To evaluate the role of different specific types of germline breast cancer susceptibility
mutations on the age of onset of high grade serous ovarian cancer.
This was a multicenter, international, ...retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations in
genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type of
genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared.
Excluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. The
gene was affected in 324 (68.4%) cases, while
was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer between
and
patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in the
and
subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55).
Different types of germline
mutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer.
This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and ...second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy.
Genomic testing expansion is accompanied by an increasing need for genetic counselling and intrafamilial communication. Genetic counselling can play an important role in facilitating intrafamilial ...communication and relationships. We conducted a cross-sectional, multicenter study including 252 Italian women, using a questionnaire divided in two sections, the first one to be filled after the pre-test counselling and the second after receiving BRCA test results. We assessed the factors influencing intrafamilial disclosure of genetic information for hereditary breast and ovarian cancer, family members with whom probands are more prone to share genetic information, and the perceived understanding of information received by counselees during genetic counselling. Women were accompanied to the counselling more often by their husband/partner. Among those with a positive BRCA test result, 49% intended to communicate it to their offspring and 27% to their husband/partner. Younger women, those living with their husband/partner, and those who described family communication as open/profound and spontaneous/sincere had a higher probability of being accompanied during genetic counselling and discuss about it with relatives. Spontaneous/sincere or open/profound family communication and joyful/happy familial relationships were associated with the decision to undergo genetic testing as a responsibility towards relatives. Women had a good understanding of counselling contents (mean score 9.27 in a scale 1-10). Genetic counselling providers should consider that genetic information disclosure does not depend only on the clarity of the information provided, but also on pre-existing intrafamilial communication and relationships, family structure and marital status, indicating the need for a personalised approach accounting for these factors.
Abstract Background Germline mutations in the STK11/LKB1 gene cause Peutz–Jeghers syndrome, an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation, hamartomatous ...gastrointestinal polyposis, and an increased risk for various malignancies. We here report the results of the first Italian collaborative study on Peutz–Jeghers syndrome. Aims To assess cancer risks in a large homogenous cohort of patients with Peutz–Jeghers syndrome, carrying, in large majority, an identified STK11/LKB1 mutation. Methods One-hundred and nineteen patients with Peutz–Jeghers syndrome, ascertained in sixteen different Italian centres, were enrolled in a retrospective cohort study. Relative and cumulative cancer risks and genotype–phenotype correlations were evaluated. Results 36 malignant tumours were found in 31/119 (29 STK11/LKB1 mutation carriers) patients. The mean age at first cancer diagnosis was 41 years. The relative overall cancer risk was 15.1 with a significantly higher risk ( p < 0.001) in females (22.0) than in males (8.6). Highly increased relative risks were present for gastrointestinal (126.2) and gynaecological cancers (27.7), in particular for pancreatic (139.7) and cervical cancer (55.6). The Kaplan–Meier estimates for overall cumulative cancer risks were 20%, 43%, 71%, and 89%, at age 40, 50, 60 and 65 years, respectively. Conclusion Peutz–Jeghers syndrome entails markedly elevated cancer risks, mainly for pancreatic and cervical cancers. This study provides a helpful reference for improving current surveillance protocols.
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder caused, in more than 80% of cases, by mutations of either the endoglin (ENG) or the activin A receptor-like type 1 ...(ACVRL1) gene. Several hundred variants have been identified in these HHT-causing genes, including deletions, missense and nonsense mutations, splice defects, duplications, and insertions. In this study, we have analyzed retrospectively collected images of magnetic resonance angiographies (MRA) of the brain of HHT patients, followed at the HHT Center of our University Hospital, and looked for the distribution of cerebrovascular phenotypes according to specific gene variants. We found that cerebrovascular malformations were heterogeneous among HHT patients, with phenotypes that ranged from classical arteriovenous malformations (AVM) to intracranial aneurysms (IA), developmental venous anomalies (DVA), and cavernous angiomas (CA). There was also wide heterogeneity among the variants of the ENG and ACVRL1 genes, which included known pathogenic variants, variants of unknown significance, variants pending classification, and variants which had not been previously reported. The percentage of patients with cerebrovascular malformations was significantly higher among subjects with ENG variants than ACVRL1 variants (25.0% vs. 13.1%, p < 0.05). The prevalence of neurovascular anomalies was different among subjects with different gene variants, with an incidence that ranged from 3.3% among subjects with the c.1231C > T, c.200G > A, or c.1120C > T missense mutations of the ACVRL1 gene, to 75.0% among subjects with the c.1435C > T missense mutation of the ACVRL1 gene. Further studies and larger sample sizes are required to confirm these findings.
An expert consensus panel convened by the Italian Association for Inherited and Familial Gastrointestinal Tumors (Associazione Italiana per lo Studio della Familiarità ed Ereditarietà dei Tumori ...Gastrointestinali, AIFEG) reviewed the literature and agreed on a number of position statements regarding the definition and management of polyposis coli without an identified pathogenic mutation on the APC or MUTYH genes, defined in the document as NAMP (non-APC/MUTYH polyposis).
PDF
