Explore the vast range of titles available.

Presymptomatic and predictive genetic testing should involve a considered choice, which is particularly true when testing is undertaken in early adulthood. Young adults are at a key life stage as they may be developing a career, forming partnerships and potentially becoming parents: presymptomatic testing may affect many facets of their future lives. The aim of this integrative systematic review was to assess factors that influence young adults' or adolescents' choices to have a presymptomatic genetic test and the emotional impact of those choices. Peer-reviewed papers published between January 1993 and December 2014 were searched using eight databases. Of 3373 studies identified, 29 were reviewed in full text: 11 met the inclusion criteria. Thematic analysis was used to identify five major themes: period before testing, experience of genetic counselling, parental involvement in decision-making, impact of test result communication, and living with genetic risk. Many participants grew up with little or no information concerning their genetic risk. The experience of genetic counselling was either reported as an opportunity for discussing problems or associated with feelings of disempowerment. Emotional outcomes of disclosure did not directly correlate with test results: some mutation carriers were relieved to know their status, however, the knowledge they may have passed on the mutation to their children was a common concern. Parents appeared to have exerted pressure on their children during the decision-making process about testing and risk reduction surgery. Health professionals should take into account all these issues to effectively assist young adults in making decisions about presymptomatic genetic testing.

Ovarian carcinomas represent a heterogeneous group of neoplasms consisting of separate entities with distinct risk factors, precursor lesions, pathogenesis, patterns of spread, molecular profiles, clinical course, response to chemotherapy, and outcomes. The histologic subtype and the related molecular features are essential for individualized clinical decision-making. The fifth edition of the World Health Organization classification of tumors of the female genital tract divides ovarian carcinomas into at least five main and distinct types of ovarian carcinomas: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma. Molecular pathology has improved the knowledge of genomic landscape of ovarian carcinomas identifying peculiar alterations for every histologic subtype. It is well-known that high-grade and low-grade serous carcinomas are separate entities with entirely different morphologic and molecular characteristics. TP53 and BRCA mutations are typical of high-grade serous carcinoma, whereas BRAF and KRAS mutations frequently occur in low-grade serous carcinoma. Endometrioid and clear cell carcinomas are frequently associated with endometriosis. Endometrioid tumors are characterized by β-catenin alterations, microsatellite instability, and PTEN and POLE mutations, while ARID1A mutations occur in both endometrioid and clear cell carcinomas. Mucinous carcinomas are uncommon tumors associated with copy-number loss of CDKN2A and KRAS alterations and metastasis from other sites should always be considered in the differential diagnosis.

BackgroundBirt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series.MethodsA comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants.ResultsOur final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers.ConclusionsThese updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

Background Genetic testing has led to a considerable enhancement in the ability to identify individuals at risk of Hereditary Breast and Ovarian Cancer syndrome related to BRCA1/2 pathogenic variants, thus necessitating personalised prevention programs. However, barriers related to intrafamilial communication, privacy regulations, and genetic information dissemination hinder preventive care, particularly in Italy, where legal constraints limit the disclosure of genetic risks to at-risk relatives. This study examines the relationship between BRCA1/2 carriers’ communication challenges and three factors: cancer status, comprehension of genetic information, and the genetic counseling pathway accessed (Traditional Genetic Counseling, TGC vs. Mainstream Cancer Genetics, MCG). Methods This multicenter, prospective, observational study included 277 BRCA1/2 carriers (probands and relatives) aged 18–80 from various Italian centers. Participants completed a sociodemographic form, a self-administered survey, and psychological assessments (Impact of Event Scale, IES and Distress Thermometer, DT). Categorical variables were compared using Pearson’s Chi-squared test or Fisher’s exact test based on sample size and expected frequencies, whereas continuous variables were analyzed using the Wilcoxon rank-sum test because of non-normal data distribution. Results Among the 277 carriers (115 probands, 162 relatives), 79.4% received TGC and 20.6% MCG. The cancer prevalence was higher in probands (83%) than in relatives (22%). The probands exhibited greater psychological distress (higher IES and DT scores), and cancer-affected relatives had higher distress levels than healthy relatives (p = 0.008). While no severe psychological distress or PTSD was found, distress was more associated with cancer diagnosis than genetic status. Genetic comprehension was significantly higher in relatives (p = 0.007) and in those who underwent TGC compared to MCG (p < 0.001). TGC carriers also better understood genetic risks and management strategies (p < 0.001). Conclusions Psychological distress and genetic comprehension significantly influenced the communication. TGC enhances understanding more effectively than MCG, highlighting the need for tailored support for both carriers and healthcare professionals to improve cascade counseling and testing rates, and cancer prevention. As we look into the future, we need to critically approach MCG, and determine how to address carriers understanding and prevention needs and reincorporate a more comprehensive genetic risk assessment into the MCG model.

