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2022 ◽  
Vol 508 (2) ◽  
Author(s):  
Phạm Trí Hiếu ◽  
Nguyễn Văn Thắng ◽  
Trần Thị Thanh Huyền

Đặt vấn đề: Hầu hết phụ nữ ung thư buồng trứng (UTBT) giai đoạn tiến xa mới chẩn đoán, sau khi điều trị chuẩn bằng phẫu thuật và hóa trị liệu có chứa Platinum sẽ tái phát trong 3 năm đầu. Olaparib là thuốc ức chế enzym poly (adenosine diphosphate–ribose) polymerase, có hiệu quả tốt trong điều trị ung thư buồng trứng tái phát, nhưng lợi ích của Olaparib trong điều trị duy trì đối với các trường hợp mới được chẩn đoán chưa được chứng minh. Phương pháp: Thử nghiệm lâm sàng pha 3, đa trung tâm, ngẫu nhiên, mù đôi, nhằm đánh giá hiệu quả của Olaparib như một liệu pháp duy trì ở những bệnh nhân mới được chẩn đoán ung thư buồng trứng giai đoạn III – IV theo FIGO; gồm các thể: ung thư biểu mô thanh dịch hoặc ung thư dạng nội mạc tử cung, độ ác tính cao, ung thư phúc mạc nguyên phát, ung thư vòi tử cung (hoặc các dạng kết hợp), với đột biến ở gen BRCA1, BRCA2 hoặc cả hai; đã có đáp ứng lâm sàng hoàn toàn hoặc một phần sau khi hóa trị liệu bằng hóa trị có chứa Platinum. Các bệnh nhân được chỉ định ngẫu nhiên, theo tỷ lệ 2:1, được uống Olaparib (300mg hai lần mỗi ngày) hoặc giả dược. Tiêu chí chính của nghiên cứu là sống thêm bệnh không tiến triển (PFS). Kết quả: Trong số 391 bệnh nhân, sau chọn ngẫu nhiên có 260 người được chỉ định nhận Olaparib và 131 nhận giả dược. Tổng cộng 388 bệnh nhân có đột biến gen BRCA1/2 dạng di truyền (germline) và 2 bệnh nhân đột biến dạng mắc phải (somatic) được xác nhận bởi phòng xét nghiệm trung tâm. Sau khi theo dõi trung vị 41 tháng, nguy cơ bệnh tiến triển hoặc tử vong ở nhóm dùng Olaparib thấp hơn 70% so với giả dược; tỷ số nguy cơ (HR) bệnh tiến triển hoặc tử vong là 0,30; CI 95% [0,23 – 0,41], p < 0,001). Các biến cố ngoại ý phù hợp với độc tính đã biết của Olaparib. Kết luận: Điều trị duy trì bằng Olaparib giúp cải thiện đáng kể thời gian sống thêm bệnh không tiến triển ở phụ nữ ung thư buồng trứng giai đoạn tiến xa mới chẩn đoán, có đột biến gen BRCA1/2; làm giảm 70% nguy cơ tiến triển bệnh hoặc tử vong so với với giả dược.


Author(s):  
Anthony McGuigan ◽  
James Whitworth ◽  
Avgi Andreou ◽  
Timothy Hearn ◽  
J. C. Ambrose ◽  
...  

AbstractMulti-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296) will facilitate more accurate prognostic predictions for specific CSG combinations.


2022 ◽  
Vol 50 (1) ◽  
pp. 030006052110707
Author(s):  
Sanjeev Kharel ◽  
Suraj Shrestha ◽  
Siddhartha Yadav ◽  
Prafulla Shakya ◽  
Sujita Baidya ◽  
...  

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.


2021 ◽  
Vol 23 (1) ◽  
pp. 348
Author(s):  
Hideki Yamamoto ◽  
Akira Hirasawa

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.


Author(s):  
Jin-Ming Zhang ◽  
Kun-Nan Wang ◽  
Yun Zhang ◽  
Jun-Ze Zhang ◽  
Xin-Pu Yuan ◽  
...  

