The purpose of this study was to estimate the consensus of Australian Health Professionals and/or Researchers (HP/Rs) and Consumers (patients/family/carers) (Cs) on international genetic testing recommendations. Modified...The purpose of this study was to estimate the consensus of Australian Health Professionals and/or Researchers (HP/Rs) and Consumers (patients/family/carers) (Cs) on international genetic testing recommendations. Modified Delphi Panel study with seven domains of interest. Fifty-five statements were devised for an online survey administered in REDCap. HP/Rs and Cs were recruited from professional networks and associations for participation in the study. Statements were rated using a Likert scale and analysed using descriptive statistics. Free text comments were allowed within each domain and analysed using thematic analysis. Thirty-six HP/Rs and 27 Cs participated. There was consensus on testing men with a family history of a high-risk hereditary gene; men with PCa and a family history of Hereditary Breast and Ovarian Cancer (HBOC) syndrome or Lynch syndrome; and men with metastatic PCa. There was consensus on testing BRCA2, BRCA1 and DNA MMR genes for men with metastatic PCa. Thematic analysis of HP/R comments revealed three main topics: the lack of information to make a decision, insufficient knowledge of genetic testing, and capacity to provide genetic testing and counselling. This is the first Australian study on genetic testing recommendations in PCa to inform who should be tested and how. Our study showed apparent deficits in knowledge and implementation, exacerbated by workforce issues around the provision of genetic counselling and testing. Future work should focus on evaluating these recommendations for implementation in Australian practice.
Genetic testing is increasingly recommended for adolescents and young adults (AYAs) with cancer; however, no AYA-specific models for cancer risk communication have been developed. We developed a chatbot-based patient- an...Genetic testing is increasingly recommended for adolescents and young adults (AYAs) with cancer; however, no AYA-specific models for cancer risk communication have been developed. We developed a chatbot-based patient- and family-centered cancer risk communication tool, the AYA-RISE (AYA-Risk Information and Screening Education) intervention for AYAs aged 12–24 years.The intervention was developed together with AYAs with cancer risk syndromes, their family members, and clinicians, using Invitae’s Gia® chatbot (study Phase 1). 17 AYAs participated in a group discussion and completed surveys for input regarding development. Content was developed for 9 different syndromes. AYA-RISE was then refined after iterative input (Phase 2) and evaluated for feasibility and preliminary outcomes in a pilot study (Phase 3).100% of AYAs used the intervention through a point at which risk information was presented via the chatbot and portal demonstrating enrollment and chatbot use feasibility. Our threshold for acceptability was exceeded, with a post-test Acceptability of Intervention Measure (AIM) score of > 4 by 80% of AYAs. In the pre-visit survey, 40% of AYAs correctly reported risk of cancer by age 30, and 20% correctly reported lifetime cancer risk. Following the visit and use of the chat, 60% correctly reported risk of cancer by age 30 and 90% correctly reported lifetime risk. No significant differences in participant pre (3.4) and post (3.6, p=.34) distress thermometer mean scores were observed.The AYA-RISE intervention was feasible and acceptable for use by AYAs. Preliminary outcomes included improved knowledge when used in conjunction with a cancer risk clinic visit, without increasing distress. A randomized trial is currently ongoing.
Hereditary renal cell carcinoma (hRCC) syndromes represent a small but significant proportion of renal cancer cases, accounting for 5-8%. They are characterized by distinct genetic etiologies, early-onset presentations,...Hereditary renal cell carcinoma (hRCC) syndromes represent a small but significant proportion of renal cancer cases, accounting for 5-8%. They are characterized by distinct genetic etiologies, early-onset presentations, and unique clinical features. Timely identification and surveillance of at-risk individuals are essential to improving outcomes, as early detection facilitates interventions at a localized stage. However, existing recommendations are highly variable and often lack robust evidence. This extensive review consolidates current knowledge on major hRCC syndromes, namely the von Hippel-Lindau (VHL) disease, hereditary papillary renal carcinoma (HPRC), fumarate hydratase deficient RCC (FHRCC), and Birt-Hogg-Dubé (BHD) syndrome, and their associated screening protocols. Through a comprehensive literature review, we summarize the cumulative risks, tumor growth patterns, and imaging recommendations for each syndrome, highlighting the challenges posed by their rarity and heterogeneous presentations. Based on these findings, we propose a standardized surveillance protocol tailored to each syndrome's risk profile, balancing early detection with the minimization of patient burden and healthcare costs. These recommendations emphasize the importance of multidisciplinary management in tertiary care centers to ensure optimal outcomes.
