Over a 46-month period, the objectives of the National Cancer Control Program (NCCP, pol. Narodowy Program Zwalczania Chorób Nowotworowych), coordinated by the Ministry of Health, were pursued by conducting genetic diagnostics on individuals at high risk of developing cancer. A total of 1097 individuals were enrolled in the study, leading to the identification of 128 cases of germline mutations. The implementation of the NCCP led to the identification of genetic mutations in 4.43% of the patients qualified for BRCA1 and BRCA2 screening tests, in 18.18% of those qualified for a comprehensive next-generation sequencing (NGS) panel in cases of breast and ovarian cancer, and in 17.36% of cases of colorectal and endometrial cancer. The research conducted allowed us to establish individualized preventive and therapeutic approaches for mutation carriers. However, the results prove that liberalizing the inclusion criteria for high-throughput diagnostics and the use of broad gene panels could significantly increase the percentage of detected carriers. This publication serves as a summary and discussion of the results obtained from the implementation of the NCCP as well as of the role of genetic consulting in personalized medicine.

Hereditary breast and ovarian cancer (HBOC) is a syndrome defined by an increased risk of developing breast and/or ovarian cancer most commonly due to germline disease-causing variants in the BRCA1 and BRCA2 genes, but also other causative genes such as PALB2, ATM and CHEK2. As genetic testing becomes more prevalent and new clinical data emerge, updates of national guidelines are required to incorporate these advances in our knowledge. The aim of this work is to review the guidelines for HBOC genetic testing and clinical surveillance across European countries, mostly affiliated to the European Reference Network (ERN) for Genetic Tumor Risk Syndroms (GENTURIS). Young onset breast cancer (BC), triple negative phenotype, or bilateral BC are considered as criteria for genetic testing in all, with differences in age limits. Testing of invasive epithelial non-mucinous ovarian cancer is also universally accepted. While breast magnetic resonance imaging (MRI) is consistently recommended in high-risk individuals, age of onset for mammograms differ between 30 and 40 years. Risk-reducing mastectomy is commonly offered as an option, while risk-reducing salpingo-oophorectomy is universally recommended. The largest differences are observed with respect to ovarian surveillance prior to risk-reducing salpingo-oophorectomy and in breast surveillance for carriers of non-BRCA1/2 genes. These differences in national guidelines reflect the variations in clinical consensus that may be reached in the absence of consistent evidence for some recommendations.

OBJECTIVE: Providing genetic counseling and genetic testing to at-risk blood relatives (cascade screening) is important for improving BRCA cancer outcomes. Intra-familial communication of risk is critical for cascade screening efforts yet relatively little is known about men\'s role in communicating BRCA risk. We sought to examine men\'s coping response to their BRCA status and intra-familial communication of risk to inform the development of tailored interventions that could promote cascade screening.
METHODS: We employed a sequential mixed-methods design. First, we measured coping response (quantitative) using the Multidimensional Impact of Cancer Risk Assessment (MICRA). MICRA scores were compared between BRCA+ men, BRCA- men and BRCA+ women. Subsequently, we used template analysis to analyze qualitative interviews exploring coping and intra-familial communication of risk. The Theory of Planned Behavior (TPB) served as a guiding framework for identifying intervention targets.
RESULTS: BRCA+ men (n = 36) had significantly higher levels of distress (p < 0.001), uncertainty (p < 0.001) and negative experiences (p < 0.05) compared to BRCA- male counterparts (n = 23). BRCA+ men had significantly lower distress (p < 0.001) and uncertainty (p < 0.001) than BRCA+ women (n = 406). Qualitative analysis of in-depth interviews with BRCA+ men (n = 35) identified promoters and barriers to active coping response and intra-familial communication of risk. Mapping results onto the TPB identified targets for tailoring person-centered approaches for men addressing beliefs/attitude, subjective norms, and perceived behavioral control.
CONCLUSIONS: Men and women appear to have different coping responses to learning their BRCA status. Developing tailored (sex-based), theory informed interventions may help promote intra-familial communication of BRCA risk and support cascade screening.