Abstract As one of the most common pathological changes in trauma and surgery practice, intestinal ischemia-reperfusion (I/R) injury is regarded as a major precipitating factor in the occurrence and development of fatal diseases. BRCA1-BRCA2-containing complex subunit 36 (BRCC36), a deubiquitinase, has been proved important in a variety of pathophysiological processes such as DNA repair, cell cycle regulation, tumorigenesis and inflammatory response. However, the effect of BRCC36 on intestinal mucosal barrier injury after I/R has not been fully elucidated. Our research found that BRCC36 aggravated intestinal mucosal barrier injury caused by BMP2 (Bone morphogenetic protein 2) after I/R by downregulating PPARγ (Peroxisome proliferator-activated receptor-γ) signaling. These results suggested that BRCC36/PPARγ axis might serve as a potential therapeutic target for preventing intestinal mucosal barrier injury after I/R.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kate E. Dibble ◽  
Avonne E. Connor

AbstractDuring the COVID-19 pandemic, breast and ovarian cancer survivors experienced more anxiety and depression than before the pandemic. Studies have not investigated the similarities of this trend among BRCA1/2-positive women who are considered high risk for these cancers. The current study examines the impact of COVID-19 experiences on anxiety and depression in a sample of BRCA1/2-positive women in the U.S. 211 BRCA1/2-positive women from medically underserved backgrounds completed an online survey. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for associations between COVID-19 experiences and self-reported anxiety and depression stratified by demographic factors. Overall, women who reported COVID-19 stigma or discrimination (aOR, 5.14, 95% CI [1.55, 17.0]) experienced significantly more depressive symptoms than women who did not report this experience. Racial/ethnic minority women caring for someone at home during COVID-19 were 3.70 times more likely (95% CI [1.01, 13.5]) to report high anxiety while non-Hispanic white women were less likely (aOR, 0.34, 95% CI [0.09, 1.30], p interaction = 0.011). To date, this is the first study to analyze anxiety and depression considering several COVID-19 predictors among BRCA1/2-positive women. Our findings can be used to inform future research and advise COVID-19-related mental health resources specific to these women.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fathi Azribi ◽  
Ehab Abdou ◽  
Emad Dawoud ◽  
Mohamed Ashour ◽  
Amgad Kamal ◽  
...  

Abstract Background Patients with pathogenic sequence variants (PSVs) in BRCA1/BRCA2 are at high risk of developing ovarian cancer (OC). However, genetic testing for BRCA1/BRCA2 PSVs is still not a routine practice in the Middle East. With the lack of epidemiological studies in the region, we aim to describe the prevalence of BRCA1/BRCA2 PSVs in patients with OC across different countries in the Gulf region. Methods The PREDICT study was an observational, prospective, epidemiological study, which consecutively recruited women with ovarian, primary peritoneal, and fallopian tube cancers from the following Gulf countries over the period from July 2017 to July 2019; United Arab Emirates (UAE), Kuwait, and Oman. The study was approved by the local ethics committee of participating centers. The BRCA1/BRCA2 PSVs were assessed by tissue genetic testing using next-generation sequencing (NGS). Results A total of 105 women were included with a median age at diagnosis of 52 years (IQR 44.5 – 61.0). Nearly 11.4% of patients reported a family history of ovarian or breast cancer, while 4.7% of patients reported a family history of other cancers. Most of the patients (70.3%) had advanced disease (FIGO stage III/IV) at presentation. Eighty-eight patients (84%) were successfully tested for somatic BRCA1/BRCA2 PSVs. Fifteen patients (17%) were found to have PSVs in either BRCA1, BRCA2, or both genes; of them, 10 patients (11.2%) had BRCA1 somatic PSVs alone, eight patients (9.1%) had BRCA2 somatic PSVs, while three patients (2.9%) had both PSVs. Five patients with BRCA1/BRCA2 somatic PSVs had germline PSVs tests, and three of them tested positive. Concerning treatment, 87.6% of patients received perioperative chemotherapy and 6.6% as first-line palliative chemotherapy. Eighty-seven (82.9%) patients underwent debulking surgery, with no residual disease in 42.5% of patients. Conclusion Our study showed that the prevalence of BRCA1/BRCA2 somatic PSVs in patients with OC is higher than the reported global figures (2-8%). However, more studies are warranted to further elucidate the prevalence of BRCA1/BRCA2 somatic and germline PSVs, as well as other relevant genetic alterations, to better understand their impact on OC patient outcomes in Gulf countries. Trial registration NCT03082976.


2021 ◽  
Vol 16 (4) ◽  
Author(s):  
Michael P. Kolinsky ◽  
Karen Y. Niederhoffer ◽  
Edmond M. Kwan ◽  
Sebastien J. Hotte ◽  
Zineb Hamilou ◽  
...  

