CHEK2*1100delC and male breast cancer risk in Israel

Dear Sir,

Fewer than 1% of all breast cancers occur in males.1 Known risk factors for male breast cancer primarily include Klinefelter syndrome and other clinical conditions associated with aberrant hormonal status (e.g., benign breast disease and gynecomastia, liver cirrhosis, estrogen therapy, testicular pathologies), exposure ionizing radiation and either personal or family history of breast cancer.2, 3 Incidence of male breast cancer varies between populations, with higher rates observed among men of African and Jewish ancestry.3, 4 In Israel, male breast cancer rates are higher for Ashkenazi (East European ancestry) than non-Ashkenazi Jews.5 These observations may be attributable in part to the relatively high carrier frequency (>2%) of the founder BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) mutations in the general Ashkenazi population.6 Combined, these 3 founder mutations account for ≥17% of all incident Israeli male breast cancer cases, with higher prevalence of mutations detected among Ashkenzi individuals with family history of breast and ovarian cancer.7, 8 In other ethnic populations, BRCA2 mutations account for 4–14% of male breast cancer cases,9, 10 and as many as 40% in the Icelandic population, where a single founder mutation (BRCA2: 999del5) occurs at a rate of 0.6% in the general population.11 The proportion of male breast cancer cases attributable to BRCA1 appears to be lower, with no mutations identified in some population-based patient series,10, 12 whereas other studies find as many as 4–10% of cases to carry deleterious BRCA1 mutations.7, 13 These differences in observed mutation frequencies may reflect enrichment for BRCA1 mutation carriers in the latter studies due to population-specific founder effects or ascertainment bias. Thus, both BRCA1 and BRCA2 germline mutations have been reported to confer elevated risk of male breast cancer. Cumulative risk estimates for BRCA2 are 2.8% (95% CI = 0.6–13%) by age 70 years, and 6.9% (95% CI = 1.2–38.6%) by age 80 years,14 whereas that estimated for BRCA1 in a smaller cohort is reported to be 5.8% by age 110 years (95% CI = 1.3–10.4).15

To date, few genes other than BRCA1 and BRCA2 have been implicated in conferring male breast cancer susceptibility. Germline mutations of androgen receptor appear to contribute to a small proportion of cases.16, 17, 18, 19 Similarly, germline mutations of the PTEN20 and hMLH121, 22 genes in male breast cancer patients suggest elevated risks in the context of Cowden and hereditary non-polyposis colorectal cancer (HNPCC) familial cancer syndromes, respectively. A modest risk is associated with a promoter polymorphism in the CYP17 gene (OR = 2.10; 95% CI = 1.04–4.27).23 Similarly, there is some suggestion, although not statistically significant, that long alleles (≥30 repeats) of the androgen receptor exon 1 polymorphic CAG repeat may be associated with disease.18, 24 More recently, an approximately 10-fold increased risk of male breast cancer associated with the CHEK2*1100delC variant was reported in high risk breast cancer families who do not harbor BRCA1 or BRCA2 mutations (non-BRCA1/BRCA2) (OR = 10.28, 95%CI = 3.54–29.87).25 The relatively high population frequency (1.1%) of this variant suggests that nearly 10% of male breast cancer cases may be attributable to this variant. Although the association of CHEK2*1100delC with non-BRCA1/BRCA2 female breast cancer risk is consistently found, particularly among cases with family history of disease,26 a role for this variant in male breast cancer has not been confirmed in a large population-based patient series from the US and UK described by Neuhausen et al., in this issue of the journal. We report the results from our evaluation of the CHEK2*1100delC variant in Israeli male breast cancer patients.

Fifty-four male breast cancer cases diagnosed in Israel were available for study, one of whom had bilateral disease. Ages at diagnosis ranged from 37–85 years (median age = 66 years, mean age = 61.3 years). Twelve patients had at least one first- or second-degree relative affected with breast cancer (22%), and 11 additional patients reported family history of other cancers. Forty-one (75.9%) patients were of Ashkenazi or Eastern European descent, and none carried any of the 3 predominant Jewish mutations in BRCA1 or BRCA2. In addition, 146 unaffected population controls were also enrolled in the study, 89 (60.9%) of whom were of Ashkenazi descent. In addition, 219 female carriers of the Ashkenazi BRCA1 and BRCA2 founder mutations were genotyoped. DNA was analyzed for CHEK2*1100delC using denaturing gradient gel electrophoresis (DGGE) for variant detection (primer sequences as published previously).25 Identity of the sequence variant was confirmed by direct DNA sequencing of abnormally migrating fragments.

No male breast cancer patient carried the CHEK2*1100delC variant. Among control samples, no carriers were detected in unaffected individuals from the population (0/146), and a single carrier of CHEK2*1100delC was detected in the series of 219 BRCA1/2 mutation carriers (0.5%). The findings of the CHEK2 Breast Cancer Consortium (2002)25 showed no difference in CHEK2*1100delC carrier frequency between breast cancer patients who carry BRCA1/2 mutations (1.0%) and population controls (1.1%). Presumably, this reflects the functional interaction of these genes, such that no additional risk is conferred by a CHEK2 mutation in individuals where the biological pathway in which these genes act is already subverted by a BRCA1 or BRCA2 mutation. The pooled results from the normal population controls and BRCA1/2 carriers lead to an estimate of the overall Ashkenazi population frequency of the CHEK2*1100delC variant in Israel to be 0.3% (1/309), which is consistent with that observed in healthy Jewish controls from the New York Cancer Project.27 In contrast to the identification of 2 CHEK2*1100delC carriers among 79 Ashkenazi female breast cancer patients reported by Offit et al.27 none of the male breast cancer cases in our study carried the variant.

In conclusion, our results are consistent with the observations of Neuhausen et al. in this issue of the journal, insofar as the low carrier frequency of CHEK2*1100delC observed in the Ashkenazi Jewish population suggests that even with a 10-fold increased risk of male breast cancer,27 this variant would account for a relatively small proportion (no more than 3%) of all cases in Israel.

Yours sincerely,

Acknowledgements

This work was partially supported by a grant from the Middle East Cancer Consortium (MECC) to E.F. We thank all the participants in the study, and acknowledge helpful discussions with D. Thompson. This work was performed in part in fulfillment of the obligations of Inbar Gal toward her Master's thesis at the Department of Human Genetics, Sackler School of Medicine, Tel-Aviv University, Israel.

Tal Ohayon, Inbar Gal, Ruth Gershoni Baruch, Csilla Szabo, Eitan Friedman