ObjectivesDespite the increasing availability of non-invasive prenatal testing (NIPT), women’s experiences and motivations remain largely unknown. The use of NIPT is increasing in Italy; however, its organisation and access paths vary considerably. Women may undergo testing in either public or private facilities, where differences in pretest information, testing procedures and result communication may influence their experience. This study aims to investigate the attitudes, awareness and experiences of Italian women undergoing NIPT.DesignA cross-sectional anonymous online survey was conducted via social media in the period March–August 2023.SettingThis nationwide study was conducted in Italy.ParticipantsWomen over 18 years old who had undergone NIPT were included.ResultsResponders were 4154 women from every part of Italy. Most participants perceived the information provided during pre-NIPT counselling as extremely/very clear (68.2%) and helpful (72.5%), with higher proportions observed when counselling was delivered by geneticists. The mean knowledge score was 12.3 (range: 0–15) and was statistically higher for women with higher education level and prior NIPT experience. Half of the women reported no change in their perceived risk of having a child with chromosomal abnormalities after pre-NIPT counselling, and risk perception reduction was associated with lower knowledge scores. Pretest negative emotions were common (54.9%) and influenced by testing context, information sources and reasons for testing. Most women reported a positive impact from results (92.7%), shaped by information delivery made and prior knowledge. Regret was rare (3.0%) and linked to reasons and perceived risk changes. Overall, satisfaction was high (97.3%), particularly among those prioritising informed decision-making.ConclusionsImproving personalised counselling and education throughout the NIPT journey seems crucial to minimise negative emotional impacts, highlighting the need for well-trained healthcare professionals.

Background Wnt/β-catenin signalling impairment accounts for 85% of colorectal cancers (CRCs), including sporadic and familial adenomatous polyposis (FAP) settings. An altered PI3K/mTOR pathway and gut microbiota also contribute to CRC carcinogenesis. We studied the interplay between the two pathways and the microbiota composition within each step of CRC carcinogenesis. Methods Proteins and target genes of both pathways were analysed by RT-qPCR and IHC in tissues from healthy faecal immunochemical test positive (FIT+, n  = 17), FAP ( n  = 17) and CRC ( n  = 15) subjects. CRC-related mutations were analysed through NGS and Sanger. Oral, faecal and mucosal microbiota was profiled by 16 S rRNA-sequencing. Results We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs. Wnt/β-catenin molecular markers positively correlated with Clostridium_sensu_stricto_1 and negatively with Bacteroides in FAP faecal microbiota. Alistipes , Lachnospiraceae , and Ruminococcaceae were enriched in FAP stools and adenomas, the latter also showing an overabundance of Lachnoclostridium , which positively correlated with cMYC . In impaired-mTOR-mutated CRC tissues, p-S6R correlated with Fusobacterium and Dialister , the latter also confirmed in the faecal-ecosystem. Conclusions Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment.

