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Women from Pakistan and India are more often diagnosed with early-onset breast cancer than Caucasian women. Given that only 12% of Pakistani women diagnosed with breast cancer at or before 30 years of age have previously been shown to harbor germ line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, the genetic causes of the majority of early-onset cases are unexplained. Since germ line mutations in the tumor suppressor gene TP53 predispose women to early-onset breast cancer, we assessed the prevalence of TP53 mutations in 105 early-onset breast cancer patients from Pakistan, who had previously been found to be negative for BRCA1 and BRCA2 germ line mutations. The patient group included 67 women diagnosed with early-onset breast cancer at or before age 30 with no family history of breast or ovarian cancer (EO30NFH group) and 38 women diagnosed with breast cancer at or before age 40 with one or more first- or second-degree relatives with breast or ovarian cancer (EO40FH group). Mutation analysis of the complete TP53 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. One deleterious mutation, c.499-500delCA in exon 5, was identified in the 105 breast cancer patients (1%). This mutation is novel in the germ line and has not been described in other populations. It was detected in a 28-year-old patient with no family history of breast or ovarian cancer. This mutation is rare as it was not detected in additional 157 recently recruited non-BRCA1 and non-BRCA2-associated early-onset breast cancer patients. Our findings show that TP53 mutations may account for a minimal portion of early-onset breast cancer in Pakistan.

Background Vitamin D is postulated to decrease the risk of breast cancer by inhibiting cell proliferation via the vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNPs) in the VDR gene, rs1544410 (BsmI) and rs2228570 (FokI), are inconsistently associated with breast cancer risk in Caucasian populations, while data for Asians are scarce. Here, we investigated the possible contribution of these SNPs to breast cancer risk in Pakistani breast cancer patients and in controls participating in a hospital-based breast cancer case-control study (PAK-BCCC). Methods Genotyping of the BsmI and FokI SNPs was performed by PCR-based restriction fragment length polymorphism (RFLP) analysis of 463 genetically enriched female breast cancer cases with known BRCA1/2 status and in 1,012 controls from Pakistan. The association between SNP genotypes and breast cancer risk was investigated by logistic regression adjusted for potential breast cancer risk factors and stratified by BRCA1/2 status and family history. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. Results The b allele of the BsmI was associated with an increased breast cancer risk (per b allele OR 1.28, 95% CI 1.09–1.49, P = 0.003). Subgroup analysis revealed that this effect was restricted to BRCA1/2 non-carriers (per b allele OR 1.33, 95% CI 1.11–1.59, P = 0.002) and was stronger in those who reported a positive family history of breast and/or ovarian cancer (per b allele OR 1.64, 95% CI 1.20–2.22, P = 0.002). No association with breast cancer risk was detected for the FokI SNP. Conclusions The BsmI polymorphism in the VDR gene may be associated with an increased breast cancer risk in Pakistani women negative for BRCA1/2 germline mutations.

The frequency and spectrum of germ line mutations in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 shows considerable variation by ethnic group. Most genetic epidemiological studies of the BRCA genes have been performed among Caucasian populations [1], with the exception of a few studies involving other ethnic groups, such as Hispanics [2–4], Asians [5, 6], and African Americans [7–9]. In most of these studies only the frequencies of sequence detectable BRCA mutations were reported and large genomic rearrangements including deletions and insertions of one or more exons, which account for 6–15% of all deleterious mutations in these genes have infrequently been considered [10–12]. Most BRCA mutations are unique; however, few recurrent mutations with founder effects have been found in European, Hispanic, American and Asian populations [13]. In a recent study on Hispanic high-risk breast/ovarian cancer families of mainly Mexican descent from South California, Weitzel and colleagues reported the identification of a novel deletion of BRCA1 exons 9 through 12 using multiplex quantitative differential polymerase chain reaction (PCR) analysis. The deletion was detected in 3.8% of families negative for sequence detectable BRCA mutations [14]. The large genomic rearrangement mutation is considered deleterious as it results in loss of critical functional domains as well as premature truncation of the BRCA1 protein. Given the relatively high prevalence of the deletion in this cohort, the authors suggest to include the screening for this mutation in the genetic testing strategy in Hispanic women without sequence detectable BRCA mutations. The spectra of recurrent sequence detectable BRCA mutations, including some with founder effects in a cohort of Hispanic breast/ovarian cancer families of predominantly Mexican descent from the United States and in a cohort from Colombia have previously been shown to differ completely, with different common mutations being identified in the two populations [2, 4]. In order to investigate, whether the novel BRCA1 founder deletion is also specific for Hispanic families of Mexican descent or whether it also occurs in other Hispanic cohorts, we screened 229 cancer Diana Torres and Muhammad U. Rashid contributed equally to this work.

