BRCA1 Polymorphisms Research Articles

Strong association of single nucleotide polymorphisms in BRCA1, ATM, and CHEK2 with breast cancer susceptibility in a sub-population of Iranian women.

Breast cancer (BC) is the most prevalent malignancy in females worldwide. Mutations in the DNA repair pathway genes contribute to a significant increase in BC risk. The present study aimed to assess the frequency of polymorphisms in BRCA1, ATM, and CHEK2 genes and their association with BC susceptibility in the Kurdish population from the West of Iran. In the present case-control study, the distribution of single nucleotide polymorphisms (SNPs) in CHEK2 (rs17879961), ATM (rs28904921), and BRCA1 (rs80357906, rs1555576855, rs1555576858, and rs397509247) genes were investigated in 335 BC cases and 354 healthy-matched controls by Taqman allelic discrimination assay. The chi-square goodness-of-fit test was employed for the assessment of Hardy-Weinberg Equation. Relative risk and odds ratios were calculated based on the Koopman asymptotic score and the Baptista-Pike method, respectively. Also, the sensitivity and specificity of each polymorphism were assessed using the Wilson-Brown test and a P-value < 0.05 indicating significant differences between the two groups in all assessments. Data showed there was a strong association between rs397509247 (OR = 7.53, 95% CI 1.88-90.91, p = 0.004), rs1555576858 (OR = 10.53, 95% CI 0.01-0.51, p = 0.0005), and rs80357906 (OR = 6.33, 95% CI 0.05-0.043, p < 0.0001) in BRCA1 gene and rs17879961 (OR = 3.52, 95% CI 0.084-0.946, p = 0.02) in CHEK2 gene, with BC risk in the population of interest. Among these, rs28904921 in ATM gene demonstrated the strongest association (OR = 72.66, 95% CI 0.007-0.214, p < 0.0001). This suggests that these SNPs, particularly rs28904921, are significantly associated with an increased risk of BC in the studied population. Our results indicated that BRCA1, ATM, and CHEK2 polymorphisms have a high frequency in the Iranian breast cancer population, with some mutant allele frequencies being much higher than those reported in other populations. We have also provided a simple, multiplex, rapid, and accurate genotyping assay that is useful in clinical settings.

BRCA2 Polymorphisms and Breast Cancer Susceptibility: a Multi-Tools Bioinformatics Approach.

The main focus of this investigation is to identify deleterious single nucleotide polymorphisms (SNPs) located in the BRCA2 gene through in silico approach, thereby,providing an understanding of potential consequences regarding the susceptibility to breast cancer. The GenomAD database was used to identify SNPs. To determine the potential adverse consequences, our study employed various prediction tools, including SIFT, PolyPhen, PredictSNP, SNAP2, PhD-SNP, and ClinVar. The pathogenicity associated with the deleterious snSNPs was evaluated bu MutPred and Fathmm. Additionally, I-Mutant and MuPro were used to assess the stability, followed by conservation and protein-protein interaction analysis using robust computational tools. The 3D structure of BRCA2 protein was generated by SwissModel, followed by validation using PROCHECK and Errat. The GenomAD database was used to identify a total of 7, 921 SNPs, including 1940 missense SNPs. A set of 69 SNPs predicted by consensus to be damaging across all platforms was identified. Mutpred and Fathmm identified 48 and 38 SNPs, respectively to be associated with cancer. While I- Mutant and MuPro assays suggested 22 SNPs to decrease protein stability. Additionally, these 22 SNPs reside within highly conserved regions of the BRCA2 protein. Domain analysis, utilizing InterPro, pinpointed 18 deleterious mutations within crucial DNA binding domains and one in the BRC repeat region. This study establishes a foundation for future experimental validations and the creation of breast cancer-targeted treatment approaches.

Association between Single Nucleotide Polymorphisms in Monoamine Oxidase and the Severity of Addiction to Betel Quid.

