scholarly journals 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

2021 ◽  
Author(s):  
Maxence Wisztorski ◽  
Philippe Saudemont ◽  
Soulaimane Aboulouard ◽  
Tristan Cardon ◽  
Fabrice Narducci ◽  
...  
Keyword(s):  
Case Reports ◽  
Brca Mutation ◽  
Hormone Replacement ◽  
Serous Carcinoma ◽  
Surgical Removal ◽  
High Grade ◽  
Fallopian Tubes ◽  
Preneoplastic Lesions ◽  
Ovarian Carcinomas ◽  
Cancer Pathogenesis

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.

scholarly journals Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3468
Author(s):  
Gulisa Turashvili ◽  
Conxi Lazaro ◽  
Shengjie Ying ◽  
George Charames ◽  
Andrew Wong ◽  
...  
Keyword(s):  
Success Rate ◽  
Limit Of Detection ◽  
Brca Mutation ◽  
Mutation Rates ◽  
Serous Carcinoma ◽  
Sample Type ◽  
High Grade ◽  
Brca Testing ◽  
Cancer Syndrome ◽  
Tissue Samples

Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in BRCA1 or BRCA2, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3–7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma. Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%. Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size (p ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks (p > 0.05). Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor BRCA testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.

scholarly journals A mini-review regarding the carcinogenesis and morphology of serous tumors of the ovary, fallopian tube and peritoneum

2021 ◽  
Vol 8 (1) ◽  
pp. 44-52
Author(s):  
Tiberiu-Augustin Georgescu ◽  
Roxana Bohiltea ◽  
Octavian Munteanu ◽  
Corina Grigoriu ◽  
Ioana Paunica ◽  
...  
Keyword(s):  
Fallopian Tube ◽  
Female Genital Tract ◽  
Molecular Classification ◽  
Genetic Alterations ◽  
Serous Carcinoma ◽  
Low Grade ◽  
High Grade ◽  
Cancer Pathogenesis ◽  
Well Differentiated ◽  
Serous Tumors

Similar to the already well-recognized adenoma-carcinoma sequence in colorectal cancer pathogenesis, it has been believed for many decades that the progression of ovarian epithelial tumors occurs from benign serous cystadenomas to borderline tumors, to well-differentiated carcinomas, and ultimately, to poorly differentiated carcinomas. However, it is currently accepted that low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC) are fundamentally different tumor types and, consequently, different diseases. In fact, whereas the benign-borderline-malignant sequence seems to apply quite well to low-grade serous carcinoma, the sequence of genetic alterations in high-grade serous carcinoma is substantially different. In this mini-review, we included the current consensus regarding the morphological and etiopathogenic results regarding serous tumors of the ovary, fallopian tube and peritoneum. It also briefly describes the history of benign, borderline and malignant serous tumors, discussing multiple types of dichotomies in serous carcinomas of the female genital tract and summarizing the current molecular classification.

scholarly journals Effect of prophylactic salpingectomy on ovarian function in premenopausal women in tertiary referral center

2017 ◽  
Vol 6 (10) ◽  
pp. 4243
Author(s):  
Tamer M. Abdel Dayem ◽  
Amira M. Badawy
Keyword(s):  
Ovarian Function ◽  
Premenopausal Women ◽  
Serous Carcinoma ◽  
Low Grade ◽  
Type I ◽  
Ovarian Cancer Risk ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Ovarian Cancers ◽  
Prophylactic Salpingectomy