Prostate cancer (PCa) ranks among the most prevalent malignancies in men, with notable associations to Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Lynch Syndrome, both linked to germline likely pathogenetic variant/pathogenetic variant (LPV/PV) in genes involved in DNA repair. Among these genes, BRCA2 in PCa patients is the most frequently altered. Despite progresses, challenges in BRCA carriers detection persist, with a quarter of PCa cases lacking family history. To address these challenges, a multidisciplinary expert panel from six Italian Scientific Societies, formulated a care pathway to integrate BRCA testing into routine clinical practice in different Italian geographical areas. The development process, promoted by the Italian Society of Uro-Oncology (SIUrO), involved three key stages. A preliminary meeting convened teams from different Italian regions to establish minimal requirements for a mini-counseling program (defined as a pre-test consultation carried out by clinicians responsible of patients’ management) and propose care pathway models. At the same time, a comprehensive survey was launched to highlight regional variations in BRCA testing and identify eventual obstacles to testing activities. A subsequent meeting synthesized care pathway proposals and formulated a unified framework, acknowledging regional legislative variations as enriching factors. Lastly, implementation of the unified framework was promoted by the project faculty and identified regional team leaders. Survey results revealed significant regional disparities in BRCA testing, reimbursement policies, and access to genetic counseling. The proposed mini-counseling program outlined essential steps for patient identification, information provision, and multidisciplinary review, aiming to streamline BRCA testing processes. Expert recommendations emphasized offering tumor genetic testing to metastatic PCa patients eligible for PARP-i treatment and outlined criteria for genetic counseling and germline testing. Key considerations included family history and tumor characteristics. In conclusion, the proposed care pathway represents a critical step towards integrating BRCA testing into routine PCa care, aiming to optimize patient management and familial risk assessment within the constraints of the Italian healthcare system. Highlights • BRCA likely pathogenetic/pathogenetic variants significantly increase the risk of developing prostate cancer (PCa) and enhance sensitivity to PARP-inhibitor treatment, underscoring the clinical need to incorporate genetic testing into the routine management of PCa patients. • A comprehensive survey revealed significant regional disparities in BRCA testing availability, reimbursement policies, and access to genetic counseling across different geographical regions of Italy. • A multidisciplinary panel from six Italian Scientific Societies, led by the Italian Society of Uro-Oncology (SIUrO), developed a care pathway to integrate BRCA testing into routine clinical practice within the Italian healthcare system.

Background In several countries, the role of the genetic nurse has developed over decades, becoming well-recognized and integrated into healthcare systems. In contrast, in Italy, this role is still emerging, with no formal legal recognition and limited awareness among healthcare professionals and hospital administrators. Given this context, it is crucial to assess how the role and activities of nurses in genetic clinics in Italy are perceived. Methods Phenomenological qualitative study was performed. Three focus groups and one individual interview were conducted to collect data between April and November 2022 and transcribed verbatim. Phenomenological analysis was used to provide a comprehensive description of the overall thematic map and to interpret the data. Results A purposive sample of 14 Italian nurses with working experience in genetic clinics were recruited for interviews. Three themes were identified: (a) Education, (b) Working in genetic clinics, and (c) Acknowledgement of genetic nurse role. The absence of genetics education in nursing programs has led to on-the-job training in this field. The activities performed were unclear since they were neither standardized nor recognized. The role of the genetic nurse was not acknowledged, and in Italy, nurses trained in genetics did not have the opportunity to choose their recruitment as it was not voluntary. Conclusions This evidence highlights the need for formally recognizing the role of the genetic nurse in Italy. This could be achieved through the definition of standard activities and the implementation of formal education in genetics and genomic fields.

Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30–50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APC gene mosaicism was investigated on DNA from colonic adenomas by Sanger sequencing or Whole Exome Sequencing (WES). Mosaicism extension to other tissues (peripheral blood, saliva, hair follicles) was evaluated using Sanger sequencing and/or digital PCR. APC second hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC in-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APC patients. In addition, we showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.

Anderson-Fabry disease (AFD) is a multisystem X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A (α-Gal A). This deficiency results in the intracellular accumulation of glycosphingolipids, primarily uncleaved globotriaosylceramide (Gb3) and its deacylated form, lyso-globotriaosylceramide (Lyso-Gb3), leading to progressive organ damage and functional impairment. The diagnostic evaluation for AFD involves clinical assessment and family history, supported by biochemical testing (α-Gal A enzyme activity and Lyso-Gb3 levels) and genetic analysis of the GLA gene. In cases of unexplained renal impairment or when genetic analysis is inconclusive, kidney biopsy is often required to confirm the diagnosis and guide targeted treatments. However, histological findings in kidney biopsies may sometimes be nonspecific, complicating the diagnostic process. This article aims to provide an updated perspective on the role of kidney biopsy in AFD, illustrating two cases that exemplify its pivotal role in confirming or excluding the suspected disease, proving to be both decisive and confounding in this complex clinical setting.