHEK2 mutation (OR = 6.6; 95% CI 1.5 to 29), but the difference was not statistically significant. In contrast, the odds ratio for women who carried two CHEK2 mutations (OR = 3.9; 95% CI 1.5 to 10) was greater than that for women who carried one CHEK2 mutation (OR = 1.9; 95% CI 1.6 to 2.1). The odds ratio for women who carried both a truncating mutation and the missense mutation in CHEK2 was 7.0 (95% CI 0.9 to 56) and was greater than for women who carried the truncating mutation alone (OR = 3.3; 95% CI 2.4 to 4.3) or the missense mutation alone (OR = 1.6; 95% CI 1.4-1.9), but the difference was not statistically significant.

                          Conclusion: Our study suggests that the risk of breast cancer in carriers of a deleterious CHEK2 mutation is increased if the second allele is the I157T missense variant. However, the presence of a CHEK2 mutation in women with a BRCA1 mutation, may not increase their risk beyond that of the BRCA1 mutation alone. These suggestive findings need to be verified in other studies.

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