BRCA1 Interacting Protein C-terminal Helicase Research Articles

Multimolecular characteristics and role of BRCA1 interacting protein C-terminal helicase 1 (BRIP1) in human tumors: a pan-cancer analysis

BackgroundThe aberrant expression of BRIP1 was associated with several cancers; however, the panoramic picture of BRIP1 in human tumors remains unclear. This study aims to explore the pan-cancerous picture of the expression of BRIP1 across 33 human cancers.MethodsBased on the data from TCGA and GTEx, a series of bioinformatic analyses were applied to systematically explore the genetic landscape and biologic function of BRIP1 in 33 human tumors.ResultsWe observed prognosis-related differential BRIP1 expressions between various carcinomas and the corresponding normal tissues. “Basal transcription factors,” “homologous recombination,” “nucleotide excision repair,” and DNA metabolism pathways may play a role in the functional mechanisms of BRIP1. Patients with uterine corpus endometrial carcinoma presented with the highest alteration frequency of BRIP1 (nearly 10%). Single-nucleotide and copy number variations of BRIP1 were noticed in multiple cancers, and the expression of BRIP1 is significantly regulated by copy number variation in breast invasive carcinoma and lung squamous cell carcinoma. BRIP1 expression is negatively correlated with the DNA methylation levels in many tumors and is associated with the activation of apoptosis, cell cycle, DNA damage response, and inhibition of hormone ER and RNS/MARK signaling pathways. Moreover, a positive correlation was observed between BRIP1 expression and the immune infiltration levels of cancer-associated fibroblasts and CD8+ T cells in lung adenocarcinoma.ConclusionOur pan-cancer analysis of BRIP1 provides a valuable resource for understanding the multimolecular characteristics and biological function of BRIP1 across human cancers.

Comparative genomics and selection analysis of Yeonsan Ogye black chicken with whole-genome sequencing.

Yeonsan Ogye (OGYE; Gallus gallus domesticus) is a rare indigenous chicken breed that inhabits the Korean Peninsula. This breed has completely black coloring, including plumage, skin, eyes, beak, and internal organs. Despite these unique morphological characteristics, the population of OGYE has declined without in-depth research into their genome research. Therefore, this study aimed to compare the whole genome of OGYE to 12 other chicken populations, including ancestral breed, commercial breeds, Chinese indigenous breeds, and Korean native chickens. We focused on revealing the selection signature of OGYE, which has occurred through environmental pressures in the Korean Peninsula. Genome-wide selection analysis has identified local adaptation traits, such as egg development, that contribute to fetal viability and innate immune response to prevent viral and microbes infection in OGYE. In particular, SPP1 (Secreted Phosphoprotein 1), HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1), and P2RX4 (Purinergic Receptor P2X 4) could have considerable involvement in egg development and RNASEL (Ribonuclease L), BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1), and TLR4 (Toll-Like Receptor 4) are crucial for the determination of the innate immune response. This study revealed the unique genetic diversity of OGYE at the genome-wide level. Furthermore, we emphasized the sustainable management of genetic resources and formulated breeding strategies for livestock on the Korean Peninsula.

Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene

More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA-mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 (BRIP1) mutation that plays an important role in BRCA1-dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk.

Calycosin stimulates the proliferation of endothelial cells, but not breast cancer cells, via a feedback loop involving RP11-65M17.3, BRIP1 and ERα.