Betel quid (BQ) is the fourth most popular psychoactive substance in the world, and BQ use disorder (BUD) is prevalent in Asian countries. Although the mechanisms underlying BUD remain unclear, studies have reported influences from monoamine oxidase inhibitor. We enrolled 50 patients with BUD and assessed their BQ consumption habits, emotional conditions, and the clinical severity of addiction-assessed using the Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] (DSM-5) criteria, Substance Use Severity Rating Scale, and Yale-Brown Obsessive Compulsive Disorder Rating Scale for BQ. Patients were categorized into the severe group when showing six or more symptoms defined by DSM-5. A genome-wide association study was conducted for single nucleotide polymorphisms in BRCA1, COL9A1, NOTCH1, HSPA13, FAT1, and MAOA by using patients' blood samples. More severe BUD symptoms were associated with younger age of using BQ and poor oral hygiene and with severe craving for and more anxiety toward BQ use. The MAOA rs5953210 polymorphism was significantly associated with severe BUD (odds ratio, 6.43; 95% confidence interval, 5.12-7.74; p < 0.01) and might contribute to BQ-associated cancer risk. Further studies are required to investigate the addictive properties of BQ and the development of novel diagnostic tools and pharmacotherapeutic alternatives to BUD treatment.

Role of Single Nucleotide Polymorphisms in BRCA1 and BRCA2 Genes Relative to Previous Studies in Pakistan in the Prognosis of Breast Cancer

Breast cancer is a complex disease characterized by a myriad of genetic alterations. Single nucleotide polymorphisms are particularly relevant due to small allelic variations. BRCA1 and BRCA2 genes are notably associated with inherited breast and ovarian cancers. Alterations in other genes were also identified. Mutations in BRCA1 and BRCA2 tumor suppressor genes play a significant role in development. Studies in the Pakistani population revealed significant differences in gene mutations. In 31 families, 8 had male and 23 had female breast cancer, substantial findings were observed. The analysis encompassed full coding sites of these genetic variations. Among eight families with male BC, changes were detected in 2 BRCA1 and 4 BRCA2 genes. Additionally, eight alterations were noted in 23 females from site-specific families, with 4 in BRCA1 and 4 in BRCA2. These findings underscore the importance of genetic variations, especially in the BRCA1 and BRCA2 genes, in the context of breast cancer susceptibility within diverse populations.

ASSOCIATION OF BRCA2 POLYMORPHISM TO SCHIZOPHRENIA IN SAARC COUNTRIES: A SYSTEMATIC REVIEW

Schizophrenia is a complex disorder of polygenic inheritance with a lifetime prevalence of 5-10%. An external study showed that the role of BRCA2 is needed for the normal neurogenesis in mice. Another recent meta-analysis showed that genetic polymorphism of BRCA2 could increase susceptibility to schizophrenia. This study conducted the possible relationship between BRCA2 polymorphisms in schizophrenic patients in participating SAARC (South Asian Association of Regional Corporation) countries (Pakistan, India, Sri Lanka, Nepal, Bhutan, Maldives, Bangladesh and Afghanistan). While conducting this review, we collected data from eight SAARC countries. We collected that articles which were published from 1997 to 2020, using PubMed, and NCBI databases to amplify data about the association of BRCA2 polymorphism to schizophrenia patients in SAARC countries. Totally 24 studies were included in this review. We have additionally reviewed fewer studies from other than SAARC countries to support the evidence concerning this issue. Major studies from each SAARC country have identified novel and pathogenic mutations in BRCA2 but have not assessed on BRCA2 polymorphism within schizophrenia patients. Yet, there is no conclusive evidence found regarding the association of BRCA2 polymorphism to schizophrenia.

Association between BRCA1 polymorphisms rs799917 and rs1799966 and breast cancer risk: a meta-analysis.

