CHEK2*1100delC and male breast cancer risk in Israel

Abstract

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 (Ͼ2%) of the founder BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) mutations in the general Ashkenazi population. 6 Combined, these 3 founder mutations account for Ն17% 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 populationspecific 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 ϭ 0.6 -13%) by age 70 years, and 6.9% (95% CI ϭ 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 ϭ 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 -19 Similarly, germline mutations of the PTEN 20 and hMLH1 21,22 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 ϭ 2.10; 95% CI ϭ 1.04 -4.27). 23 Similarly, there is some suggestion, although not statistically significant, that long alleles (Ն30 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 ris...

The CHEK2 1100delC mutation is not present in Korean patients with breast cancer cases tested for BRCA1 and BRCA2 mutation

“…Based on this observation, the CHEK2 1100delC mutation could represent an important moderate to high risk susceptibility allele for male breast cancer. To evaluate the overall contribution of CHEK2 1100delC to male breast cancer incidence, many studies were subsequently done and a role for this mutation in male breast cancer has not been confirmed from Finland, US, UK, Israel [28][29][30], and recently from Italia [31]. CHEK2 1100delC has been reported in 18% of hereditary breast and colorectal cancer families from Netherlands [17], but this mutation was not identified in any of 152 familial breast cancer patients who had first-, second-, or third-degree relatives with colorectal cancers [16].…”

CHEK2 1100delC and male breast cancer in the Netherlands

“…In addition to a female breast cancer risk, 4 of 33 (12%) index cases of families with at least one MBC case were CHEK2 1100delC positive suggesting that the mutation also might confer a risk for MBC [4]. Thus far, the prevalence of CHEK2 1100delC in MBC has been evaluated in 12 additional studies [7][8][9][10][11][12][13][14][15][16][17][18]. Yet, only 3 of 627 genotyped samples carried the CHEK2 1100delC mutation, raising doubts on the association of CHEK2 1100delC with MBC.…”

Male Breast Cancer

“…Other genes have been investigated for a potential role in the etiology of MBC, but none have clearly been associated with an increased risk. Mutations in the androgen receptor gene, PTEN (Cowden's syndrome), and mismatch repair genes (hMLH1) have been reported in male patients with breast cancer [13,14]. However, none of these genes have been demonstrated to have a causal association with MBC.…”