It is widely accepted that estrogen can be replaced by phytoestrogens to treat postmenopausal cardiovascular disease and possibly decrease the risk of breast cancer. However, few studies have investigated the effects of phytoestrogens on vascular endothelial cells (ECs). In the present study, we show that the phytoestrogen calycosin (20 μM) stimulated the proliferation of ECs (HUVECs and HMEC-1) but inhibited the growth of breast cancer cells (BCCs) expressing ERα (MCF-7 and T47D). Here we provide evidence for the presence of a positive feedback loop between ERα and long noncoding RNA RP11-65M17.3 in both normal and cancer cells, and calycosin stimulated this feedback loop in ECs but decreased RP11-65M17.3 expression in BCCs. Subsequently, the calycosin-induced activation of this loop decreased the expression of the target of BRIP1 (BRCA1 interacting protein C-terminal helicase 1), increased the phosphorylation of Akt and ERK1/2, and finally inhibited the cleavage of PARP-1 in ECs. In nude mice bearing MCF-7 xenografts, calycosin did not stimulate tumor growth as strongly as 17β-estradiol. Together, these results suggest that calycosin promotes the proliferation of ECs, and notable inhibits the growth of BCCs. A possible reason for these results is the involvement of a feedback loop between ERα and RP11-65M17.3.

Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells

ObjectivePathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity. MethodsWe engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices. ResultsBRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality. ConclusionsBRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.

Abstract P6-08-31: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) as a cancer susceptibility gene

Abstract Background: Breast cancer is the most common cancer as well as the most common cause of cancer associated deaths in women worldwide. National Comprehensive Cancer Network has detailed criteria for identifying patients at risk for hereditary breast and ovarian cancer syndromes. Many multigene genetic testing panels are in use for screening and prognostication purposes. While pathogenic mutation in BRCA 1 and 2 mutations have been established as risk factors for developing breast cancer, the association of other germ line mutations with breast cancer is less defined. BRCA1 interacting protein C-terminal helicase 1 (BRIP1) influences the DNA repair ability as well as tumor suppressor function of BRCA1 and is associated with increased risk of ovarian cancer. Studies looking at association of BRIP1 mutation with risk of breast cancer have provided conflicting data and currently, BRIP1 is not implicated in causing breast cancer. Methods: We conducted chart review of patients who were referred for genetic testing at the Lipson Cancer Institute/Rochester General Hospital, Rochester, NY and tested positive for BRIP1 mutation alone. Samples were sent to Myriad Genetics for Integrated BRACAnalysis® testing with myRisk® panel looking at 35 genes for mutation. BRIP1 mutations with abnormal protein production and/or function thought to increase risk for ovarian cancer (pathogenic or likely pathogenic) are reported as clinically significant. BRIP1 mutations with currently insufficient data to determine an increased risk are reported as variations of uncertain significance. The panel does not report benign and likely benign mutations. Results: We found nine patients who tested positive for BRIP1 mutation and were negative for other genomic alteration including BRCA1 and BRCA2 mutation (Table 1 and 2). Four patients carried the known high risk BRIP1 mutation and five carried BRIP1 mutations of undetermined significance. One of four patients with known high risk BRIP1 mutations had a personal history but no family history of breast cancer while the remaining three had a family history but no personal history of breast cancer. All five patients with BRIP1 mutations of uncertain significance had both personal and family history of breast cancer. Conclusion: The known high risk BRIP1 mutations are probably not associated with increased risk of breast cancer. However, at least some of the BRIP1 mutations of uncertain significance are likely very significant and associated with increased risk of breast cancer. This association needs to be confirmed in a larger patient population. Table 1: Carriers of BRIP1 variations of uncertain significanceSerial NumberAge at time of screeningPositive BRIP 1 mutation Personal history of breast cancerFamily history of breast cancerAncestry164BRIP1 mutation, c.817A>GYesYesGerman/ Irish278BRIP1 mutation, c. 2220G>TYesYesHolland344BRIP1 mutation, c3237T>GYesYesAfrican430BRIP1 mutation, c.380-17T>AYesYesIrish/ English/ German555BRIP1 mutation, c.139C>GYesYesScottish Table 2: Carriers of high risk BRIP1 mutationsSerial NumberAge at time of screeningPositive BRIP 1 mutation Personal history of breast cancerFamily history of breast cancerAncestry169BRIP1 mutation, c.2255_2256delYesNoItalian/ Hungarian263BRIP1 mutation, c548delNoYesFrench Canadian337BRIP1 mutation, c.1045G>CNoYesDutch460BRIP1 mutation, c.2099T>ANoYesUnknown Citation Format: Mukul Singal, Manasi M Godbole, Kim Povenzano, Beth Elmore, Mehul P Patel. BRCA1 interacting protein C-terminal helicase 1 (BRIP1) as a cancer susceptibility gene [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-31.