The contribution of deep intronic splice-altering variants to hereditary breast and ovarian cancer (HBOC) is unknown. Current computational in silico tools to predict spliceogenic variants leading to pseudoexons have limited efficiency. We assessed the performance of the SpliceAI tool combined with ESRseq scores to identify spliceogenic deep intronic variants by affecting cryptic sites or splicing regulatory elements (SREs) using literature and experimental datasets. Our results with 233 published deep intronic variants showed that SpliceAI, with a 0.05 threshold, predicts spliceogenic deep intronic variants affecting cryptic splice sites, but is less effective in detecting those affecting SREs. Next, we characterized the SRE profiles using ESRseq, showing that pseudoexons are significantly enriched in SRE-enhancers compared to adjacent intronic regions. Although the combination of SpliceAI with ESRseq scores (considering ∆ESRseq and SRE landscape) showed higher sensitivity, the global performance did not improve because of the higher number of false positives. The combination of both tools was tested in a tumor RNA dataset with 207 intronic variants disrupting splicing, showing a sensitivity of 86%. Following the pipeline, five spliceogenic deep intronic variants were experimentally identified from 33 variants in HBOC genes. Overall, our results provide a framework to detect deep intronic variants disrupting splicing.

Up to 10% of individuals with breast cancer (BC) belong to families with hereditary syndromes. The aim of this study was to develop an instrument to identify individuals/families at high-hereditary risk for BC and offer dedicated surveillance programs according to different risks.
The instrument consisted of a primary questionnaire collecting history of BC and ovarian cancer (OC). This questionnaire was applied to women enrolled in the Emilia-Romagna Breast Cancer Screening Program. General practitioners (GPs) and specialists could propose the same questionnaire too. Women with a score of ≥ 2, were invited to complete an oncogenetic counseling. According to the Tyrer-Cuzick evaluation, women considered at high risk were invited to involve the most representative alive individual of the family affected with BC/OC for BRCA1/2 genetic testing.
Since January 2012 and December 2016, 660 040 women were evaluated by the regional screening program, of which 22 289 (3.5%) were invited to the Spoke evaluation, but only 5615 accepted (25.2%). Totally, also considering women sent by GPs and specialists, 11 667 were assessed and 5554 were sent to the Hub evaluation. Finally, 2342 (42.8%) women fulfilled the criteria for genetic testing, and 544 (23.2%) resulted BRCA1/2 mutation carriers.
To our knowledge, this is the first regional population-based multistep model that is aimed to identify individuals with BRCA1/2 mutations and to offer an intensive surveillance program for hereditary-high risk women. This tool is feasible and effective, even if more efforts must be performed to increase the acceptance of multiple assessments by the study population.

Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (<0.2%). For VHL (6.5%) and LFS (4.9%) the difference was not statistically significant. PND for Rb started 3 years after introduction of diagnostic DNA testing and remained stable over the years. For the other cancer syndromes PND started 10-15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences.

More than 40 years ago Lynch et al. described several multigenerational breast cancer family pedigrees which demonstrated autosomal dominant inheritance of a trait(s) that increased risks for both breast and ovarian cancers. Mutation carriers in at least 90 % of these hereditary breast ovarian cancer (HBOC) syndrome families have been linked to cancer-associated mutations in the genes BRCA1 and BRCA2. This review focuses on the contributions of Lynch, colleagues and collaborators and pertinent literature, toward defining the HBOC syndrome, the cancer risks that the inherited adverse mutations convey, the gynecologic tissues and organs from which the malignancy may arise to disseminate throughout the pelvic and abdominal organs and peritoneum and how this information can be used to reduce the risk and morbidities of intra-abdominal carcinomatosis in effected individuals.

暂无摘要。

Hereditary ovarian cancers account for 10% of all cases. Two major syndromes with dominant autosomal transmission are identified. The most common one is breast-ovarian cancer syndrome due to BRCA1 and BRCA2 genes mutations, and the Lynch syndrome with mutated MMR genes is the other. Alterations in homologous recombination specifically observed in ovarian cancer with BRCA defects associated to Parp inhibition create a synthetic lethality of special interest. Numerous studies are in progress to explore this promising new approach. Furthermore, it seems that carcinogenesis of these two syndromes are different, suggesting alternative therapeutic options in the near future in order to improve prognosis of ovarian carcinomas.