BackgroundSeveral studies have reported correlations between BRCA1 polymorphisms rs799917 and rs1799966 with the risk of breast cancer (BC). However, this relationship remains controversial.MethodsWe conducted a meta-analysis of seven studies to assess the associations between BRCA1 rs799917 and rs1799966 and BC risk, with the aim of more accurately determining the potential correlation. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the correlation of rs799917 and rs1799966 with BC risk.ResultsThere was no overall correlation between BRCA1 rs799917 and BC risk (TT vs CC: OR = 0.87, 95% CI = 0.66–1.16; CT vs CC: OR = 1.02, 95% CI = 0.89–1.15; dominant model: OR = 0.99, 95% CI = 0.88–1.11; recessive model: OR = 0.87, 95% CI = 0.65–1.16). Subgroup analysis by ethnicity also revealed no significant correlation between rs799917 and BC risk in either Asians or Caucasians. There was also no significant association between BRCA1 rs1799966 and BC risk (GG vs AA: OR = 0.70, 95% CI = 0.33–1.47; AG vs AA: OR = 0.68, 95% CI = 0.35–1.30; dominant model: OR = 0.76, 95% CI = 0.49–1.06; recessive model: OR = 0.82, 95% CI = 0.49–1.36).ConclusionBRCA1polymorphisms rs799917 and rs1799966 were not significantly associated with BC risk in this meta-analysis.

Meta-Analysis of BRCA1 Polymorphisms and Breast Cancer Susceptibility.

BRCA1 codes for a tumor suppressor protein involved in DNA repair. Based on the role of single nucleotide polymorphisms (SNPs) in the modification of gene expression and function and the existence of certain SNPs within 3-untranslated region of BRCA1 with the ability to change binding sites for mirRNAs, several association studies have been designed to explore the significance of SNPs within BRCA1 gene in conferring breast cancer (BC) risk. This study aims to assess the relationship between BRCA1 SNPs and BC using meta-analysis. To conduct a meta-analysis for retrieving case-control studies on the associations between the rs11655505, rs1799966, rs3737559, rs1799950, rs799917 and rs16941 BRCA1 polymorphisms and BC. The pooled odds ratios and its 95% confidence intervals were measured using fixed and random model to define the association between these polymorphisms and BC risk. No significant association was found for any of these polymorphisms and BC risk in the allelic, homozygote, dominant or recessive models. Overall, our study implies that the mentioned polymorphisms are not associated with BC risk. However, our study did not exclude the possible contribution of other SNPs within this gene in BC nor substantial contribution of multiple variants within this gene in conferring BC risk. Key words: BRCA1 - breast cancer - meta-analysis.

The association between BRCA1 gene polymorphism and cancer risk: a meta-analysis.

Many studies have reported that BRCA1 polymorphisms are associated with cancer risk, but the results remain controversial. The purpose of this meta-analysis is to evaluate the relationship between BRCA1 polymorphisms (rs799917, rs1799950, rs1799966, or rs16941) and cancer risk. Relevant studies were identified via a systematic search of the PubMed, Embase, and Web of Science databases up to July 31, 2017. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to examine the strength of the associations. Thirty-five studies published in 19 publications involving 28,094 cases and 50,657 controls were included in this meta-analysis. There was no obvious association between rs799917, rs1799966, or rs16941 polymorphisms and overall cancer risk in any genetic models. However, subgroup analyses revealed that the rs799917 polymorphism could decrease the risk of cervical cancer, esophageal squamous cell carcinoma (ESCC), gastric cancer, and non-Hodgkin lymphoma (NHL) among Asian populations in one or more genetic models and that rs16941 could increase overall cancer risk among Caucasian populations in the homozygote and recessive models. Our meta-analysis also indicated that rs1799950 could decrease the breast cancer (BC) risk among Caucasian populations in the homozygote and recessive models. In summary, our results suggest that BRCA1 polymorphisms may play an important role in the etiology of cancer. However, due to the limited number of studies, these findings should be confirmed by new studies with larger sample sizes that address various types of cancer.