Olaparib is the first Health Canada-approved agent in metastatic prostate cancer to use a companion diagnostic to identify alterations in BRCA1, BRCA2, or ATM. As olaparib is introduced, clinicians must learn to access and interpret germline and somatic next-generation sequencing (NGS) results, and how to manage affected patients who appear to have distinct clinical features. The traditional model of referring patients to a hereditary cancer clinic (HCC) for germline testing is likely impractical in this disease, as the metastatic prostate cancer patient population would be overwhelming. Alternate approaches to this are clinician-ordered genetic testing (so-called “mainstreaming”), out-of-pocket payment for third-party private company genetic testing, or germline testing done in conjunction with somatic testing, particularly cell free circulating tumor DNA (ctDNA). Germline testing alone is not sufficient for identifying Olaparib-eligible patients, as less than half of BRCA1, BRCA2, or ATM alterations are germline in origin, but it is critically important to identify family members who are carriers so that risk-reduction measures can be undertaken. Somatic testing is not widely available in Canada, but some patients can access it through research protocols or by paying out-of-pocket. Somatic testing can be performed on archival or fresh solid tissue biopsy samples, or through whole blood samples to access plasma-derived circulating tumor DNA (ctDNA). Both testing approaches have relative advantages and disadvantages, but neither may be informative in all patients and, therefore, ideal somatic NGS pathways should provide options for both tissue and ctDNA testing. We advocate that clinicians begin discussions with their provincial lab formularies, HCC, and molecular pathology labs to highlight the importance of germline and somatic testing in this population and identify pathways for patient access. While olaparib has approval for use in BRCA1, BRCA2, and ATM-altered mCRPC, emerging evidence suggests that PARP inhibitors have variable activity in these three genes, with BRCA2 alterations appearing to be the most responsive. Retrospective and prospective series have reported varying outcomes to standard of care therapies, such as ARATs and taxane-based chemotherapy, in metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) gene alterations, such as BRCA2. In the absence of high-level evidence showing a lack of benefit, we believe this patient population should still be considered for these treatments. In addition, platinum-based chemotherapy appears to have activity in DDR gene-altered mCRPC and should be considered another option when access to olaparib is not possible. At present, there is no evidence to support an optimal treatment sequence in this patient population, therefore, physician and patient preferences will need to be taken into consideration when selecting therapies. As olaparib and other PARP inhibitors are tested in different disease states and in combination with other therapies, we will likely see a more refined approach to use of these agents and management of this new biomarker-defined patient population.


2021 ◽  
Vol 10 (29) ◽  
pp. 107-119
Author(s):  
Jackeline de Fátima Martínez González ◽  
Marlene del Rosario Muñoz Gaitán ◽  
Marianela Corriols Molina ◽  
José René Silva Arrechavala

Introducción: La etiología del cáncer de mama es multifactorial, sin embargo, se ha evidenciado que la mayoría son esporádicos y del 5 al 10% de origen genético. Los genes conocidos hasta la fecha y asociados con una predisposición hereditaria al cáncer de mama se han clasificado según su función en genes de alta, moderada y baja penetrancia. Objetivo: Determinar mutaciones genéticas asociadas a cáncer de mama hereditario en mujeres nicaragüenses. Materiales y método: 39 mujeres con diagnóstico histopatológico de cáncer de mama fueron reclutadas para participar en el estudio, previo consentimiento informado. Se tomó 5ml de sangre periférica de cada una de las pacientes para la extracción del ADN, luego se realizó el test genético a los genes BRCA1, BRCA2, Tp53, PALB2, CDH1, PTEN y CHEK2, determinando su significado clínico comparando las secuencias con las bases de datos del Breast Cancer Information Core (BIC) y ClinVar. Resultados: El 10.2% (4/39) de las pacientes estudiadas son portadoras de una mutación patogénica en BRCA2 (5%), Tp53 y PALB2 (2.5% respectivamente), asociadas a cáncer de mama de origen hereditario. También se identificaron variaciones de significado clínico benigno, inciertas, variantes que aún no han sido reportadas en las bases de datos y otras con conflicto de patogenicidad. Conclusión: Es necesario e importante incluir el diagnóstico molecular en pacientes nicaragüenses en riesgo a desarrollar cáncer de mama de origen hereditario, para su propio bienestar y el de sus familiares, logrando un diagnóstico precoz, mejorar la terapia y el seguimiento. Por lo tanto, recomendamos se integre el cribado genético para las mujeres nicaragüenses en riesgo a desarrollar esta enfermedad y en aquellas que ya la padecen.


2021 ◽  
Author(s):  
Shahan Mamoor

In these brief notes we document work using published microarray data (1, 2) to pioneer integrative transcriptome analysis comparing vulvar carcinoma to its tissue of origin, the vulva. We report the differential expression of BRCA1/BRCA2-containing complex subunit 3, encoded by BRCC3, in cancer of the vulva. BRCC3 may be of pertinence to understanding transformation and disease progression in vulvar cancer (3).


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