Low-penetrance Breast Cancer Susceptibility Genes Research Articles

Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing.

Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes

BackgroundRecent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined.MethodsWe applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence.ResultsFirst, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk.ConclusionThis study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.

PALB2—new breast-cancer susceptibility gene

PALB2 (PArtner and Localiser of BRCA2) has been identified as a low penetrance breast-cancer susceptibility gene (Nat Genet published online Dec 31, 2006; DOI:10.1038/ng1959). “We estimate that faults in the PALB2 gene contribute to around 100 cases of breast cancer in the UK each year”, says lead author Nazneen Rahman (Institute of Cancer Research, Sutton, UK).

Inconsistent Association Between the STK15 F31I Genetic Polymorphism and Breast Cancer Risk

STK15 may be a low-penetrance breast cancer susceptibility gene, and several reports suggest that women who are homozygous for the polymorphic variant F31I have an increased risk of breast cancer. To evaluate this potential breast cancer allele, we genotyped 507 patients with two primary breast cancers and 875 population-based control subjects for the STK15 F31I polymorphism. All statistical tests were two-sided. The Ile/Ile homozygous genotype was not associated with an increased risk in white women of British descent. The odds ratio for developing two primary breast cancers) in Ile/Ile homozygotes was 0.63 (95% confidence interval [CI] = 0.34 to 1.13), which corresponds to an odds ratio of 0.79 (95% CI = 0.58 to 1.06) for a first primary breast cancer. A meta-analysis of this study and other published studies showed statistically significant heterogeneity in the odds ratio estimates (P<.001). This heterogeneity could reflect either population-specific linkage disequilibrium with a functional variant or artifacts such as population stratification or publication bias.

High-throughput genomic technology in research and clinical management of breast cancer. Evolving landscape of genetic epidemiological studies

Candidate polymorphism-based genetic epidemiological studies have yielded little success in the search for low-penetrance breast cancer susceptibility genes. The lack of progress is partially due to insufficient coverage of genomic regions with genetic markers, as well as economic constraints, limiting both the number of genetic targets and the number of individuals being studied. Recent rapid advances in high-throughput genotyping technology and our understanding of genetic variation patterns across the human genome are now revolutionizing the way in which genetic epidemiological studies are being designed and conducted. Genetic epidemiological studies are quickly progressing from candidate gene studies to comprehensive pathway investigation and, further, to genomic epidemiological studies where the whole human genome is being interrogated to identify susceptibility alleles. This paper reviews the evolving approaches in the search for low-penetrance breast cancer susceptibility gene variants and discusses their potential promises and pitfalls.

FANCD2 associated with sporadic breast cancer risk

Several components of the Fanconi anaemia (FA) family of proteins allow the formation of the DNA repair complex foci formed by proteins such as BRCA1/2 and RAD51. Because the genes that participate in the DNA repair pathway have been described as low-penetrance breast cancer susceptibility genes, we postulated that variants in FA genes could also be associated with sporadic breast cancer risk. We studied seven SNPs in FANCA, FANCL and FANCD2 in a total of 897 consecutive and non-related sporadic breast cancer cases and 1033 unaffected controls from the Spanish population. We observed a statistically significant association with sporadic breast cancer for the variant rs2272125 (L1366L) located on FANCD2 (OR per allele=1.35; 95% C.I. 1.09-1.67; P=0.005). Both haplotype and diplotype analyses confirmed this association, where one haplotype and pooled diplotypes carrying it were associated with more than 4-fold risk (P=0.007 and P=0.006, respectively). Screening for potential causal variants in FANCD2 was performed, detecting one in the putative promoter region, which is located in a phylogenetically conserved motif with consensus binding sites for some transcriptional factors, suggesting a functional implication. Our data indicate that a relationship between FANCD2 and sporadic breast cancer risk may exist.