Polymorphism rs144848 in BRCA2 may Reduce Lung Cancer Risk in Women: A Case-Control Study in Southeast China

Whereas lung cancer incidence among men has declined in recent years, the incidence rate among women has increased rapidly. Sex could affect DNA repair capacity. Although BRCA2 is important in DNA repair, few data are available on the association between BRCA2 polymorphisms and lung cancer in women. Therefore, we investigated this in a case-control study among Chinese women. We enrolled 226 women with lung cancer and 269 age-matched healthy controls in our study. Polymorphisms studied were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Unconditional logistic regression showed no association between rs1799943 or rs1799944 and cancer risk. However, the AC and CC genotypes of rs144848 were significantly associated with reduced risk after adjustment for age and education, with adjusted odds ratios (ORs) of 0.66 (95% confidence interval [CI] 0.45-0.97) and 0.37 (95% CI 0.16-0.78), respectively. The adjusted OR of carriers with the C allele was 0.62 (95% CI 0.44-0.81) compared with the A allele. The rs144848 mutation may have a protective effect against lung cancer among women.

Possible association of the BRCA2 gene C5972T variant with gastric cancer: a study on Polish population.

Gastric cancer (GC) belongs to a group of cancers linked to BRCA2 gene mutations and observed in patients with a family history of breast and ovarian cancers. A common variant allele (C5972T) observed in the BRCA2 gene in the Polish population is associated with an increased risk of breast cancer. The objective of the study was to assess a relationship between the BRCA2 C5972T variant and GC. A total of 380 patients with GC (234 men and 146 women; mean age, 59.0 ±12.8 years) and 380 sex- and age-matched healthy individuals (234 men and 146 women; mean age, 59.0 ±12.9 years) were included in this retrospective study. Polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) was used to detect the BRCA2 C5972T variant. We compared the frequency of BRCA2 allele carriers among patients and controls. We also compared selected clinical and pathological features between allele carriers and noncarriers among patients with GC. The BRCA2 C5972T variant was observed in 28 patients with GC (7.4%) and in 18 controls (4.7%) (P = 0.17). The odds ratio [OR] for GC in allele carriers was 1.59 (95% confidence interval [CI], 0.87-2.94). A comparison of selected clinical and pathological features between carriers and noncarriers did not show any significant differences. The analysis of a family history showed a trend for an increased risk of breast or ovarian cancer in the families of patients with GC carrying the C5972T allele (OR, 2.51; 95% CI, 0.80-7.88, P = 0.11). Our study showed that the C5972T allele is a low-penetrant variant of the BRCA2 gene, which tended to increase the risk of GC. Further research is needed to fully elucidate the role of BRCA2 polymorphisms in GC.

BRCA1 polymorphism in breast cancer patients from Argentina.

Breast cancer is the most common type of cancer in females in Argentina, with an incidence rate similar to that in the USA. However, the contribution of the BRCA1 or BRCA2 mutation in breast cancer incidence has not yet been investigated in Argentina. In order to evaluate which BRCA1 polymorphisms or mutations characterize female breast cancer in Argentina, the current study enrolled 206 females with breast cancer from several hospitals from the southeast of Argentina. A buccal smear sample was obtained in duplicate from each patient and the DNA samples were processed for polymorphism analysis using the single-strand conformational polymorphism technique. The polymorphisms in BRCA1 were investigated using a combination of 15 primers to analyze exons 2, 3, 5, 20 and 11 (including the 11.1 to 11.12 regions). The BRCA1 mutations were confirmed by direct sequencing. Samples were successfully examined from 154 females and, among these, 16 mutations were identified in the BRCA1 gene representing 13.9% of the samples analyzed. One patient was identified with a polymorphism in exon 2 (0.86%), four in exon 20 (3.48%), four in exon 11.3 (3.48%), one in exon 11.7 (0.86%), two in exon 11.8 (1.74%), one in exon 11.10 (0.86%) and one in exon 11.11 (0.86%). The most prevalent alteration in BRCA1 was located in exon 11 (11 out of 16 patients; 68.75%). The objective of our next study is to evaluate the prevalence of mutations in the BRCA2 gene and analyze the BRCA1 gene in the healthy relatives of BRCA1 mutation carriers.