If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2*1100delC should be ∼5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be ∼9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2*1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (Ptrend = 0.0003) and Finland (Ptrend = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2*1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2*1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2*1100delC and other moderate penetrance alleles in women with a family history of breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):230–4)

The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1416–21)

Background: The Breast Cancer Association Consortium (BCAC) is an international collaboration that was established to provide large sample sizes for examining genetic associations. We conducted combined analyses on all single-nucleotide polymorphisms (SNPs) whose associations with breast cancer have been investigated by at least three participating groups. Methods: Data from up to 12 studies were pooled for each SNP ( ADH1C I350V, AURKA F31I, BRCA2 N372H, CASP8 D302H, ERCC2 D312N, IGFBP3 −202 c > a , LIG4 D501D, PGR V660L, SOD2 V16A, TGFB1 L10P, TP53 R72P, XRCC1 R399Q, XRCC2 R188H, XRCC3 T241M, XRCC3 5′ UTR, and XRCC3 IVS7-14). Genotype frequencies in case and control subjects were compared, and genotype-specific odds ratios for the risk of breast cancer in heterozygotes and homozygotes for the rare allele compared with homozygotes for the common allele were estimated with logistic regression. Statistical tests were two-sided. Results: The total number of subjects for analysis of each SNP ranged from 12 013 to 31 595. For five SNPs— CASP8 D302H, IGFBP3 −202 c > a , PGR V660L, SOD2 V16A, and TGFB1 L10P—the associations with breast cancer were of borderline statistical significance ( P = .016, .060, .047, .056, and .0088 respectively). The remaining 11 SNPs were not associated with breast cancer risk; genotype-specific odds ratios were close to unity. There was some evidence for between-study heterogeneity ( P

CHEK2 *1100delC is associated with a twofold increased breast cancer risk. This was shown in a collaborative analysis of European populations, but not in other populations from Europe and the US. Accordingly, there is a need to clarify the role of CHEK2 *1100delC in breast cancer. We established its prevalence in two German populations GENICA (Northrhine-Westphalia, n = 724) and KORA (Bavaria, n = 600) and in women with breast cancer. The latter included cases ( n = 688) from the GENICA breast cancer case-control study, patients with early-onset breast cancer ( n = 86) and patients with familial breast cancer ( n = 71). The latter patient groups were previously investigated for BRCA1/2 -mutations and tested negative. Mutation analysis was performed by combined PCR/DHPLC methodology. CHEK2 *1100delC was found in 0.9% of GENICA controls and was absent in the KORA controls indicating a significant difference between the two populations ( P = 0.03). The frequency of CHEK2 *1100delC in age-matched cases of the GENICA collection was 0.8% and thus not different from controls (OR 0.88, 95% CI 0.21–3.50). In patients with early-onset disease CHEK2 *1100delC was found at a frequency of 2.3% referring to an increased breast cancer risk of 2.56 (95% CI 0.25–14.58). In patients with familial disease the frequency was 1.4% referring to an increased risk of 1.53 (95% CI 0.03–12.93). Our data showed variations in CHEK2 *1100delC prevalence within German populations suggesting possible inaccuracies in breast cancer risk assessments from non population-based studies. In patients with a high-risk profile however, CHEK2 *1100delC was indicative for this risk and highest for early-onset breast cancer.

BackgroundLess than 20% of Pakistani women with early-onset or familial breast/ovarian cancer harbor germ line mutations in the high-penetrance genesBRCA1,BRCA2andTP53. Thus, mutations in other genes confer genetic susceptibility to breast cancer, of whichCHEK2is a plausible candidate.CHEK2encodes a checkpoint kinase, involved in response to DNA damage.MethodsIn the present study we assessed the prevalence ofCHEK2germ line mutations in 145BRCA1/2-negative early-onset and familial breast/ovarian cancer patients from Pakistan (Group 1). Mutation analysis of the completeCHEK2coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments.ResultsTwo potentially deleterious missense mutations, c.275C>G (p.P92R) and c.1216C>T, (p.R406C), were identified (1.4%). The c.275C>G mutation is novel and has not been described in other populations. It was detected in a 30-year-old breast cancer patient with a family history of breast and multiple other cancers. The c.1216C>T mutation was found in a 34-year-old ovarian cancer patient from a family with two breast cancer cases. Both mutations were not detected in 229 recently recruitedBRCA1/2-negative high risk patients (Group 2).ConclusionOur findings suggest thatCHEK2mutations may not contribute significantly to breast/ovarian cancer risk in Pakistani women.