The CHEK2 gene confers a moderate risk for breast cancer, but existing knowledge is largely based on the European founder variant, 1100delC. This study aimed to characterize the distinct phenotypes associated with unique...The CHEK2 gene confers a moderate risk for breast cancer, but existing knowledge is largely based on the European founder variant, 1100delC. This study aimed to characterize the distinct phenotypes associated with unique CHEK2 variants in Brazilian families. In this cross-sectional study, 1055 patients meeting criteria for Hereditary Breast and Ovarian Cancer syndrome underwent germline multigene panel testing. Pathogenic/likely pathogenic variants (PVs) were found in 141 patients (13.4%), of whom 13 (9.2%) had a CHEK2 PVs. Subsequent family cascade testing brought the total number of individuals studied to 57. Three distinct CHEK2 PVs were identified: c.846 + 1G > C, c.349 A > G, and c.593-1G > T. While breast cancer was the most frequent tumor, specific PVs correlated with different cancer spectra. The c.349 A > G variant showed an enrichment for papillary thyroid cancer. In contrast, the c.846 + 1G > C variant was associated with melanoma, prostate, and testicular cancer, in addition to breast, colon, and kidney cancers. These findings suggest that different CHEK2 PVs may confer distinct cancer risks. Investigating these variants across diverse populations is crucial for refining phenotype characterization and improving genetic counseling as access to genetic testing expands.
Li-Fraumeni Syndrome (LFS) is an autosomal dominant condition associated with germline pathogenic variants in the tumor suppressor gene TP53. Carriers have a higher risk of developing multiple primary tumors and a broad...Li-Fraumeni Syndrome (LFS) is an autosomal dominant condition associated with germline pathogenic variants in the tumor suppressor gene TP53. Carriers have a higher risk of developing multiple primary tumors and a broad spectrum of cancers. The main tumors include premenopausal breast cancer, sarcomas, adrenocortical carcinoma and central nervous system tumors. Melanoma is a recognized but uncommon manifestation of LFS, with few reports in the literature linking the syndrome to this malignancy. The main objective of this study is to evaluate the occurrence of melanoma in patients carrying the germline pathogenic variant in the TP53 gene, registered in the Brazilian Li-Fraumeni Syndrome Study (BLISS) database from 2018 to 2023. From our database, six out of 512 patients developed melanoma, with melanoma representing the sole clinical manifestation of LFS in half of these patients. Of the 512 patients with LFS, 417 were carriers of the R337H variant, and among them, three patients developed melanoma. Three melanomas were detected during routine surveillance with total-body photography and digital dermoscopy. This study shows that melanoma is one of the manifestations of LFS, highlighting the importance of its screening within the Toronto protocol. It is essential for healthcare professionals who manage patients with LFS to recognize this risk in order to enable early diagnosis and identification of precursor lesions.
NF2-Schwannomatosis (NF2-SWN) is a disease characterized by multiple tumors of the central and peripheral nervous system. Surgery remains an important treatment option, sometimes performed on an urgent basis, but usually...NF2-Schwannomatosis (NF2-SWN) is a disease characterized by multiple tumors of the central and peripheral nervous system. Surgery remains an important treatment option, sometimes performed on an urgent basis, but usually planned within the context of complex multi-tumour burden and morbidity. It is difficult to provide a comprehensive generic decision tree because each patient has a unique disease burden, but we will detail in this review the therapeutic indications for each tumor type, vestibular schwannomas, meningiomas, spinal schwannomas and meningiomas, spinal ependymomas and peripheral schwannomas. The experience of the multidisciplinary team impact outcomes in this rare disease and centralized care has been shown to improve the disease course.
Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant cancer predisposition syndrome primarily associated with germline mutations in BRCA1 and BRCA2. Nevertheless, the implementation of multigene panels us...Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant cancer predisposition syndrome primarily associated with germline mutations in BRCA1 and BRCA2. Nevertheless, the implementation of multigene panels using Next Generation Sequencing (NGS) has expanded the mutational spectrum for this hereditary syndrome. As a result, the number of variants of uncertain clinical significance (VUS) has increased, and their functional and clinical interpretations remains a challenge for genetic counseling. This article reports three splice variants in susceptibility genes detected in women diagnosed with invasive ductal breast cancer. According to in silico predictions, these splicing-disrupting mutations in cancer susceptibility genes are likely to be pathogenic. Splicing functional assays were performed by reverse transcription polymerase chain reaction (RT-PCR) followed by capillary electrophoresis and Sanger sequencing. The characterization of these splicing events has enabled the identification of variants susceptible to alternative or abnormal splicing and their clinical classification according to the consensus criteria of the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP). This research increases our current knowledge about splice variants, thereby improving diagnostic performance and their clinical classification to support appropriate genetic counseling.
While the physical manifestations of NF2-related schwannomatosis (NF2-SWN) have been well documented, there are a limited number of qualitative studies on health-related quality of life in NF2-SWN. The present study soug...While the physical manifestations of NF2-related schwannomatosis (NF2-SWN) have been well documented, there are a limited number of qualitative studies on health-related quality of life in NF2-SWN. The present study sought to explore the cumulative impact of symptoms, treatments, and healthcare on the quality of life of individuals with NF2-SWN. We interviewed 16 adolescent and adult patients with NF2-SWN enrolled in the INTUITT-NF2 clinical trial and 10 clinicians with NF2-SWN expertise from the United States, United Kingdom, and Australia. Analysis of patient and clinician interviews yielded five overall themes: (1) impacts on daily living, (2) impacts on life roles, (3) impacts on relationships and social integration, (4) impacts on psychological and emotional wellbeing, and (5) burden of treatment and healthcare. Multiple symptom areas contributed to impairments in quality of life across each theme. These findings reveal that quality of life in NF2-SWN is shaped not only by individual symptoms, but by their complex, cumulative impact-highlighting the urgent need for disease-specific tools and holistic care approaches that reflect the lived realities of patients across the lifespan.
