BRCA1/BRCA2 mutation spectrum analysis in South Asia: a systematic review

Objective Breast cancer (BC) is the most common form of cancer among Asian females. Mutations in the BRCA1/ BRCA2 genes are often observed in BC cases and largely increase the lifetime risk of having BC. Because of the paucity of high-quality data on the molecular spectrum of BRCA mutations in South Asian populations, we aimed to explore these mutations among South Asian countries. Methods A systematic literature search was performed for the BRCA1 and BRCA2 gene mutation spectrum using electronic databases such as PubMed, EMBASE, and Google Scholar. Twenty studies were selected based on specific inclusion and exclusion criteria. Results The 185delAG (c.68_69del) mutation in exon 2 of BRCA1 was the most common recurrent mutation and founder mutation found. Various intronic variants, variants of unknown significance, large genomic rearrangements, and polymorphisms were also described in some studies. Conclusions The South Asian population has a wide variety of genetic mutations of BRCA1 and BRCA2 that differ according to countries and ethnicities. A stronger knowledge of various population-specific mutations in these cancer susceptibility genes can help provide efficient strategies for genetic testing.

Regular Exercise, Thombocyte, Collagen and Breast Cancer

Platelets, which play a very important role in the continuation of vital activities, play an important role in blood coagulation. Various chronic diseases can reduce the platelets produced by our body below the standard level or increase them in a dangerous way. Diseases related to malignancy, that is, malignant tumors, come at the beginning of the diseases that disrupt the platelet balance. One of them is breast cancer. Breast cancer is a type of cancer that occurs as a result of mutations in the BRCA1 (17q21) and P53 (17p13) genes located on the 17th chromosome and the BRCA2 gene located on the 13th chromosome. It is known that the amount of bone mass due to estrogen hormone is closely related to the formation of breast cancer. Collagen is the protein that forms bones, cartilage fibers and joints, which are the building blocks of our motor (movement) system. The main protein that forms the main structure of the bone is Type I collagen and about 30 types of collagen have been defined. It acts as a support for bone and cartilage tissue. Regular exercise, on the other hand, is a type of regular, systematic and programmed physical activity done with the aim of improving the physical and mental state of the person. There are many studies that found that exercise increases the tendency of platelet aggregation (aggregation, aggregation, aggregation). In addition, there are scientific studies that show that regular exercise and regularly used collagen stop the progression of breast cancer. The aim of this scientific review is to describe the relationship between platelet, collagen, breast cancer and regular exercise. Keywords: Quiet eye, Platelet, Collagen, Breast Cancer, Regular exercise

In silico comparative analysis of BRCA2 gene in some selected animal species in Africa

Background: BRCA2 genes are not only found in humans, but in other animal species. BRCA2 gene plays a vital role in maintaining the stability of a cell's genetic information. BRCA2 is considered as a gatekeeper gene; however, if mutated or abnormally expressed, it causes the destruction of normal cell structure and promotes the growth of cancer cells. Objective: This study aimed to assess the differences and similarities of BRCA2 gene from different animal species in Africa through In silico genomics analysis providing further insight on its comparative genomics features. Materials and Methods: Fifteen nucleotide sequences of BRCA2 gene of different mammals and bird species were retrieved from National Centre for Biotechnology Information (NCBI). Multiple sequence alignment was done with MEGA 7.0 software, while identity and similarities were determined by constructing a pairwise comparison. Conserved domains on the sequences were identified with NCB1-CDD. Results: BRCA2 gene was found to be present not only in humans, but other lower animals and birds across African countries. The phylogenetic tree for Homo sapiens BRCA2 gene in Tunisia belongs to the same ecological niche with the Theropithecus gelada BRCA2 gene in Ethiopia and BRCA2 from the same African region has high bootstrap, implying that they share the same homology. Conserved regions identified in the all the sequences were absent in Miniopterus natalensis and most present in Chrysochloris asiatica, Theropithecus gelada, Apaloderma vittatum, Pterocles gutturalis, Rousettus aegyptiacus, Homo sapiens, Echinops telfairi, and Cavia porcellus. Conclusion: Based on the findings obtained from this study, BRCA2 gene in humans and other lower animals, particularly from same region, share the same homology and similarities.

