Breast Cancer BRCA2 Research Articles

Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice

The BRCA1-PALB2-BRCA2 axis, or the BRCA pathway, plays key roles in genome stability maintenance and suppression of breast and several other cancers. Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brca1, Brca2 and Palb2 conditional knockout models, it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis. Here, we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds. Rather than mammary tumors, Palb2 and Trp53 compound mutant mice developed, with greatly reduced latencies, lymphomas and sarcomas that are typically associated with germline Trp53 inactivation. Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice. These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development, possibly without altering the fundamental tumorigenic processes.

BROCADE3: a challenge to the treatment paradigm in BRCA breast cancer?

BROCADE3: a challenge to the treatment paradigm in BRCA breast cancer?

The role of pathologists in recognition of morphologic and biologic features of genetically mutated breast cancer.

The recent introduction of genomic medicine and emphasis on optimizing breast cancer risk reduction mortalities has provided opportunities for pathologists to partner with clinicians in advancing the diagnosis and management of breast cancer patients. The discovery of breast cancer genes BRCA1, BRCA2, and other breast cancer genes is considered a major breakthrough in the understanding of hereditary breast cancer. These discoveries have contributed to investigate the nature of tumorigenesis and the genetic and molecular pathology in multistep tumor development, as well as their relationship to endocrine and environmental factors. The recognition of unique morphologic and biological features associated with genetically mutated breast cancer by pathologists may have an impact on appropriate follow-up management of breast cancer patients.

Multimodality Imaging Features of Breast Carcinoma in Women with Neurofibromatosis Type 1 (NF 1) – A Report of Two Cases

With a prevalence of approximately 1 out of 2,500 to 4,000 births, neurofibromatosis type 1 (NF1), also known as von Recklinghausen’s disease, is one of the most prevalent autosomal dominant diseases in humans. There is four- to five-fold increased risk of malignancy in these patients due to the presence of NF1 gene mutation which is a tumour suppressor inhibiting RAS activation. NF1 is known to be closely associated with central nervous system (CNS) tumours; however, its association with other non-CNS malignancies is not uncommon. Mutation of BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, susceptibility protein) genes has long been recognized as an important risk factor for the of breast cancer. Incidentally, breast cancer 1 (BRCA1) and NF1 genes are both located in the long arm of chromosome 17. The association between NF1 and breast cancer has long been debated; recent studies, on the other hand, have established this association, with NF1 unequivocally identified as breast cancer susceptibility gene conferring a moderate risk of breast cancer development. In this report, we described multimodality imaging features related to two female cases of breast cancer with NF1; we further reviewed the literatures on the association between NF1 and breast cancer and its diagnostic challenge.

Protein-Protein interactions uncover candidate 'core genes' within omnigenic disease networks.

Genome wide association studies (GWAS) of human diseases have generally identified many loci associated with risk with relatively small effect sizes. The omnigenic model attempts to explain this observation by suggesting that diseases can be thought of as networks, where genes with direct involvement in disease-relevant biological pathways are named 'core genes', while peripheral genes influence disease risk via their interactions or regulatory effects on core genes. Here, we demonstrate a method for identifying candidate core genes solely from genes in or near disease-associated SNPs (GWAS hits) in conjunction with protein-protein interaction network data. Applied to 1,381 GWAS studies from 5 ancestries, we identify a total of 1,865 candidate core genes in 343 GWAS studies. Our analysis identifies several well-known disease-related genes that are not identified by GWAS, including BRCA1 in Breast Cancer, Amyloid Precursor Protein (APP) in Alzheimer's Disease, INS in A1C measurement and Type 2 Diabetes, and PCSK9 in LDL cholesterol, amongst others. Notably candidate core genes are preferentially enriched for disease relevance over GWAS hits and are enriched for both Clinvar pathogenic variants and known drug targets-consistent with the predictions of the omnigenic model. We subsequently use parent term annotations provided by the GWAS catalog, to merge related GWAS studies and identify candidate core genes in over-arching disease processes such as cancer-where we identify 109 candidate core genes.

Correction to: Frequency of heterozygous germline pathogenic variants in genes for Fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis.

In the original publication of the article, the first sentence in the abstract was published incorrectly.