Interaction between CHEK2 *1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study

The allele CHEK2*1100delC doubles the risk of breast cancer in unselected women, but could confer a greater risk in women with a family history of the disease, particularly of bilateral breast cancer. Our aim was to measure the risk of breast cancer in relatives of women with bilateral breast cancer who were carriers of this allele. A population-based series of 469 bilateral breast cancer cases ascertained through English cancer registries were genotyped for CHEK2*1100delC. Standardised incidence ratios (SIRs) and cumulative risks were calculated for breast cancer, prostate cancer, and all other cancers in the first-degree relatives of carriers and non-carriers. The relatives of bilateral cases who were wild-type for CHEK2 had three times the population risk of female breast cancer (145 cases: SIR 3.48 (95% CI 2.96-4.09), twice the risk of prostate cancer (34 cases: SIR 2.41, 1.67-3.36) and a large excess of male breast cancer (five cases: SIR 15.06, 4.92-35.36). Relatives of those who were carriers of CHEK2*1100delC had a substantially higher risk of breast cancer (eight cases: SIR 12.11, 5.23-23.88) and possibly prostate cancer (two cases: SIR 9.87, 1.20-35.67). These data suggest a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. In women with a family history of bilateral disease, CHEK2*1100delC confers a high lifetime risk and might be useful for predictive testing. Bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast-cancer genes.

No increased susceptibility to breast cancer from combined CHEK2 1100delC genotype and the HLA class III region risk factors

CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al. The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 2003, 12, 2311–2319] and tested whether it interacted with 1100delC mutation. The CHEK2 1100delC mutation was analysed in the same series of patients and controls as in the HLA breast cancer study. In 962 unselected breast cancer patients, the 1100delC mutation was observed in 2.9% and in 367 controls in 1.4% (NS). The highest 1100delC frequency occurred in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low genetic risk patients (2.4%, P trend 0.029). In HLA risk haplotype carriers no increased breast cancer risk was observed in the presence of 1100delC mutation. Patients more often had one than both genetic risk factors. The 1100delC mutation and the HLA risk haplotype confer increased breast cancer risks, but an interactive effect on breast cancer between both factors is unlikely. In contrast, the effect of 1100delC mutation on breast cancer risk was limited to individuals without HLA risk haplotype, suggesting a mutual excluding effect between these risk factors.

Increased CHEK2 1100delC genotype frequency (also) in unselected breast cancer patients

9536 Background. CHEK2 was recently identified as a low-penetrance breast cancer susceptibility gene, with an increased genotype frequency of the 1100delC variant in familial cases without detectable BRCA1/2 mutations (4.2–5.5%) compared to controls (1.1–1.4%) in 2 studies. No difference in genotype frequency of the variant was observed between unselected breast cancer cases (0.3–2.0%) and controls in 3 different studies. This could be due to lack of power of the individual studies. Methods. The 1100delC variant was studied in 962 unselected breast cancer cases and 367 controls (spouses of the unselected patients) and in familial breast cancer cases with (n=75) and without (n=288) BRCA1/2 mutations. The unselected breast cancer cases were assigned to ‘high’, ‘moderate’ or ‘low’ genetic risk groups, based on age at diagnosis, bilaterality of breast cancer, number of first degree relatives with breast cancer, and co-occurrence of ovarian cancer and male breast cancer in the family. In addition, the data of the published studies and the present one were combined. Results. In unselected breast cancer patients, the variant was observed in 2.9% and in controls in 1.4% (NS). After stratifying the patients according to genetic risk, the frequency was highest in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low-risk patients (2.4%), P-value for trend <0.05. In 288 familial cases without BRCA1/2 mutations, 6.3% carried the variant, this is higher than in controls (P-value <0.001). None of the familial cases with a BRCA1/2 mutation had the variant. The pooled analysis revealed an association with the 1100delC variant in unselected breast cancer cases (OR=2.25, P-value <0.0005) and in familial cases without BRCA1/2 mutations (OR=5.09, P-value <0.0001). Conclusion. Apart from an increased 1100delC genotype frequency in familial breast cancer cases without BRCA1/2 mutations, the genotype frequency of the CHEK2 1100delC variant increased with assumed genetic risk in unselected breast cancer cases. The pooled analysis revealed an increased 1100delC genotype frequency in unselected breast cancer cases. No significant financial relationships to disclose.