A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings

ObjectivesTo investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.Materials and MethodsOne family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.ResultsA novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings’ mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.ConclusionIn summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.

RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers

High mammographic density (MD) increases breast cancer (BC) risk and creates a stiff tissue environment. BC risk is also increased in BRCA1/2 gene mutation carriers, which may be in part due to genetic disruption of the tumour suppressor gene Ras association domain family member 1 (RASSF1A), a gene that is also directly regulated by tissue stiffness. High MD combined with BRCA1/2 mutations further increase breast cancer risk, yet BRCA1/2 mutations alone or in combination do not increase MD. The molecular basis for this additive effect therefore remains unclear. We studied the interplay between MD, stiffness, and BRCA1/2 mutation status in human mammary tissue obtained after prophylactic mastectomy from women at risk of developing BC. Our results demonstrate that RASSF1A expression increased in MCF10DCIS.com cell cultures with matrix stiffness up until ranges corresponding with BiRADs 4 stiffnesses (~16 kPa), but decreased in higher stiffnesses approaching malignancy levels (>50 kPa). Similarly, higher RASSF1A protein was seen in these cells when co-cultivated with high MD tissue in murine biochambers. Conversely, local stiffness, as measured by collagen I versus III abundance, repressed RASSF1A protein expression in BRCA1, but not BRCA2 gene mutated tissues; regional density as measured radiographically repressed RASSF1A in both BRCA1/2 mutated tissues. The combinatory effect of high MD and BRCA mutations on breast cancer risk may be due to RASSF1A gene repression in regions of increased tissue stiffness.

Lynch syndrome-associated lung cancer: pitfalls of an immunotherapy-based treatment strategy in an unusual tumor type

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in mismatch repair (MMR) genes leading to increased risk of colon cancer as well as other cancer types. Non-small cell lung cancer (NSCLC) is not among typical Lynch syndrome-associated tumors: pembrolizumab, an immune checkpoint inhibitor, is actually approved for the treatment of NSCLC patients and represents a promising treatment option for patients with advanced metastatic MMR-deficient cancer, regardless of tumor origin. This case report describes the clinical presentation and management of a 74-year-old female with a history of rectal adenocarcinoma and ovarian cancer, who has a documented frameshift pathogenic variant in the exon 8 of MSH6 gene and an intronic variant in the BRCA2 gene (classified as a variant of uncertain significance), affected by NSCLC with brain metastases. Despite these premises, the patient was treated with pembrolizumab and she did not benefit from this kind of treatment.

Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules

Pathological mutations in homology-directed repair (HDR) genes impact both future cancer risk and therapeutic options for patients. HDR is a high-fidelity DNA repair pathway for resolving DNA double-strand breaks throughout the genome. BRCA2 is an essential protein that mediates the loading of RAD51 onto resected DNA breaks, a key step in HDR. Germline mutations in BRCA2 are associated with an increased risk for breast, ovarian, prostate, and pancreatic cancer. Clinical findings of germline or somatic BRCA2 mutations in tumors suggest treatment with platinum agents or PARP inhibitors. However, when genetic analysis reveals a variant of uncertain significance (VUS) in the BRCA2 gene, precision medicine-based decisions become complex. VUS are genetic changes with unknown pathological impact. Current statistics indicate that between 10–20% of BRCA sequencing results are VUS, and of these, more than 50% are missense mutations. Functional assays to determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer risk and treatment options. In this review, we provide a brief overview of BRCA2 functions in HDR, describe how BRCA2 VUS are currently assessed in the clinic, and how genetic and biochemical functional assays could be integrated into the clinical decision process. We suggest a multi-step workflow composed of robust and accurate functional assays to correctly evaluate the potential pathogenic or benign nature of BRCA2 VUS. Success in this precision medicine endeavor will offer actionable information to patients and their physicians.