Preneoplastic Lesions Fimbria Early Diagnosis Markers Underlying Timeline Mechanisms at The Origin of Ovarian Cancer in BRAC1/2 Patients: Case Reports Based on Proteogenomic Study

Abstract

Background : BRCA 1 or 2 mutations have been known to be drivers of high-grade serous ovarian carcinomas (HGSC). As no efficient screening is currently available, a bilateral prophylactic salpingo-oophorectomy is the recommended procedure to avoid this often lethal carcinomas. However, a proportion of BRCA mutation carriers refuse to undergo this procedure due to significant impacts on quality and quantity of life, especially if a hormone replacement therapy is contra-indicated. Such decision expose them to developing a pelvic serous carcinoma. A better undersanding of high-grade serous cancer pathogenesis, rather stemming from fallopian tubes than from ovary itself, makes interesting a two-step prophylactic strategy in which tubes are removed as soon as possible, followed by oophorectomies at the time of menopause. Thus women are protected against HGSC with no immediate need of an HRT. Following this idea and considering the concept of junctional “hot spots “ (called mesothelo-müllerian junctions) for the development of HGSC, we suggested as first step to perform a bilateral prophylactic radical fimbriectomy rather than salpingectomy with a delayed oophorectomy (RF/DO). This operation was tested in a national phase 2 trial from 2011-2014 (NCT01608074). Radical Fimbriectomy (RF) consists of the surgical removal of both fallopian tubes along with a tiny part of the adherent ovary to suppress the tubal source of possible dysplastic cells from which can stem a high-grade invasive tumor, through stepwise cellular and genomic altereations ranging from p53 signatures to serous tubal intraepithelial carcoinoma (STIC), just before genuine invasive HGSC, through intermediate aspects (STIL) and (TILT). Methods : In this context, we carried out an in-depth proteomics analysis of these “pre-invasive ” epithelial lesions based on spatially resolved proteomic/ and bioinformatics systems biology platforms platform guided by immunohistochemistry (IHC) technique. Results : Specific markers related to each preneoplastic lesions and in particular from normal to p53 signatures were evaluated. We identified EIF3B, MOB1B and Emilin2, CAVIN1 as bad prognosis markers of P53 signature whereas CAVIN2, SPTANi, FBLN5 as good prognosis markers. Among the novel markers identified, mutated proteins as well as hidden proteins translated from alternative ORF Proteome have been sequenced and characterized. Conlusion : In summary, our results represent a novel pioneer approach to identify the unique under investigated markers that can characterize the molecular mechanism occurring in the preneoplastic lesion in fimbria at the origin of the HGSC.