Increased CHEK2 1100delC genotype frequency (also) in unselected breast cancer patients

9536 Background. CHEK2 was recently identified as a low-penetrance breast cancer susceptibility gene, with an increased genotype frequency of the 1100delC variant in familial cases without detectable BRCA1/2 mutations (4.2–5.5%) compared to controls (1.1–1.4%) in 2 studies. No difference in genotype frequency of the variant was observed between unselected breast cancer cases (0.3–2.0%) and controls in 3 different studies. This could be due to lack of power of the individual studies. Methods. The 1100delC variant was studied in 962 unselected breast cancer cases and 367 controls (spouses of the unselected patients) and in familial breast cancer cases with (n=75) and without (n=288) BRCA1/2 mutations. The unselected breast cancer cases were assigned to ‘high’, ‘moderate’ or ‘low’ genetic risk groups, based on age at diagnosis, bilaterality of breast cancer, number of first degree relatives with breast cancer, and co-occurrence of ovarian cancer and male breast cancer in the family. In addition, the data of the published studies and the present one were combined. Results. In unselected breast cancer patients, the variant was observed in 2.9% and in controls in 1.4% (NS). After stratifying the patients according to genetic risk, the frequency was highest in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low-risk patients (2.4%), P-value for trend <0.05. In 288 familial cases without BRCA1/2 mutations, 6.3% carried the variant, this is higher than in controls (P-value <0.001). None of the familial cases with a BRCA1/2 mutation had the variant. The pooled analysis revealed an association with the 1100delC variant in unselected breast cancer cases (OR=2.25, P-value <0.0005) and in familial cases without BRCA1/2 mutations (OR=5.09, P-value <0.0001). Conclusion. Apart from an increased 1100delC genotype frequency in familial breast cancer cases without BRCA1/2 mutations, the genotype frequency of the CHEK2 1100delC variant increased with assumed genetic risk in unselected breast cancer cases. The pooled analysis revealed an increased 1100delC genotype frequency in unselected breast cancer cases. No significant financial relationships to disclose.

Recent advances in breast cancer biology.

Developments in breast cancer biology over the last year have brought molecular medicine closer to the clinic. Within the past year, two major advances have taken place. First, microarray-based expression profiling has shown promise with the preliminary demonstration that clustering techniques can predict clinical outcome in lymphoma, pediatric leukemia, and breast cancer. Data in breast cancer have demonstrated the ability of microarray-based expression profiling to detect tumor cells in peripheral blood samples, to predict chemotherapy responses in fine-needle aspiration samples in neoadjuvant chemotherapy, and, most importantly, to predict disease-free survival and overall survival from profiles in breast cancer surgical specimens. Second, in breast cancer genetics, CHEK2 was identified as one of what are likely to be many low-penetrance breast cancer susceptibility genes. These studies demonstrate the transition of basic biologic research to clinical application.

Mammary tumor induction and premature ovarian failure in ApcMin mice are not enhanced by Brca2 deficiency.

Inherited BRCA2 mutations predispose individuals to breast cancer and increase risk at other sites. Recent studies have suggested a role for the APC I1307K allele as a low-penetrance breast cancer susceptibility gene that enhances the phenotypic effects of BRCA1 and BRCA2 mutations. To model the consequences of inheriting mutant alleles of the BRCA2 and APC tumor suppressor genes, we examined tumor outcome in C57BL/6 mice with mutations in the Brca2 and Apc genes. We hypothesized that if the Brca2 and Apc genes were interacting to influence mammary tumor susceptibility, then mammary tumor incidence and/or multiplicity would be altered in mice that had inherited mutations in both genes. Female and male offspring treated with a single IP injection of 50 mg/kg N-ethyl-N-nitrosourea (ENU) at 35 days of age developed mammary adenoacanthomas by 100 days of age. The female Apc-mutant and Brca2/Apc double-mutant progeny had mean mammary tumor multiplicities of 6.7+/-2.8 and 7.2+/-2.7, respectively, compared to wild-type and Brca2-mutant females, which had mean mammary tumor multiplicities of 0.1+/-0.4 and 0.3+/-0.5, respectively. Female ENU-treated Apc-mutant and Brca2/Apc double heterozygotes were also susceptible to premature ovarian failure. Thus, the inheritance of an Apc mutation predisposes ENU-treated female and male mice to mammary tumors and, in the case of female mice, to ovarian failure. These results indicate that mammary tumor development in Apc-mutant mice can progress independently of ovarian hormones. The Apc mutation-driven phenotypes were not modified by mutation of Brca2, perhaps because Brca2 acts in a hormonally dependent pathway of mammary carcinogenesis.