Abstract 259: Analysis of Q356R polymorphism in BRCA1 gene of Jamaican ovarian cancer patients

Abstract Studies in different populations worldwide have demonstrated that germ line mutations in BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancers. In addition, polymorphic variants in these genes have been implicated in an increased breast and ovarian cancer risks. Indeed, it has been known that the germ line mutations in the BRCA1 gene can strikingly increase the life time risk of ovarian cancer by 15-30%. Among BRCA mutations the Q356R polymorphism is a variant causing the amino acid switch from glutamine (Q) to arginine (R) in the putative functional domain of the protein. The present study was carried out to assess the frequency of Q356R polymorphism in BRCA1 gene among Jamaican ovarian cancer patients, since there is lack of data for this population pertaining to this polymorphism. For this analysis the ovarian cancer samples were collected from 23 Jamaican women with 21 benign and 2 malignant tumors. The genomic DNA of cancer samples was extracted and the purity of the DNA was analyzed prior to polymorphism determination. Polymerase chain reaction was performed using the DNA of cancer patients as a template with the primers specific for BRCA1 gene. The Q356R polymorphism status within BRCA1 gene was analyzed through restriction enzyme digestion. The undigested or partially digested arginine (R) coding allele was seen as a band at 211 bp of length, whereas the glutamine (Q) alleles represented by the digestion products were seen at 134 and 77 bp length. The incomplete digestion of R allele indicates a high risk and the digested Q alleles signify the medium or low risk category. Genotyping analyses were performed in all 23 cases using the restriction fragment length analysis. Out of 23 samples, 22 showed digestion fragments of 134 bp and 77 bp, remaining one was partially digested and showed a 211 bp band. Among the samples analyzed the percentage of R allele was (4.34%) and the Q alleles were (95.65%). Our current analysis indicates that the QR genotype frequency for Jamaican women with non-malignant ovarian tumors is only 0.04. However, the QR genotype frequency for Jamaican women with malignant ovarian cancer appears to be 0.5. Thus, functional polymorphisms in BRCA1 might be postulated to be more likely affecting ovarian cancer risk than those in BRCA2. Though the frequency of R allele is only 4.3% in Jamaican population, this polymorphism seems to correlate very well with the malignant status of the tumor. Therefore, patients with this polymorphism can be selected for more aggressive surveillance and therapeutic options. The results presented here are from a small population of Jamaican women with ovarian tumors but further validation of this conclusion can be obtained by conducting a study with larger population of patients (The authors would like to thank the Royal Dames of Cancer Research Inc., Ft. Lauderdale, FL, for their generous support). Citation Format: Aiyavu Chinnaiyan, Colleen Salmon, Thiagarajan Venkatesan, Arkene Levy, Sivanesan Dhandayuthapani, Appu Rathinavelu. Analysis of Q356R polymorphism in BRCA1 gene of Jamaican ovarian cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 259. doi:10.1158/1538-7445.AM2014-259

Rapid evolution of BRCA1 and BRCA2 in humans and other primates.

BackgroundThe maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers.ResultsTo obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection.ConclusionsWhile mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.

Association of BRCA2 variants with cardiovascular disease in Saudi Arabia.