Rare BRIP1 Missense Alleles Confer Risk for Ovarian and Breast Cancer.

Germline loss-of-function mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand cross-link (ICL) repair and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants, for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next-generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 patients with ovarian cancer revealed nearly 2% of patients carry a very rare missense variant (minor allele frequency < 0.0001) in BRIP1. This is 3-fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (P < 0.0001, χ 2 test). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair ICL damage. A total of 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 patients with breast and ovarian cancer who underwent panel testing, the combined OR associated with BRIP1 hypomorph or null missense carriers compared with the general population was 2.30 (95% confidence interval, 1.60-3.30; P < 0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants. SIGNIFICANCE: Functional characterization of rare variants of uncertain significance in BRIP1 revealed that 75% demonstrate loss-of-function activity, suggesting rare missense alleles in BRIP1 confer risk for both breast and ovarian cancer.

Association between single nucleotide polymorphism of BRCA1-interacting protein C-terminal helicase 1 and early-onset breast cancer in Uygur and Han women in Xinjiang of China

The study investigated the association between single nucleotide polymorphisms (SNPs) of BRCA1-interacting protein C-terminal helicase 1 (BACH1) gene and early-onset breast cancer in Uygur and Han women in Xinjiang. SNPs of BACH1 gene exons were detected by direct sequencing and snapshot technique in 80 Uygur and 80 Han patients with breast cancer and 240 healthy Uygur and 240 healthy Han women (all younger than 40 years old). In Uygur and Han breast cancer patients, the variant C allele of rs4986764 SNP can reduce the risk of breast cancer. The protective effect of this locus is more obvious in Han breast cancer patients without tumor family history (P = 0.001, OR = 0.079). In Uygur breast cancer patients, the GG genotype of rs4986765 (OR = 5.617) and the G genotypes (AG + GG) in the dominant model (OR = 4.254) and the AG of c.587A > G SNP (OR = 7.590) and G genotypes (AG + GG) in the dominant model (OR = 7.590) significantly increased the risk of breast cancer. However, they did not significantly increase the risk of breast cancer in Han population. The present study demonstrates that the rs4986764 mutation of BACH1 gene may reduce the risk of early-onset breast cancer in Uygur and Han populations in Xinjiang. The protective effect was more obvious in Han population without family history of cancer. The change of rs4986765 and c.587A > G sites both increased the risk of breast cancer for Uygur. However, there was no significant correlation with early-onset breast cancer in Han population.

MiR-21 enhances the protective effect of loperamide on rat cardiomyocytes against hypoxia/reoxygenation, reactive oxygen species production and apoptosis via regulating Akap8 and Bard1 expression.

