ORIGINAL PAPER Journal of Pathology J Pathol 2011; 225: 106–117 Published online 8 July 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.2927 Identification of abrogated pathways in fallopian tube epithelium from BRCA1 mutation carriers Sophia HL George, 1,2 James Greenaway, 1,4 Anca Milea, 2,4 Victoria Clary, 1 Sanjeev Shaw, 1 Monika Sharma, 3 Carl Virtanen 3 and Patricia A Shaw 1,4 * 1 Department of Pathology, University Health Network, Toronto, Ontario, Canada 2 Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada 3 Microarray Centre, University Health Network, Toronto, Ontario, Canada 4 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada *Correspondence to: Patricia A Shaw, Department of Pathology, University Health Network, Eaton Wing, Room 11-444, 200 Elizabeth Streeet, Toronto, Ontario M5G 2C4, Canada. e-mail: patricia.shaw@uhn.on.ca Abstract The discovery of occult invasive and intra-epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the fallopian tube epithelium as the source of serous cancer. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations present in morphologically normal tubal epithelium from BRCA1 heterozygotes reflect the earliest events in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Genetic profiling of microdissected tubal epithelium from histologically normal BRCA1 mutation carriers and controls was performed. We sought to define a signature which differentiated BRCA1 mutant tubal epithelium from women with low risk of developing ovarian cancer. Molecular differences between the follicular and luteal phases were prominent and, by using filtering techniques and a two-way ANOVA without a False Discovery Rate correction, we identified 440 probe sets with a more than two-fold change in gene expression related to BRCA1 mutation status. Using gene ontology and known associations to cancer pathways, we selected five genes for further analysis by qPCR and immunohistochemistry, and were able to demonstrate statistically significant differentiation of BRCA1 and control cases in an independent set of cases. The altered expression profiles in histologically normal tubal epithelium from BRCA1 heterozygotes suggest that these cells may respond differently to microenvironmental stresses. Copyright  2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: BRCA1; fallopian tube; serous carcinoma; GADD45-β; C/EBP-δ; NAMPT; STAT3 Received 9 February 2011; Revised 25 March 2011; Accepted 17 April 2011 No conflicts of interest were declared. Introduction Epithelial ovarian cancer (EOC) is a highly hetero- geneous group of cancers classified into five main histotypes, based on histopathological features: endometrioid, clear cell, mucinous, low-grade serous and high-grade serous carcinoma. Of these, high- grade serous carcinoma (HGSC) is the most common and aggressive histotype, accounting for approxi- mately 70% of carcinomas and 90% of deaths due to ovarian cancer. It is rarely detected while con- fined to the ovary, with > 90% of women hav- ing intra-abdominal spread when diagnosed. HGSC is also the predominant histotype associated with inherited mutations of BRCA1 and BRCA2 [1,2], and recently occult (clinically undetected) invasive and serous tubal intra-epithelial carcinomas (STICs) have been identified in the fallopian tubes of muta- tion carriers undergoing risk-reducing surgery [3,4]. Detailed histopathological examination of tubal epithe- lium in this genetically high-risk population has sub- sequently led to the discovery of putative cancer pre- cursor lesions in the fallopian tube, some of which, ie the p53 signature, are found with a similar fre- quency in BRCA mutation carriers and non-carriers. Others, including STICs, are more frequent in muta- tion carriers [5–8]. Little is known, however, of the molecular events leading up to the malignant trans- formation resulting in STICs and invasive HGSC. Loss of BRCA1 protein and loss of heterozygosity is seen once malignant transformation has occurred but not in early precancerous lesions [9], indicating the possibility of BRCA1 haploinsufficiency preceding transformation. Copyright  2011 Pathological Society of Great Britain and Ireland. J Pathol 2011; 225: 106–117 Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com