Immunohistochemical and molecular pattern of p53 in epithelial ovarian cancers negative for germline BRCA1/2 variants.

Epithelial ovarian cancers (EOC) associated with germline or somatic BRCA pathogenetic variants have a significantly higher rate of TP53aberrations. The majority of TP53 mutations are detectable by immunohistochemistry and several studies demonstrated that an abnormal p53 pattern characterized high-grade EOCs. An abnormal p53 immunohistochemical staining in fallopian tube (serous tubal intraepithelial carcinoma (STIC) and "p53 signature" is considered as a precancerous lesion of high-grade EOCs and it is often found in fallopian tube tissues of BRCA germline mutated patients suggesting that STIC is an early lesion and the TP53 mutation is an early driver event of BRCA mutated high-grade EOCs. No relevant data are present in literature about the involvement of p53 abnormal pattern in EOC carcinogenesis of patients negative for germline BRCA variants. We describe TP53 mutation results in relationship to the immunohistochemical pattern of p53 expression in a series of EOCs negative for BRCA1 and BRCA2 germline mutations. In addition, we also investigated STIC presence and "p53 signature" in fallopian tube sampling of these EOCs. Our results demonstrate that TP53 alterations are frequent and early events in sporadic EOCs including also low-grade carcinomas. Also in this series, STIC is associated with an abnormal p53 pattern in fallopian tubes of high-grade EOCs. In summary, TP53 aberrations are the most frequent and early molecular events in EOC carcinogenesis independently from BRCA mutation status.

Strategies for Lynch syndrome identification in selected and unselected gynecological cancers.

BACKGROUND: Endometrial carcinoma represents a sentinel cancer for Lynch syndrome (LS) identification. It is crucial to highlight how other types of tumors can arise in the gynecological tract acting as sentinel tumors in LS patients.Up to now, no established LS patient management strategy has incorporated the presence of these additional candidate sentinel tumors to improve the prevention and management of LS tumors. METHODS: In order to investigate the involvement of the most frequent gynecological cancers in gynecological cancers, we studied different subsets of gynecological cancers using both somatic approaches, including mismatch repair (MMR) gene immunohistochemical expression, microsatellite instability, and germline analyses ofMSH2, MSH6, MLH1, PMS2 and EPCAM genes.A total of 261 patients referring to the Cancer Genetic Counselling Service of our institution were included in the study. In detail, our series was composed of 131 patients affected by uterus cancers including endometrial, isthmus and non-HPV endocervical carcinomas, 113 patients affected by ovarian cancers and 17 patients affected by synchronous endometrial/ovarian carcinomas (SEOC).In addition, we studied 115 cases of endometrial cancers identified by 2 years of universal testing (endometrial cancers/UTs) using IHC analysis of four MMR proteins. RESULTS AND CONCLUSIONS: The incidence of MMR defective gynecological cancers ranged from 7.1 to 47.1% depending on cancer site and selection. LS patients carriers of pathogenetic MMR variants were identified in 19.8% of uterus cancers, 35.3% of SEOC, 4.4% of ovarian cancers. In addition, pathogenetic MMR variants were identified in 4.3% of endometrial cancers/universal testing investigated with universal screening.In conclusion, gynecological cancers are heavily involved in LS and our study shows that MMR screening using immunohistochemical pattern and MSI analysis of endometrial and ovarian cancers as well as of rare entities such as non-HPV related endocervical cancers and synchronous endometrial and ovarian cancers are sentinels for LS.Tumor testing approach improves early identification of MMR defective gynecological cancers and this is an effective strategy to detect high-risk patients and to offer them and their relatives personalized cancer prevention.

BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor.

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.

HPV nonrelated endocervical adenocarcinoma in hereditary cancer syndromes.

INTRODUCTION: The relationship between endocervical cancer and cancer susceptibility syndromes is not yet fully understood. We present 2 cases of endocervical cancer: 1 arising in a patient carrier with a pathogenic BRCA1 variant and the second detected in a Lynch syndrome family carrying the MSH2 germline pathogenic variant. CASE DESCRIPTION: Somatic analyses including loss of heterozygosity and fluorescent in situ hybridization demonstrated that the second hit in patient 1 is BRCA1-related. Mismatch repair somatic analyses in the second family demonstrated that the endocervical cancers of patient 2 and of her sister are MSH2-related. These data confirm the relationship between the pathogenesis of endocervical cancer and the presence of germline BRCA1 and MSH2 mutations. CONCLUSIONS: Our study confirms that gynecologic cancers including rare entities such as non-human papillomavirus-related endocervical cancer (NHPVA) are sentinels for inherited cancer syndromes. Endocervical cancer NHPVAs might be considered for cancer genetic counseling in order to improve cancer prevention. For this reason, the role of pathologists is particularly important for the correct identification of the cervical tumor site.