scholarly journals brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

2021 ◽  
Author(s):  
Vassili A Kouprianov ◽  
Aubrie A Selmek ◽  
Jordan L Ferguson ◽  
Xiaokui Mo ◽  
Heather R Shive
Keyword(s):  
High Risk ◽  
Embryonic Development ◽  
Cancer Susceptibility ◽  
Brca2 Mutation ◽  
Embryonic Lethality ◽  
Cell Behaviors ◽  
Cancer Susceptibility Genes ◽  
Adult Tissues ◽  
Cellular Phenotypes ◽  
The Impact

Cancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.

Prostate cancer susceptibility genes: lessons learned and challenges posed.

2003 ◽  
pp. 225-259 ◽  
Author(s):  
J Simard ◽  
M Dumont ◽  
D Labuda ◽  
D Sinnett ◽  
C Meloche ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Genetic Variants ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Screening Methods ◽  
Cancer Susceptibility Genes ◽  
Prostate Cancer Susceptibility ◽  
Common Genetic Variants

In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes.

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

2022 ◽  
Vol 50 (1) ◽  
pp. 030006052110707
Author(s):  
Sanjeev Kharel ◽  
Suraj Shrestha ◽  
Siddhartha Yadav ◽  
Prafulla Shakya ◽  
Sujita Baidya ◽  
...  
Keyword(s):  
South Asian ◽  
Cancer Susceptibility ◽  
Brca2 Mutation ◽  
Brca2 Gene ◽  
Mutation Spectrum ◽  
Quality Data ◽  
Brca1 And Brca2 ◽  
Exon 2 ◽  
Cancer Susceptibility Genes ◽  
Brca1 Brca2

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.

Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers to detect clinically significant disease: Results from the initial screening round of the IMPACT study.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 8-8
Author(s):  
Christos Mikropoulos ◽  
Elena Castro ◽  
Elizabeth Bancroft ◽  
Elizabeth Page ◽  
Natalie Taylor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Brca2 Mutation ◽  
Psa Testing ◽  
Mutation Carriers ◽  
High Risk Disease ◽  
Brca1 Carriers ◽  
Clinically Significant ◽  
The Impact ◽  
Significant Disease

8 Background: Men with germline BRCA1/2 mutations have a higher risk of developing prostate cancer (PrCa) than non-carriers. IMPACT is an international consortium of 62 centers in 20 countries evaluating the use of targeted PrCa screening in men with BRCA1/2 mutations. This analysis reports the first year’s screening results for all men at enrolment in the study. Methods: We recruited men aged between age 40 and 69 with germline BRCA1/2 mutations and a control group that tested negative for a BRCA1/2 mutation. All men underwent prostate-specific antigen (PSA) testing at enrollment and those with a PSA of greater than 3ng/ml threshold were offered prostate biopsy. All men are offered a biopsy irrespective of PSA level after five years of screening. Results: We recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls) of whom 199 (8%) presented with a PSA greater than 3ng/ml. We performed a total of 162 biopsies and diagnosed 59 PrCas (18 BRCA1 carriers, ten BRCA1 controls; 24 BRCA2 carriers, seven BRCA2 controls); 66% of the tumors were classified as intermediate or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3·0ng/ml in BRCA2 mutation carriers was 48%, double that reported in population screening studies. A significant difference in detecting intermediate or high-risk disease was observed in BRCA2 carriers using this threshold. Conclusions: The IMPACT screening network will be useful for targeted PrCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this yields a high proportion of aggressive disease. Early data indicate that the majority of BRCA1/2 mutation carriers diagnosed with prostate cancer at biopsy had developed clinically significant disease (requiring radical treatment). Clinical trial information: NCT00261456.

Germline alterations in cancer susceptibility genes in women with high-risk bladder cancer: Implications for germline testing and clinical management.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 418-418
Author(s):  
Hong Truong ◽  
Rania Sheikh ◽  
Aliya Khurram ◽  
Yelena Kemel ◽  
Andrew Thomas Lenis ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
Stage At Diagnosis ◽  
Germline Variants ◽  
Cancer Susceptibility Genes ◽  
High Penetrance ◽  
Germline Testing

418 Background: Gender differences exist in bladder cancer incidence, stage at diagnosis, and outcomes. Women have lower incidence of bladder cancer but are diagnosed with more advanced disease at presentation. They also have less favorable outcomes even after adjusting for tumor stage and treatment modality. The biologic mechanisms underlying gender disparities in bladder cancer remain unknown. Methods: We leveraged a prospective matched tumor-normal genomic profiling initiative to determine the prevalence and spectrum of pathogenic/likely pathogenic (P/LP) germline variants in women with bladder cancer. Germline DNA was tested for mutations in ≥77 cancer susceptibility genes using next-generation sequencing in 686 patients with bladder cancer. Mutation frequency and clinical characteristics were assessed by gender. Results: A total of 184 (27%) women and 502 (73%) men with bladder cancer underwent germline testing; median age of diagnosis was 66 ± 11.3 and 65 ± 11.3 years, respectively. Twenty-two women (12%) had bladder cancer diagnosis at age ≤ 50 years. Both groups had similar rate of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.5), and disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 54% vs 54%, MIBC 38% vs 39%, and metastatic disease 8% vs 6%, p = 0.7). Women had more non-urothelial carcinoma histology than men (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001). More P/LP germline variants were found in women than men (38 [21%] vs. 70 [14%], p = 0.04). Twenty-eight women (15%) had P/LP variants in DNA-damage repair (DDR) genes; 23 (13%) carried moderate/high penetrance germline mutations, the most common were BRCA1/ 2, CHEK2, NBN, ATM, and MITF. Current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. Nine women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers ( BRCA1/ 2 [5], ATM [2], MLH1 [1], TP53 [1]). Conclusions: Deleterious germline alterations are commonly present in women with high-risk bladder cancer. The presence of germline variants in some genes, such as BRCA1/2, can guide cancer screening and risk-reducing surgeries for patients and their families. Women with high-risk bladder cancer should be evaluated for suitability of germline testing, especially those who desire preservation of uterus and ovaries at the time of radical cystectomy, to rule out the presence of P/LP variants that increase risk of future gynecologic malignancies.

Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel

2015 ◽  
Vol 155 (1) ◽  
pp. 133-138 ◽  
Author(s):  
Tamar Yablonski-Peretz ◽  
Shani Paluch-Shimon ◽  
Lior Soussan Gutman ◽  
Yulia Kaplan ◽  
Addie Dvir ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
Cancer Susceptibility Genes ◽  
High Risk Families
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