Investigator
University Of Insubria
From Therapy to Cancer Prevention Using HRD Testing on Patients with High-grade Ovarian Cancer
Abstract Approximately half of high-grade ovarian cancers are characterized by genetic and epigenetic alterations in genes involved in homologous recombination repair (HRR), most commonly BRCA1 and BRCA2. HRR defects (HRD) identified by tests of genomic instability confer PARP inhibitor sensitivity in ovarian cancers. Commercial tests that combine tumor BRCA testing with a genomic instability score (HRD test) are available in clinical practice. We seek to determine the performance of three different HRD tests to improve therapy management and prevention of ovarian cancer. Tumor samples from 50 patients with high-grade ovarian cancers were investigated for tumoral BRCA status, genomic instability, and BRCA1 promoter methylation for treatment purposes. Patients with ovarian cancer that tested positive for BRCA variants and/or genomic instability defect were referred to the Cancer Genetics Service for germline testing. A positive HRD status was observed in 54% of cases, and pathogenic variants in BRCA genes were identified in 41% of cases presenting genomic instability. BRCA1 methylation assay revealed promoter hypermethylation in 20% of ovarian cancers that tested positive for HRD and negative for BRCA1/2 variants. Among 26 women referred to cancer genetic counseling, 10 carried germline variants in HRR genes. HRD status determined eligibility for PARP inhibitor treatment in all but two ovarian cancers. This study outlines that determining genomic instability helps identify inherited ovarian cancers. HRD testing, crucial for making high-grade ovarian cancer treatment choices, must be linked to an established path of cancer genetic counseling and management of individuals at high cancer risk. Prevention Relevance: Genomic instability status (HRD testing), which is essential for making therapy choices, is useful to identify inherited ovarian cancers. Identifying these families with high cancer risk is critical for implementing targeted cancer prevention strategies.
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.
MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis
(1) Background: MLH1 hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly, MLH1 hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However, MLH1 hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of MLH1 protein expression and microsatellite instability. All cases were investigated for MLH1 promoter methylation and MLH1/PMS2 germline variants. (3) Results: Somatic MLH1 promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of MLH1 germline pathogenic variants. In two families, primary and secondary MLH1 epimutations were demonstrated. (4) Conclusions: MLH1 hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are MLH1 hypermethylated. Current flow charts for universal LS screening, which include MLH1 methylation, should be applied, paying attention to a patient’s family and personal history.