Employing Label‐free Electrochemical Biosensor Based on 3D‐Reduced Graphene Oxide and Polyaniline Nanofibers for Ultrasensitive Detection of Breast Cancer BRCA1 Biomarker

AbstractA label‐free DNA biosensor based on three‐dimensional reduced graphene oxide (3D‐rGO) and polyaniline (PANI) nanofibers modified glassy carbon electrode (GCE) was successfully developed for supersensitive detection of breast cancer BRCA1. The results demonstrated that 3D‐rGO and PANI nanofibers had synergic effects for reducing the charge transfer resistance (Rct), meaning a huge enhancement in electrochemical activity of 3D‐rGO‐PANI/GCE. Probe DNA could be immobilized on 3D‐rGO‐PANI/GCE for special and sensitive recognition of target DNA (1.0×10−15–1.0×10−7 M) with a theoretical LOD of 3.01×10−16 M (3S/m). Furthermore, this proposed nano‐biosensor could directly detect BRCA1 in real blood samples.

Frequency of heterozygous germline pathogenic variants in genes for Fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis.

Germline pathogenic variants in BRCA1 (FANCD1) and BRCA2 (FANCS) do not explain all familial or sporadic cases with breast cancer. Several reports indicate a role for pathogenic variants in other genes in the Fanconi anemia/breast cancer DNA repair pathway; the strengths of these associations vary widely. Publications from 2006 through 2017 were reviewed to provide a better estimate of the role of pathogenic variants in genes in this pathway in breast cancer. We identified cohorts and case-control reports describing heterozygous pathogenic variants in Fanconi anemia genes in breast cancer cases with high risk of a germline pathogenic variant in a non-BRCA1/2 breast cancer susceptibility gene ("familial"), and cases unselected for family history ("unselected"). Meta-analysis and meta-regression were used to estimate the frequencies of pathogenic variants in cohorts and the odds ratios (OR) in case-control studies. Meta-analysis of more than 100 reports of FANCN/PALB2 in familial breast cancer cases provided an overall pathogenic variant prevalence of 1.29% and an OR of 8.45. The prevalence in unselected cohorts was 0.64%, and the OR was 4.76. Pathogenic variants in FANCJ/BRIP1 had a prevalence of 0.5% in familial cases, and an OR of 1.62; their prevalence in unselected cases was 0.39%. FANCO/RAD51C, FANCP/SLX4, FANCU/XRCC2, FANCD2, and other FA-related genes all had prevalences of ≤ 0.5% among familial cases, and even lower in unselected cases. Heterozygous pathogenic variants in FANCN/PALB2 and possibly FANCJ/BRIP1 may account for 1-2% of familial non-BRCA1/2 breast cancer cases and 0.5-1% of unselected cases. Genetic counseling and testing may be suggested for unaffected relatives.

Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1

The BRCA2 tumor suppressor protein is involved in the maintenance of genome integrity through its role in homologous recombination. In mitosis, BRCA2 is phosphorylated by Polo-like kinase 1 (PLK1). Here we describe how this phosphorylation contributes to the control of mitosis. We identify a conserved phosphorylation site at T207 of BRCA2 that constitutes a bona fide docking site for PLK1 and is phosphorylated in mitotic cells. We show that BRCA2 bound to PLK1 forms a complex with the phosphatase PP2A and phosphorylated-BUBR1. Reducing BRCA2 binding to PLK1, as observed in BRCA2 breast cancer variants S206C and T207A, alters the tetrameric complex resulting in unstable kinetochore-microtubule interactions, misaligned chromosomes, faulty chromosome segregation and aneuploidy. We thus reveal a role of BRCA2 in the alignment of chromosomes, distinct from its DNA repair function, with important consequences on chromosome stability. These findings may explain in part the aneuploidy observed in BRCA2-mutated tumors.

Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline.

To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. Patients with newly diagnosed BC and BRCA1/2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

Hereditary Breast Cancer

Breast cancer occurs when breast cells grow out of control because they escape the fine controls that regulate cell multiplication, resulting in cell proliferation unresponsive to regulation. Most cases of breast cancer have no identifiable cause, but approximately 5% to 10% are caused by inherited genetic mutations. Although other genes are known to cause hereditary breast cancer, most studies evaluating clinical management strategies have focused on women with mutations in the BRCA1 or BRCA2 (Breast Cancer) genes. People with these mutations have a significantly increased lifetime risk of cancer compared to the general population.

