Pathology of Ovarian Cancers in 
 BRCA1
 and 
 BRCA2
 Carriers

Lakhani, Sunil R.; Manek, Sanjiv; Penault‐Llorca, Frédérique; Flanagan, Adrienne M.; Arnout, Laurent; Merrett, Samantha; McGuffog, Lesley; Steele, Dawn; Devilee, Peter; Klijn, Jan G.M.; Meijers-Heijboer, Hanne; Radice, Paolo; Pilotti, Silvana; Nevanlinna, Heli; Bützow, Ralf; Sobol, Hagay; Jacquemier, J; Lyonet, D Stoppa; Neuhausen, Susan L.; Weber, Barbara; Wagner, Teresa; Winqvist, Robert; Bignon, Yves Jean; Monti, Franco; Schmitt, Fernando; Lenoir, Gilbert; Seitz, Susanne; Hamman, Ute; Pharoah, Paul D.P.; Lane, Geoff; Ponder, Bruce A.J.; Bishop, D. Timothy; Easton, Douglas F.

doi:10.1158/1078-0432.ccr-1029-3

Cited by 227 publications

(167 citation statements)

References 22 publications

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“…For example, somatic activating KRAS mutations are found to some extent in most OC subtypes, but are much more common in mucinous ovarian tumours. Also, germline BRCA1 and BRCA2 mutations tend to predispose to serous OCs (Lakhani et al, 2004). We found some evidence of association with disease risk for different histological subtypes, for SNPs in all five of the oncogenes studied, and it is perhaps interesting that SNPs in the KRAS gene and its downstream effector BRAF were associated with mucinous OC.…”

Section: Discussionmentioning

confidence: 62%

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

et al. 2009

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Low -moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in B1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P dominant ¼ 0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case -control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80 -0.99) and remained statistically significant (P dominant ¼ 0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P global ¼ 0.034) and a haplotype in BRAF that had a protective effect (P global ¼ 0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

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Section: Discussionmentioning

confidence: 62%

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

et al. 2009

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“…[28][29][30] Whether tumors exhibiting these architectural patterns should be classified as high-grade serous carcinoma is controversial. Immunohistochemical data demonstrate that tumors reported as ovarian transitional cell carcinomas are not only immunophenotypically dissimilar from urothelial carcinomas of the urinary tract, but also express WT1 at rates that are nearly identical to typical high-grade serous carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma

et al. 2012

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This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n ¼ 43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n ¼ 4, BRCA1 somatic mutation, n ¼ 6, BRCA1 promoter methylation, n ¼ 13) with unassociated cases (n ¼ 12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinomalike morphology (SET features) (P ¼ 0.0045), higher mitotic indexes (P ¼ 0.012), more TILs (P ¼ 0.034), and either geographic or comedo necrosis (P ¼ 0.034). BRCA2-associated cases (germline mutation, n ¼ 4 and somatic mutation, n ¼ 4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TILs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P ¼ 0.0016 and P ¼ 0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P ¼ 0.0072; sensitivity of 1.0 (95% CI, 0.66-1.0); specificity of 0.57 (95% CI, 0.29-0.82); positive predictive value of 0.60 (95% CI, 0.32-0.84) and a negative predictive value of 1.0 (95% CI, 0.63-1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas.

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“…15 Ovarian cancers associated with BRCA1 or BRCA2 mutations are more likely than sporadic tumors to be serous cystadenocarcinomas with an aggressive pattern and are expected to have a poor prognosis. 16 Due to the absence of reliable methods for early ovarian cancer detection and the high mortality of advanced ovarian cancer, 17 bilateral prophylactic salpingo-oophorectomy (SO) has been recommended for BRCA1 or BRCA2 mutation carriers at the age of 40 or between the ages of 35 and 39 if childbearing is complete 18,19 (and http://www.nice.org.uk). In various series, SO has been demonstrated to achieve a 96% reduction of the ovarian cancer risk and about a 50% reduction of the risk of either a first BC in women with no previous BC or contralateral BC in women with a previous BC.…”

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confidence: 99%

Prophylactic salpingo‐oophorectomy in a series of 89 women carrying a BRCA1 or a BRCA2 mutation

Laki

Kirova

This

et al. 2007

Cancer

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BACKGROUND.Prophylactic salpingo‐oophorectomy (SO), which is recommended in BRCA1/2 mutation carriers, still needs to be reappraised.METHODS.In all, 89 BRCA1/BRCA2 mutation carriers underwent SO between 1994–2004. Past medical and familial history, SO, results and survival after SO were analyzed.RESULTS.The series consisted of 56 BRCA1 and 33 BRCA2 mutation carriers. All but 1 had a family history of breast (BC) and/or ovarian cancer; 42 BRCA1 and 31 BRCA2 had a personal history of BC. The median age at SO was 44 (BRCA1) and 49.5 (BRCA2) years for women without previous BC (not significant) and 48 (BRCA1) and 53 BRCA2) years (P = .03) for women with previous BC. Occult ovarian (n = 2) and/or fallopian (n = 3) carcinomas were found in 4 patients (4.5%): 1 experienced recurrence (4 years), 2 are disease‐free (26 and 38 months of follow‐up), and 1 died from BC (12 months). Among the other 69 patients with previous BC (median follow‐up, 42 months), 14 developed ipsilateral or contralateral BC and 8 developed metastatic disease. Among the 16 patients without previous BC (median follow‐up, 27 months), 3 developed BC. Of the 89 patients, 85 are still alive: 3 died from BC and 1 died from pancreatic cancer. No peritoneal malignancy was observed.CONCLUSIONS.This study shows that prophylactic SO remains an important option for BRCA1/2 mutation carriers as asymptomatic ovarian/fallopian cancers were found in 4.5% of patients. However, a longer follow‐up and larger series are required to more precisely evaluate the benefits of this procedure in terms of BC incidence, peritoneal malignancy, or recurrence. Cancer 2007. © 2007 American Cancer Society.

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Pathology of Ovarian Cancers in BRCA1 and BRCA2 Carriers

Cited by 227 publications

References 22 publications

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma

Prophylactic salpingo‐oophorectomy in a series of 89 women carrying a BRCA1 or a BRCA2 mutation

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