Familial Breast/Ovarian Cancer and <i>BRCA1/2</i> Genetic Screening: The Role of Immunohistochemistry as an Additional Method in the Selection of Patients

Vaz, Fátima; Machado, Patrícia Maria Abreu; Brandão, Rita D.; Laranjeira, Cátia; Eugénio, Joana S.; Fernandes, Aires; André, Saudade

doi:10.1369/jhc.7a7209.2007

Cited by 25 publications

(16 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, we could not find similar association between loss of expression and mutation in BRCA 2 gene. This data is in concordance with similar results previously shown by other authors …”

Section: Discussionsupporting

confidence: 94%

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

Siraj

Alobaisi

et al. 2016

Intl Journal of Cancer

View full text Add to dashboard Cite

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost‐effective screening strategy.

show abstract

“…However, we could not find similar association between loss of expression and mutation in BRCA 2 gene. This data is in concordance with similar results previously shown by other authors …”

Section: Discussionsupporting

confidence: 94%

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

Siraj

Alobaisi

et al. 2016

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…A study evaluating IHC expression and mutational status of BRCA1 in HGOSC reported that IHC was an accurate and highly reproducible method for detecting germ line, somatic, or epigenetic mechanisms of BRCA1 loss. These findings were consistent with results from other studies examining the use of BRCA1 IHC (Byrne et al 2000, Vaz et al 2007, Garg et al 2013). …”

Section: Brca Immunohistochemistrysupporting

confidence: 92%

Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

Lim

Ngeow

2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway. Advances in molecular profiling techniques together with increased research efforts have led to a better understanding of the molecular aberrations underlying this BRCA-like phenotype and helped broaden the concept of BRCAness. Hence, it is likely that the list of predictive biomarkers for PARPi therapy will increase in future. There is currently no gold standard method of testing for PARPi response and no universal guidelines are in place on how to incorporate biomarker testing into routine clinical diagnostics. In this review, we explore the concept of BRCAness and highlight the different methods that have been used to identify patients who may benefit from the use of these anticancer agents. The identification of predictive biomarkers is crucial in improving patient selection and expanding the clinical applications of PARPi therapy. 23:6 Review D Lim and J NgeowEvaluating BRCAness for PARP inhibitor use

show abstract

“…Recently, investigators have described tight associations between the loss of BRCA1 expression and relatively improved survival, although genetic analyses were not performed (14–16). There is also a number of papers describing loss of BRCA1 expression in the setting of BRCA1 gene mutation (12, 17, 18). Kashima described loss of expression in 8 cases with BRCA1 germline mutation (12), while Skytte (17) reported a sensitivity of 80%, a specificity of 93%, and an estimated PPV of 73% based on having studied 15 “BRCA1 cancers.” In comparison, our study included significantly larger numbers of carcinomas lacking germline mutations and a detailed analysis of genetic abnormalities other than germline mutations.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 Immunohistochemistry in a Molecularly Characterized Cohort of Ovarian High-Grade Serous Carcinomas

Garg¹,

Levine²,

Olvera³

et al. 2013

American Journal of Surgical Pathology

View full text Add to dashboard Cite

BRCA1 and BRCA2 dysfunction, frequently seen in high-grade serous ovarian carcinomas, often results from germline mutations, somatic mutations, and promoter methylation. Identification of tumors with BRCA defects has therapeutic and prognostic implications. Identifying germline BRCA mutations is also important given the increased risk for hereditary breast and ovarian carcinoma. Our goal was to assess if immunohistochemistry for BRCA1 is an effective method for detection of BRCA1 dysfunction in molecularly characterized high-grade ovarian serous carcinoma. We identified 43 high-grade ovarian serous carcinomas with known events in BRCA1 and BRCA2 included in The Cancer Genome Atlas Project (TCGA). BRCA1 stain was first assessed without knowledge of BRCA status, and a semiquantitative assessment for intensity and amount of staining was performed. The stains were re-evaluated and divided into 3 categories (retained, loss, and equivocal) based on correlation with genotyping data. Presence of retained BRCA staining was considered normal, while the other patterns, including equivocal staining or loss of staining, were considered abnormal. Two pathologists, blinded to BRCA status, then scored 2 sets of validation cases selected based on available molecular data—one with only germline mutation status available (n=31) and one with comprehensive genomic data (n=39). The pathologists agreed 88% of the time in the training set and 91% in the validation sets. In the training set, abnormal BRCA staining was seen in 24 cases, of which 21 (87%) showed BRCA1 genetic abnormalities, one showed BRCA2 mutations, and 2 showed no BRCA abnormalities. Abnormal BRCA1 staining was noted in all 5 cases with BRCA1 germline mutations, in 3 (60%) of 5 with BRCA1 somatic mutations, and in 13 (93%) of 14 with BRCA1 promoter methylation. The 2 validation sets included 70 additional patients, and all cases with germline BRCA1 mutations (n=11) showed abnormal BRCA1 staining. Tumors with BRCA1 promoter methylation also showed abnormal staining in 6 (86%) of 7 cases. In the entire study, no cases with BRCA1 germline mutation showed intact immunostaining (negative predictive value= 100%). This study shows BRCA1 immunohistochemistry is well correlated with molecular events in ovarian carcinoma. Considering the high negative predictive value for germline mutations, BRCA1 immunohistochemistry appears to be an effective approach to stratify patients for germline genetic testing and to detect other mechanisms of BRCA1 dysfunction in high-grade serous ovarian carcinomas.

show abstract

Familial Breast/Ovarian Cancer and BRCA1/2 Genetic Screening: The Role of Immunohistochemistry as an Additional Method in the Selection of Patients

Cited by 25 publications

References 43 publications

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

BRCA1 Immunohistochemistry in a Molecularly Characterized Cohort of Ovarian High-Grade Serous Carcinomas

Contact Info

Product

Resources

About