Effective therapies to reduce ischemia/reperfusion and hypoxia/reoxygenation injury are currently lacking. Furthermore, the effects of loperamide and microRNA (miR)-21 on hypoxia/reoxygenation injury of cardiomyocytes have remained to be elucidated. Therefore, the present study aimed to investigate the effect of loperamide and miR-21 on cardiomyocytes during hypoxia/reoxygenation injury, and to explore the underlying molecular mechanisms. H9c2 rat cardiomyocytes were pre-treated with loperamide prior to hypoxia/reoxygenation. The viability of H9c2 cells was measured with a cell counting kit 8 and apoptosis was detected with an Annexin V-phycoerythrin/7-aminoactinomycin D apoptosis kit. Furthermore, reactive oxygen species were detected with a specific kit. Genes regulated by miR-21 were screened with an mRNA chip and confirmed using reverse-transcription quantitative polymerase chain reaction analysis. The direct targeting relationship of miR-21 with certain mRNAs was then confirmed using a Dual-Luciferase Reporter Assay system. The results indicated that the apoptotic rate and reactive oxygen species levels in rat cardiomyocytes were markedly increased after hypoxia/reoxygenation treatment. Pre-treatment with loperamide significantly protected H9c2 cells against apoptosis and reactive oxygen species production after hypoxia/reoxygenation. The protection was markedly decreased by miR-21 inhibitor and enhanced by miR-21 mimics. Screening for genes associated with cardiomyocyte apoptosis revealed that the relative expression of A-kinase anchoring protein 8 (Akap8) and BRCA1 associated RING domain 1 (Bard1) was consistent with the experimental results on apoptosis and reactive oxygen species. Compared with the group treated by hypoxia/reoxygenation alone, pre-treatment with loperamide markedly decreased the expression of BRCA1-interacting protein C-terminal helicase 1, Akap8 and Bard1 after hypoxia/reoxygenation. The decrease in the expression of Akap8 and Bard1 was markedly attenuated by miR-21 inhibitor and enhanced by miR-21 mimics. miR-21 mimics directly targeted the 3′-untranslated region (UTR) of Akap8 and Bard1 mRNA to thereby decrease their expression. In conclusion, the protection of rat cardiomyocytes against hypoxia/reoxygenation-induced apoptosis and reactive oxygen species production by loperamide was markedly enhanced by miR-21. miR-21 directly targets the 3′-UTR of Akap8 and Bard1 mRNA and enhances the inhibitory effects of loperamide on Akap8 and Bard1 expression in rat cardiomyocytes after hypoxia/reoxygenation.

Genetic testing for hereditary prostate cancer: Current status and limitations.

A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society.

BRCA1, DNA repair associated (BRCA1)- and BRCA1 Interacting Protein C-terminal Helicase 1 (BRIP1)-Mutated Ovarian Epithelial Cells Acquire a Cancer Stem Cell-Like Phenotype and Decreased Sensitivity to Cisplatin and Olaparib in Three Dimensional Spheroid Culture

BRCA1, DNA repair associated (BRCA1)- and BRCA1 Interacting Protein C-terminal Helicase 1 (BRIP1)-Mutated Ovarian Epithelial Cells Acquire a Cancer Stem Cell-Like Phenotype and Decreased Sensitivity to Cisplatin and Olaparib in Three Dimensional Spheroid Culture

Germline genetic variants in men with prostate cancer and one or more additional cancers.

Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of the disease. The aim of the current study was to describe the prevalence of pathogenic germline variants in cancer-predisposing genes in men with prostate cancer and at least 1 additional primary cancer. Using a multigene panel, the authors sequenced germline DNA from 102 men with prostate cancer and at least 1 additional primary cancer who also met ≥1 of the following criteria: 1) age ≤55 years at the time of diagnosis of the first malignancy; 2) rare tumor type or atypical presentation of a common tumor; and/or 3) ≥3 primary malignancies. Cancer family history and clinicopathologic data were independently reviewed by a clinical genetic counselor to determine whether the patient met established criteria for testing for a hereditary cancer syndrome. Sequencing identified approximately 3500 variants. Nine protein-truncating deleterious mutations were found across 6 genes, including BRCA2, ataxia telangiectasia mutated (ATM), mutL homolog 1 (MLH1), BRCA1 interacting protein C-terminal helicase 1 (BRIP1), partner and localizer of BRCA2 (PALB2), and fibroblast growth factor receptor 3 (FGFR3). Likely pathogenic missense variants were identified in checkpoint kinase 2 (CHEK2) and homeobox protein Hox-B13 (HOXB13). In total, 11 of 102 patients (10.8%) were found to have pathogenic or likely pathogenic mutations in cancer-predisposing genes. The majority of these men (64%) did not meet current clinical criteria for germline testing. Men with prostate cancer and at least 1 additional primary cancer are enriched for harboring a germline deleterious mutation in a cancer-predisposing gene that may impact cancer prognosis and treatment, but the majority do not meet current criteria for clinical genetic testing. Cancer 2017;123:3925-32. © 2017 American Cancer Society.

Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair.

Unraveling the molecular mechanisms that regulate the biology of metastasis-competent circulating tumor cells (CTCs) is urgently needed to understand metastasis formation and tumor relapse. Our group previously established the first cell line (CTC-MCC-41) derived from metastasis-competent CTCs of a patient with colon cancer. In this study, we analyzed the transcriptome of CTC-MCC-41 cells using Human Genome U133 Plus 2.0 microarrays with the aim of unraveling the molecular basis of their special features (stem cell properties and ability to initiate and support metastasis formation). Comparison of the transcriptome data of metastasis-competent CTC-MCC-41 cells and of HT-29 cells (derived from a primary colon cancer) highlights the differential expression of genes that regulate energy metabolism [peroxisome proliferator-activated receptor γ coactivator 1A (PPARGC1A), peroxisome proliferator-activated receptor γ coactivator 1B (PPARGC1B), fatty acid binding protein 1 (FABP1), aldehyde dehydrogenase 3 family member A1 (ALDH3A1)], DNA repair [BRCA1 interacting protein C-terminal helicase 1 (BRIP1), Fanconi anemia complementation group B (FANCB), Fanconi anemia complementation group M (FANCM)], and stemness [glutaminase 2 (GLS2), cystathionine-beta-synthase (CBS), and cystathionine gamma-lyase (CTH)]. The differential expression of 20 genes was validated by quantitative reverse transcription PCR. This study gives a comprehensive outlook on the molecular events involved in colon cancer progression and provides potential CTC biomarkers that may help develop new therapies to specifically target CTCs with stem cell properties that cause metastases and tumor relapse in patients with colon cancer.

A study of over 35,000 women with breast cancer tested with a 25‐gene panel of hereditary cancer genes

As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. A total of 35,409 women with a single diagnosis of BC who underwent clinical genetic testing with a 25-gene panel were included in the current analysis. Women with multiple BCs and men with BC were excluded. The frequency and distribution of PVs were assessed for the overall cohort, among women with triple-negative BC (TNBC) (n = 4797), and by age at diagnosis. PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%), and partner and localizer of BRCA2 (PALB2) (9.3%). The prevalence of PVs in BRCA1, PALB2, BRCA1-associated RING domain 1 (BARD1), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and RAD51 paralog C (RAD51C) was statistically higher among women with TNBC. The PV rate was higher among women aged <40 years, lower among women aged >59 years, and relatively constant (8.5%-9.0%) among women who were diagnosed between ages 40 and 59 years. These results demonstrate that panel testing increased the number of women identified as carrying a PV in this cohort compared with BRCA testing alone. Furthermore, the proportion of women identified who carried a PV in this cohort did not decrease between ages 40 and 59 years. Cancer 2017;123:1721-1730. © 2017 American Cancer Society.

Inactivation of the Tumor Suppressor BRCA1 Interacting Protein C-terminal Helicase 1 (BRIP1) Gene Confers Increased Susceptibility to Platinum Antineoplastic Agents and Augments the Synergistic Response to Poly (ADP-ribose) Polymerase (PARP) Inhibition in Ovarian Epithelial Cells

Objectives: Inactivating mutations of the tumor suppressor gene, BRIP1, are frequently identified by genetic testing. Here, we characterize a deleterious germline mutation of BRIP1 and assess response to platinum-induced DNA damage and PARP inhibition.