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

BackgroundBRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies.MethodsMining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas.ResultsWe found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD.ConclusionsTMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of “BRCAness” and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition.Trial registrationPhase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.

Occult Tubal Carcinoma After Risk-Reducing Salpingo-oophorectomy: A Systematic Review.

To perform a systematic review of the literature to estimate the prevalence and outcomes of occult tubal carcinoma in BRCA mutation carriers and high-risk patients undergoing risk-reducing salpingo-oophorectomy. A search was done using OVID MEDLINE, EMBASE, and ClinicalTrials.gov between 1946 and March 2019 with keywords and MeSH terms selected by an expert medical librarian and coauthors. Two independent reviewers performed study selection with an initial screen on abstracts and a second on full articles. Articles were rejected if they were irrelevant to the study question, pertained to a different population or did not report occult tubal neoplasia. Quality was assessed using methodologic index for nonrandomized studies criteria. Data were extracted and recorded in an Excel database. Forest plots for the prevalence of occult carcinoma were done using STATA. Among 2,402 studies assessed, 27 met the inclusion criteria for qualitative and quantitative analysis. A total of 6,283 patients underwent risk-reducing salpingo-oophorectomy between 2002 and 2019: 2,894 cases were BRCA1, 1,579 BRCA2, and 1,810 high-risk based on family history. Among these, 75 patients were diagnosed with occult tubal carcinoma at the time of surgery. The pooled prevalence was 1.2% (I=7.1%, P=.363) occurring at a median age of 53.2 years (range 42.4-67). In a subanalysis of 18 studies reporting follow-up data, 10 recurrences (18.7%, 95% CI 7.5-53%) and 24 cases of post-risk-reducing salpingo-oophorectomy peritoneal cancer (0.54%, 95% CI 0.4-1.9%) were reported after a median follow-up of 52.5 months. BRCA1, older age, and previous breast cancer were more often associated with occult malignancy. Occult tubal carcinomas found at risk-reducing salpingo-oophorectomy in high-risk patients and BRCA mutation carriers have significant potential for recurrence despite the frequent administration of postoperative chemotherapy.

Proteomic Analysis of Medicinal Plant Calotropis Gigantea by In Silico Peptide Mass Fingerprinting

The Peptide Mass Fingerprinting (PMF) identifies the proteins from a reference protein database by comparing the amino acid sequence that is previously stored in the database and identified. The purpose of the study is to identify the peptides having anti-cancerous properties by in silico peptide mass fingerprinting. The calculation of in silico peptide masses is done through the ExPASy PeptideMass and these masses are used to identify the peptides from the MASCOT online server. Anticancer probability is calculated by iACP server, docking of active peptides is done by CABS-dock the server. The anti-cancer peptides are identified with the MASCOT peptide mass fingerprinting server, the identified peptides are screened and only the anti-cancer are selected. De-novo peptide structure prediction is used for 3D structure prediction by PEP-FOLD 3 server. The docking results confirm strong bonding with the interacting amino acids of the receptor protein of breast cancer BRCA1 which shows the best peptide binding to the active chain, the human leukemia protein docking with peptides shows the accurate binding. These peptides are stable and functional and are the best way for the treatment of cancer and many other deadly diseases.

Abstract P6-08-17: When BRCA2-breast cancer is more prevalent than BRCA1-breast cancer: Prospective follow-up data from a multidisciplinary program