Background: Epithelial ovarian cancers (EOCs) are the most common cause of death from gynaecological malignancy. Serous ovarian carcinomas represent (68%) of Epithelial ovarian cancers, they are further divided into low-grade (type I) and high-grade (type II) serous ovarian carcinomas. There has been increasing evidence that fallopian tubes are considered the most important site of origin of pelvic high grade serous carcinoma. Salpingectomy is thought to be effective in reducing ovarian cancer risk in the future and prolonging average life expectancy, however, there are some concerns regarding ovarian function after elective salpingectomy in premenopausal women. The current study was carried out to assess the effect of salpingectomy on ovarian function in premenopausal women.Methods: 60 premenopausal cases were recruited and subjected to open abdominal hysterectomy without oophorectomy (for benign indications). Included cases were below 45 years, with documented active ovarian functions. Cases with genital malignancy, ovarian gross pathology and suspected or known ovarian failure were excluded. Cases were randomly allocated to one of two groups; group-A (where salpingectomy was performed), and group-B (where salpingectomy was not done). For all patients, ovarian functions were assessed prior operation, and at one and three months after operation using serum anti-Mullarian hormone (AMH) as well as early follicular antral follicular count (AFC), serum follicle stimulating hormone (FSH) and serum oestradiol (E2).Results: The mean pre-operative AFC, AMH, FSH, and E2 levels showed no significant changes after operation at one and three months postoperative follow up in both studied groups, denoting preserved ovarian function in both groups.Conclusions: Prophylactic salpingectomy is a safe and simple procedure that has no effect on ovarian reserve or function when performed in premenopausal women.

Critical molecular abnormalities in high-grade serous carcinoma of the ovary

2008 ◽  
Vol 10 ◽  
Author(s):  
Martin Köbel ◽  
David Huntsman ◽  
C. Blake Gilks
Keyword(s):  
Serous Carcinoma ◽  
Molecular Pathways ◽  
High Grade ◽  
Body Site ◽  
Ovarian Carcinomas ◽  
Research And Practice ◽  
Molecular Abnormalities ◽  
Morphological Heterogeneity ◽  
Molecular Events ◽  
Carcinoma Of The Ovary

Ovarian carcinomas show more morphological heterogeneity than adenocarcinomas of any other body site. It has recently become clear that the morphologically defined subtypes of ovarian carcinoma are distinct diseases, with different risk factors, molecular events during oncogenesis, likelihood of spread, responses to chemotherapy, and outcomes. This review focuses on molecular abnormalities (in genes expressing BRCA1/2, TP53 and RB1/CCND1/CDKN2A/E2F) found in high-grade serous carcinomas of the ovary, which account for most ovarian cancer deaths. These highly aggressive but chemosensitive tumours are associated with perturbation of molecular pathways leading to genomic instability and extreme mutability and present unique challenges in oncological research and practice.

scholarly journals The Ovary Is an Alternative Site of Origin for High-Grade Serous Ovarian Cancer in Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 1975-1981 ◽  
Author(s):  
Jaeyeon Kim ◽  
Donna M. Coffey ◽  
Lang Ma ◽  
Martin M. Matzuk
Keyword(s):  
Ovarian Cancer ◽  
Double Mutant ◽  
P53 Mutation ◽  
Mutant Mice ◽  
Serous Carcinoma ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Fallopian Tubes ◽  
Double Knockout ◽  
Triple Mutant

Abstract Although named “ovarian cancer,” it has been unclear whether the cancer actually arises from the ovary, especially for high-grade serous carcinoma (HGSC), also known as high-grade serous ovarian cancer, the most common and deadliest ovarian cancer. In addition, the tumor suppressor p53 is the most frequently mutated gene in HGSC. However, whether mutated p53 can cause HGSC remains unknown. In this study, we bred a p53 mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, a mouse model duplicating human HGSC, to generate triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop metastatic HGSCs originating from the fallopian tube. Unlike DKO mice, however, even after fallopian tubes are removed in TKO mice, ovaries alone can develop metastatic HGSCs, indicating that a p53 mutation can drive HGSC arising from the ovary. To confirm this, we generated p53R172H-Pten double-mutant mice, one of the genetic control lines for TKO mice. As anticipated, these double-mutant mice also develop metastatic HGSCs from the ovary, verifying the HGSC-forming ability of ovaries with a p53 mutation. Our study therefore shows that ovaries harboring a p53 mutation, as well as fallopian tubes, can be a distinct tissue source of high-grade serous ovarian cancer in mice.

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