Further evidence for the contribution of the BRCA1-interacting protein-terminal helicase 1 (BRIP1) gene in breast cancer susceptibility

BRCA1-interacting protein C-terminal helicase 1 (BRIP1) is a DNA helicase that influences the DNA repair ability and tumor suppressor function of BRCA1. Truncating BRIP1 mutations have been described as cancer susceptibility alleles. To evaluate BRIP1 polymorphisms as risk factors for breast cancer, we performed a detailed analysis of possible single nucleotide polymorphisms (rs2048718, rs4988344, rs8077088, rs6504074, rs4986764, rs4986763, rs11079454, rs7213430, rs34289250, rs4988345, and rs12937080) using the MassARRAY system. A total of 319 patients with breast cancer and 306 healthy control females from the Chinese Han population enrolled in the study. A weak association was found between the rs4986764 allele (exon 18) and breast cancer. The frequency of the rs4986764 C allele was significantly higher in breast cancer patients than in healthy controls [χ(2) = 4.089, P = 0.043, odds ratio (OR) = 0.781, 95% confidence interval (CI) = 0.614-0.992]. Additionally, our study is the first to identify a significant association between rs7213430 and breast cancer. Compared to healthy controls, patients with breast cancer had a higher frequency of the rs7213430 A allele (χ(2) = 8.865, P = 0.003, OR = 0.700, 95%CI = 0.553-0.886). Furthermore, linkage disequilibrium was observed in two blocks (D' > 0.9). While significantly more T-A-C haplotypes (P = 0.001, block 1) were found in breast cancer patients, the frequency of T-T haplotypes (P = 0.008, block 2) was significantly higher in healthy controls. The possible association among rs4986764, rs7213430, and breast cancer risk merits further validation in an independent case-control study.

BRCA Gene Structure and Function in Tumor Suppression

Germline mutations in the BRCA1 and BRCA2 genes are characterized by deficient repair of DNA double-strand breaks by homologous recombination. Defective DNA double-strand break repair has been not only implicated as a key contributor to tumorigenesis in mutation carriers but also represents a potential target for therapy. The transcriptional similarities between BRCA1-deficient tumors and sporadic tumors of the basal-like subtype have led to the investigation of homologous recombination repair-directed therapy in triple-negative tumors, which demonstrates overlap with the basal-like subtype. We broaden the scope of this topic by addressing a "repair-defective" rather than "BRCA1-like" phenotype. We discuss structural and functional aspects of key repair proteins including BRCA1, BRCA2, BRCA1 interacting protein C-terminal helicase 1, and partner and localizer of BRCA2 and describe the phenotypic consequences of their loss at the cellular, tissue, and organism level. We review potential mechanisms of repair pathway dysfunction in sporadic tumors and address how the identification of such defects may guide the application of repair-directed therapies.

Polymorphisms in BRCA1, BRCA1-interacting genes and susceptibility of breast cancer in Chinese women

BRCA1-interacting protein C-terminal helicase 1 (BRIP1) and zinc finger protein 350 (ZNF350) work with BRCA1 in tumor suppression procedures. Low penetrance variants of these three genes may jointly affect individuals' breast cancer susceptibility in general population. We focused on potentially functional single nucleotide polymorphisms (SNPs) in the coding regions of BRIP1, ZNF350 and BRCA1 and pairwise-tagging approach was used to minimize the number of SNPs. Five SNPs were selected and genotyped by PCR-restriction fraction length polymorphism or PCR-primer introduced restriction analysis assays in a case-control study with 568 breast cancer cases and 624 controls in a Chinese population. All of the five SNPs except rs2278415 of ZNF350 conferred a modestly increased risk, although, with no statistical significance. Joint effect analyses indicated that all the variant genotypes of ZNF350 polymorphisms accounted for increased breast cancer risk among subjects carrying variant homozygote of BRCA1 rs799917, particularly for ZNF350 rs4986773 (OR = 2.03, 95%CI = 1.02-4.05, the test for gene-gene interaction P (int) = 0.059). BRCA1 and ZNF350 may jointly contribute to individuals' susceptibility of breast cancer in Chinese women. Further functional studies are warranted to validate our findings.