Abstract PURPOSERecent studies questioned the role of BRCA2 as a prognostic factor. Although differences between clinicopathological characteristics of BRCA1-breast cancer (BC) and BRCA2-BC have been described, long-term follow-up data related to prognosis and survival is lacking. We report the analysis of our cohort of BRCA1/2-BC patients (pts) included in our multidisciplinary program. This cohort includes BRCA2-BC c.156_157insAlu carriers, which was previously described as a Portuguese founder mutation. PATIENTS AND METHODS All pts underwent comprehensive BRCA1/2 testing. Data was obtained from all BRCA1/2 pts included in prospective follow up from January 2000 to June 2019, with BC as first cancer diagnosis. Follow-up started after genetic testing. RESULTSFrom 5504 cases (4021 index, 1483 family relatives) that consented on BRCA1/2 testing, 613 BRCA1/2 were cancer pts, of which 478 (78%) had BC as their first cancer diagnosis. These were mostly BRCA2 (n=321, 67.2% vs BRCA1 n=156, 32.6%) females (95.2%), and 129 (40%) of all BRCA2 cases were 156_157insAlu. Three pts had double pathogenic mutations (BRCA1+CHEK2, BRCA2+CHEK2 and BRCA1+BRCA2). Median follow-up was 4.3 yrs (0-17.8).Median age at testing was 50.3 (21-84) yrs and median age at BC diagnosis was significantly higher for BRCA2-BC (45.9 (21-80) vs 42.7 yrs (28-65), p<0.02) than for BRCA1-BC. Compared to BRCA1 pts, BRCA2 pts had higher prevalence of tumors <1cm at diagnosis (10.6% vs 5.8%, p=0.057), hormone receptor positive status (60.4% vs 28.8%, p<0.0001), and lower prevalence of TN phenotype (9.3% vs 48.7%, p<0.0001). BRCA2-BC was associated with longer median time to relapse (TTR) (63.6m, 95% CI 43.1-84.2, vs 23.3m, 95% CI 18.6-28.5, p<0.05), even if relapse rates were similar (9.9% vs 9.6%) and, for a median follow up of 4.3 yrs, no statistically significant difference for survival was observed (7.2 yrs (95% CI 4.1-10.3) vs 5.9 yrs (95% CI 3.8-7.9) for BRCA2-BC and BRCA1-BC respectively).Uptake of preventive surgeries (bilateral or contralateral mastectomy*, adnexectomy, or both) was similar between both groups (BRCA2 17.8%, 27.1% and 11.5% vs BRCA1 18.6%, 26.9% and 10.9%, respectively). Subsequent cancers occurred in 169 pts (35.4%), and were mostly BC (BRCA2 69.1% vs BRCA1 58.7%). Having subsequent cancer was associated with BRCA2 status (72.8% vs 27.2%, p<0.04), not undergoing risk-reducting mastectomy (91.7% vs 8.3%, p<0.0001) and not undergoing risk-reducting mastectomy with bilateral anexectomy (95.3% vs 4.7%, p=0.001). Regarding subsequent cancers, 116 cases were detected during prospective follow-up, 89 in 66 BRCA2-BC and [CB1] 27 cancers in 27 BRCA1-BC. CONCLUSIONIn our population, there is a higher prevalence of BRCA2-BC than BRCA1-BC, not completely explained by the founder effect of c.156_157insAlu. For the described follow up, TTR was longer for BRCA2-BC pts but survival was not different between the two groups, even though BRCA2 status was associated with more subsequent cancer diagnoses. As expected, preventive surgeries were inversely associated with second cancers. Data on prognosis and survival needs to be confirmed with longer follow up. *- includes pts previously treated with conservative surgery Citation Format: Catarina Bexiga, Priscila Nejo, Inês Oliveira, Paula Rodrigues, Patrícia Pereira, Sofia Fragoso, Alexandra Mayer, Joana Parreira, Sidónia Santos, Pedro Louro, Ana Luís, Sandra Bento, Isália Miguel, Cecília Moura, Ana Clara, Fátima Vaz. When BRCA2-breast cancer is more prevalent than BRCA1-breast cancer: Prospective follow-up data from a multidisciplinary program [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 P6-08-17.