Abnormalities in the breast cancer tumor suppressor genes (BRCA1 and BRCA2) are associated with breast and ovarian cancer. Recently, two single nucleotide polymorphisms (SNPs; rs11571836 and rs1799943) were identified, both located in untranslated regions of chromosome 13, associated with cardiovascular disease (CVD) in a multi-ethnic population. We examined the association between these BRCA2 polymorphisms and traits of CVD patients from Saudi Arabia. We genotyped rs11571836 and rs1799943 in 159 unrelated CVD patients and 176 healthy controls. The genotype and allele distributions in the overall population revealed a statistically significant association between rs1799943 and CVD (P = 0.01-0.022), whereas no risk association was identified for rs11571836. Additionally, haplotype analysis using both SNPs demonstrated no association between the SNPs and CVD. The genotype distribution of the 2 SNPs in the normal Saudi population deviated significantly (P < 0.000001) from that of the 6 different HapMap populations (CEU, CHB-Han, JPT, YRI, GIH, and MKK), except for the JPT population for rs1799943. This is the first study to examine the association between these SNPs and CVD in a Saudi population. Our results suggest that the increased health risk associated with the rs11571836 genotype is specific to male patients suffering from CVD. Stratification of patients and controls based on gender revealed no association between rs1799943 and the risk of CVD in either gender. These SNPs should be evaluated in larger cohorts in different populations to determine their suitability as screening markers for predicting CVD risk earlier in life to implement necessary preventive measures.

BRCA1 polymorphisms and breast cancer epidemiology in the Western New York Exposures and Breast Cancer (WEB) study

BRCA1 polymorphisms and breast cancer epidemiology in the Western New York Exposures and Breast Cancer (WEB) study

BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan.

BackgroundA large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women.AimTo evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer.MethodsWe investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing.ResultsWe identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05); higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations.ConclusionsConsidering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation.

BRCA1 Polymorphisms and Breast Cancer Epidemiology in the Western New York Exposures and Breast Cancer (WEB) Study

Results of studies for the association of BRCA1 genotypes and haplotypes with sporadic breast cancer have been inconsistent. Therefore, a candidate single nucleotide polymorphism (SNP) approach was used in a breast cancer case-control study to explore genotypes and haplotypes that have the potential to affect protein functions or levels. In a breast cancer case-control study, genotyping of BRCA1 polymorphisms Q356R, D693N, and E1038G was performed on 1,005 cases and 1,765 controls. Unconditional, polytomous logistic regression and χ(2) -tests were used to examine the associations of breast cancer with genotypes and haplotypes. In addition, interactions between genotype and smoking, benign breast disease, family history of breast cancer, body mass index (BMI), alcohol consumption, and hormonal risk factors, hormone receptor status, and breast cancer pathology were calculated also using logistic regression and χ(2) . Although sporadic breast cancer was not associated with BRCA1 genotypes or haplotypes overall or by menopausal status, there was evidence of an interaction between the E1038G BRCA1 genotype, smoking, and BMI among premenopausal women (P for interaction = 0.01 and 0.045, respectively) and between E1038G and D693N BRCA1 genotypes and hormone therapy use among postmenopausal women (P for interaction = 0.01 and 0.02, respectively). There were no other associations found between BRCA1 genotypes and stage, histological grade, or nuclear grade. However, the D693N SNP was associated with the risk of triple negative breast cancer (odds ratio = 2.31 95% confidence interval 1.08-4.93). The BRCA1 variants studied may play a role in the etiology of triple negative breast cancer and may interact with environmental factors such as hormone therapy or smoking and increase sporadic breast cancer risk.

Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined “Complementary Lethality”

A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers. Paradoxically, however, genomic instability can also render tumors vulnerable to therapeutic attack. Thus, targeting DNA repair may induce an intolerable level of DNA damage in tumor cells. BRCA2 mediates homologous recombination repair, and BRCA2 polymorphisms increase cancer risk. However, tumors with BRCA2 mutations respond better to chemotherapy and are associated with improved patient prognosis. Thymidylate synthase (TS) is also involved in DNA maintenance and generates cellular thymidylate. We determined that antisense downregulation of BRCA2 synergistically potentiated drugs with mechanisms of action related to BRCA2 function (cisplatin, melphalan), a phenomenon we named “complementary lethality.” TS knockdown induced complementary lethality to TS-targeting drugs (5-FUdR and pemetrexed) but not DNA cross-linking agents. Combined targeting of BRCA2 and TS induced complementary lethality to both DNA-damaging and TS-targeting agents, thus creating multidrug sensitive tumors. In addition, we demonstrated for the first time that simultaneous downregulation of both targets induced combined complementary lethality to multiple mechanistically different drugs in the same cell population. In this study, we propose and define the concept of “complementary lethality” and show that actively targeting BRCA2 and TS is of potential therapeutic benefit in multidrug treatment of human tumors. This work has contributed to the development of a BRCA2-targeting antisense oligdeoxynucleotide (ASO) “BR-1” which we will test in vivo in combination with our TS-targeting ASO “SARI 83” and attempt early clinical trials in the future.

BRCA1 and BRCA2 unclassified variants and missense polymorphisms in Algerian breast/ovarian cancer families.

Background: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs) (variants with unknown clinical significance) and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis. Methods: We analyzed 101 DNA samples from 79 breast/ovarian cancer families. The approach used is based on BRCA1 and BRCA2 sequence variants screening by SSCP or High-Resolution Melting (HRM) curve analysis followed by direct sequencing. In silico analyses have been performed using different bioinformatics programs to individualize genetics variations that can disrupt the BRCA1 and BRCA2 genes function. Results: Among 80 UVs and polymorphisms detected in BRCA1/2 genes (33 BRCA2 and 47 BRCA2), 31 were new UVs (10 BRCA2 and 21 BRCA2), 7 were rare UVs (4 BRCA2 and 3 BRCA2) and 42 were polymorphic variants (19 BRCA2 and 23 BRCA2). Moreover, 8 new missense UVs identified in this study: two BRCA1 (c.4066C>A/p.Gln1356Lys, c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and six BRCA2 (c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys1290Ser, c.5428G>T/p.Val1810Phe, c.6346C>G/p.His2116Asp and c.9256G>A/p.Gly3086Arg) located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded by PolyPhen2 program and could be pathogenic. In addition, 5 new BRCA2 missense UVs out of six that were found to be damaging by PolyPhen2 program, also were deleterious according to SIFT program. The rare BRCA2 UV c.5332G>A/p.Asp1778Asn was found here for the first time in co-occurrence in trans with the deleterious BRCA1 mutation c.798_799delTT/p.Ser267LysfsX19 in young breast cancer patient. Moreover, 10 new identified intronic variants with unknown clinical significance (3 BRCA1 and 7 BRCA2) in the present study, could be considered as benign, because GeneSplicer, SpliceSiteFinder and MaxEntScan prediction programs show no splice site alteration for these variants. Several missense polymorphisms of BRCA1 c.2612C>T/p.Pro871Leu, c.3548A>G/p.Lys1183Arg, c.4837A>G/p.Ser1613Gly and BRCA2 c.865A>C/p.Asn289His, c.1114A>C/p.Asn372His, c.2971A>G/p.Asn991Asp, c.7150C>A/p.Gly2384Lys have been identified with high frequency in patients who were tested negative for BRCA1 and BRCA2 mutations. These missense polymorphisms could have a role as susceptibility breast cancer markers in Algerian breast/ovarian cancer families where pathological BRCA1 and BRCA2 mutations were not present. Conclusions: For the first time, UVs and missense polymorphisms in BRCA1 and BRCA2 genes have been identified in Algerian breast/ovarian cancer families. Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs and common polymorphisms detected in our present work is on going in a larger study.

Correction: Missense Polymorphisms in BRCA1 and BRCA2 and Risk of Breast and Ovarian Cancer

In this article (1), which was published in the August 2009 issue of Cancer Epidemiology, Biomarkers &amp; Prevention, the authors reported risk of breast and ovarian cancer by BRCA2 Tyr1915Met. The BRCA2 variant Tyr1915Met should not be “Tyr” but Thr1915Met.