Abstract ES12-1: Clinical indications of PARP1 inhibitors and other targets

Abstract Two PARP1 inhibitors, olaparib and talazoparib, garnered regulatory approvals for the treatment of advanced HER2-negative breast cancer associated with a germline BRCA1 or BRCA2 mutation in 2018. The approvals were based on a prolongation of progression-free survival with PARP inhibitor monotherapy compared to non-DNA damaging single agent chemotherapy in the 1st - 4th line metastatic setting. While the availability of these therapies has increased therapeutic options for this group of patients, median progression-free survival ranged from 7 - 8.6 months and no overall survival advantage has been observed to date. While response rates with PARP inhibitor monotherapy are high, development of resistance remains a significant clinical problem. Further, how PARP inhibitor monotherapy compares with platinum-based chemotherapy in this group of patients has been unclear. The recently reported phase III BROCADE 3 clinical trial examining carboplatin and paclitaxel with the addition of veliparib or placebo added important insights. This was the first phase III trial in patients with advanced germline BRCA1 and BRCA2 mutation-associated HER2-negative breast cancer that examined the use of a PARP inhibitor combined with DNA damaging chemotherapy in the 1st-3rd line setting followed by blinded monotherapy after discontinuation of chemotherapy. The median progression-free survival was significantly prolonged with the addition of veliparib (14.5 versus 12.6 months) with 26% of patients in the veliparib arm remaining progression-free at 36 months. Median overall survival was 33.5 months in the veliparib arm compared to 28.2 months in placebo with 44% of patients in the placebo arm crossing over to receive veliparib after disease progression. While important differences exist between these three trials, BROCADE 3 has reported the longest progression-free and overall survival to date with PARP inhibitor therapy in advanced germline BRCA1 and BRCA2 mutation-associated breast cancer. Beyond BRCA1 and BRCA2, PARP inhibitors are also being investigated in homologous recombination deficient advanced breast cancer in a number of clinical trials. In the Talazoparib Beyond BRCA study, high clinical activity was noted in germline PALB2 mutation carriers. The Olaparib Expanded trial is ongoing. Citation Format: ML Telli. Clinical indications of PARP1 inhibitors and other targets [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 ES12-1.

Abstract P2-10-13: Genetics and pathological correlation of BRCA status in patients of Asian origin diagnosed with breast or ovarian cancer; a UK Reference Genetics Laboratory Study

Abstract Background/objective: Epidemiological and phenotypic differences exist in breast and ovarian cancers among patients of different ethnicity. Reasons for this are unclear and likely multifactorial. In Asian countries breast and ovarian cancers occur a decade earlier (1). In India, 15% of breast and ovarian cancer is diagnosed in patients over 65 years compared to approximately 50% in the UK, despite an increased UK incidence(1). Triple negative breast cancer is also more prevalent in India(1). A recent systematic review by our group examined the prevalence and spectra of BRCA1/2 mutations in the Indian population and concluded that there is a lack of high-quality genetic and histopathology data (2). This study examines BRCA mutation prevalence, spectra, and clinico-pathological features of breast and ovarian cancers in patients of Asian origin with familial risk. Methods: 89 patients of Asian origin were identified out of a total of 3359 patients referred to the regional genetics service for BRCA1/2 testing between 2006-2016. Genetics data were correlated with recorded histopathological including the type of surgical excision, tumour type, size, grade and receptor status (breast cancers). Outcome data, where available, was also recorded. The BRCA1/2 genetic variants were searched in the ClinVar (3) and BIC (Breast cancer Information Core)databases (4) to confirm their pathogenicity. Results: 51 patients were of Indian (57.30%), 21 of Pakistani (23.59%) and 3 of Bangladeshi (3.37%) origin with the remaining 14 of other unspecified or mixed Asian ethnicities (15.73%). 25 BRCA variants across 21 patients were identified. 16.85% (n=15) had a pathogenic variant (BRCA1 n= 11, BRCA2 n= 4) and 11.23% (n=10) had a variant of unknown significance (VUS) (BRCA1 n=1, BRCA2 n=9). One BRCA1 variant (c.3770_3771delAG, p.Glu1257GlyfsX9) occurred in 2 different patients, both of Indian origin. The Genome Aggregation Database (gnomAD) allele frequency of this variant in the South Asian population is reported as 3.27e-5. Pathology data for one or more parameters was available for 78 patients (87.64%). The majority were breast cancers, with a median age of 39 years. 90.90% of the BRCA1 and BRCA2 pathogenic variant breast cancers (PVBC) were of no special type (n =10, total 11). 87.50% of BRCA1 PVBCs (n=7, total 8) were HER2/oestrogen receptor (ER) negative and 85.71% were grade 3 (n=6, total 7). 100% (n=4, total 4) of BRCA2 PVBCs were grade 3 and ER positive. Two patients with a BRCA2 PVBC were male. Conclusion: This study shows, for the first time, the real-time genetic and pathological correlation of BRCA status in breast and ovarian cancer patients of Asian origin with familial risk. The higher number of pathogenic BRCA1 alterations compared to BRCA2 as well as the higher number of BRCA2 VUS compared to BRCA1 VUS is consistent with our previous work of the Indian population(2). The BRCA1/2 histological and molecular features are consistent with profiles reported in the literature. The genetic makeup may explain, at least partly, the phenotypic and epidemiological breast and ovarian cancer differences observed within different ethnicities.

Peripheral Blood-Based Biopsy for Breast Cancer Risk Prediction and Early Detection.

Among women, breast cancer (BC) is not only the most common cancer worldwide but also the leading cause of cancer death. Only 5–10% of breast cancer cases are attributed to inherited mutations (BRCA1, BRCA2, and other breast cancer susceptibility genes). Breast cancer incidence has been rising particularly in young women who are not eligible for mammography, and it has been acting as a burden especially in developing countries that lack screening and awareness programs. For this reason, research has shifted to use minimally invasive liquid biopsies especially blood-based biomarkers with potential value for breast cancer risk prediction and early detection. This mini-review will tackle the different blood-based biomarkers focusing mainly on circulating miRNA, circulating proteins, cell-free nucleic acids, methylation patterns, and exosomes. It also introduces the potential opportunities for the clinical use of these blood-based biomarkers for breast cancer risk prediction.

BRCA and Beyond: Comprehensive Image-rich Review of Hereditary Breast and Gynecologic Cancer Syndromes.

In addition to the well-characterized BRCA1 and BRCA2 hereditary breast and ovarian cancer syndromes, many other syndromes that are associated with genetic mutations predispose individuals to an increased risk of breast and gynecologic malignancies. Many mutated genes encode for tumor-suppressor products and are inherited in an autosomal dominant manner. Mutations markedly increase an individual's lifetime risk of cancers in different organ systems, depending on the associated syndrome. These syndromes include Lynch syndrome, the most common hereditary cause of endometrial cancer, and Peutz-Jeghers syndrome, which increases the risks of breast cancer, ovarian cancer, and cervical adenoma malignum. Li-Fraumeni syndrome and Cowden syndrome increase the risk of breast cancer, and Gorlin syndrome increases the risk of ovarian fibromas. With advances in genetic testing, clinicians' knowledge and awareness of the numerous additional genes associated with breast and ovarian cancers, such as ATM, CHEK2, and PALB2, are rapidly expanding. Radiologists have essential roles in patient management, which include developing optimal screening protocols for these patients and closely monitoring them for the development or recurrence of disease-specific malignancies. Radiologists' roles continue to increase and evolve as more mutations are identified and high-risk imaging screening recommendations expand to identify these patients. Understanding the epidemiologic, genetic, and pathophysiologic features and the cancers associated with these syndromes enables radiologists to appropriately contribute to patient management, ensure accurate and timely diagnosis, and make syndrome-specific imaging recommendations. ©RSNA, 2020.

Bioinformatics and Molecular Analysis of the Breast Cancer Susceptibility Gene BRCA1 in Breast Cancer

Background: The breast cancer susceptibility gene (BRCA1) encodes a tumor suppressor protein which plays a vital role in the DNA damage repair and transcriptional regulation among other functions. Bioinformatics is a newly-emerged discipline that uses computer, mathematics, and statistics in molecular biology in order to analyze the large amounts of biological data quickly, freely, and accurately. Methods: The BRCA1 transcript (mRNA) levels were checked by using real-time quantitative polymerase chain reaction (RT-qPCR) in four sporadic breast cancer cell lines: MCF-7, T47D, MDA-MB-231, and MDA-MB-468 compared to the normal breast tissue. Bioinformatics tools were also used to compare and analyze different aspects of BRCA1 transcripts (multiple different mRNAs produced by a single gene) and splice variants (multiple proteins encoded by the same gene). Results: The level of BRCA1 mRNA was overexpressed in the studied breast cancer cell lines relative to the normal breast cDNA. Also, the bioinformatics software tools provided many important features of this gene that would help explain numerous controversial laboratory findings. Conclusions: The data presented here support a role for BRCA1 overexpression in the pathogenesis of sporadic breast cancer. The bioinformatics analysis of BRCA1 mRNA and protein variants can provide information essential for cancer diagnosis or therapy. The biological data gained from these tools can help authors make better decisions before launching expensive experiments.