PURPOSE: This study explored healthcare professionals’ attitudes toward counselling patients on disclosing genetic cancer risk to relatives. Genetic counselling practices in Sweden are undergoing significant changes due...PURPOSE: This study explored healthcare professionals’ attitudes toward counselling patients on disclosing genetic cancer risk to relatives. Genetic counselling practices in Sweden are undergoing significant changes due to the increased use of genetic testing to assess hereditary risk and the implementation of mainstreamed testing in oncology care. These developments require an assessment of healthcare professionals’ perceived roles and responsibilities when working with patients with hereditary risk. Best practices need to be developed to effectively support risk disclosure, and subsequently risk management, to relatives. METHOD: Data was collected through interviews with oncologists, gynaecologists, surgeons, clinical geneticists, and genetic counsellors, working in oncology care or at cancer genetics units. Data was analysed using reflective thematic analysis. RESULTS: The results are presented as four positions that healthcare professionals take, describing their attitudes towards counselling patients about risk disclosure to relatives. The position depends on whether they perceive healthcare or the patient as ultimately responsible for risk information reaching relatives, and whether their focus is on the patient or the at-risk relatives. There are several stakeholders involved, and hence 'characters in play'. CONCLUSION: These results could serve as a basis for discussions on roles and responsibilities, while developing best practices regarding genetic counselling on hereditary cancer risk communication.
Pancreatic cancer is a highly aggressive malignancy, with 10%-20% of cases linked to inherited genetic risk factors. Pathogenic variants (PVs) in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene have been associate...Pancreatic cancer is a highly aggressive malignancy, with 10%-20% of cases linked to inherited genetic risk factors. Pathogenic variants (PVs) in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene have been associated with pancreatic cancer among Caucasians. However, data from South Asians are lacking. We investigated the prevalence of CDKN2A germline variants in 200 consecutively and prospectively enrolled, unselected pancreatic cancer patients from Pakistan. Comprehensive variant detection was performed using high-resolution melting analyses followed by DNA sequencing. Novel variants were investigated for pathogenicity using in-silico tools, and potentially functional variants were screened in 200 healthy controls. Five unique CDKN2A variants were identified, including one novel synonymous variant c.285G > T (p.Val95Val), one missense variant c.442G > A (p.Ala148Thr), one intronic variant (c.150 + 32A > T), and two variants (c.*29G > C and c.*69C > T) in the 3' untranslated region. No PVs in CDKN2A were detected. All variants were classified as benign, except the novel synonymous variant (p.Val95Val), which was categorized as a variant of uncertain significance (VUS) based on in-silico protein function prediction scores (Revel 0.38; PhyloP 2.88). This variant was identified in a 61-year-old male patient of Punjabi ethnicity with Grade 2 periampullary ductal adenocarcinoma with lymphovascular invasion and was absent in 200 healthy controls. Our study showed that CDKN2A PVs are very rare among unselected Pakistani pancreatic cancer patients, suggesting a negligible contribution to inherited pancreatic cancer risk in this population.
The 2024 Biennal Meeting of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) was held in Barcelona from June 19th to 22nd. The meeting featured a diverse program, including lectures, abstract pr...The 2024 Biennal Meeting of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) was held in Barcelona from June 19th to 22nd. The meeting featured a diverse program, including lectures, abstract presentations, flash talks, debates and poster presentations. Over 400 attendants from various countries participated. The primary focus of the program was on Lynch syndrome and polyposis syndromes. Other conditions addressed included constitutional mismatch repair deficiency (CMMRD), hereditary pancreatic cancer, hereditary gastric cancer, early-onset colorectal cancer, and familial colorectal cancer. This personal report summarizes a selection of lectures and debates, highlighting the progress made in the understanding of each hereditary cancer syndrome and its related conditions.
Genetic testing advancements have improved detection of hereditary polyposis syndromes. Many individuals with unexplained adenomatous polyposis previously underwent limited genetic testing and may benefit from updated te...Genetic testing advancements have improved detection of hereditary polyposis syndromes. Many individuals with unexplained adenomatous polyposis previously underwent limited genetic testing and may benefit from updated testing to identify underlying hereditary polyposis syndromes. We aimed to evaluate the yield of updated testing in adenomatous polyposis cases with previously negative germline genetic testing. Individuals with adenomatous polyposis with uninformative genetic testing prior to 2016 and subsequent updated multi-gene panel testing were analyzed. The updated multi-gene panel testing included the currently recommended 12 polyposis-associated genes. Twenty-one individuals met study criteria. Updated genetic testing identified pathogenic variants (PV) in 6/21 (29%) with four (19%) of the PVs associated with a polyposis phenotype (APC [× 2], AXIN2, and biallelic PMS2) and two (10%) were associated with other cancer predisposition syndromes (ATM and RAD51C). Although APC was included in the initial testing for the two patients found to have APC PVs, the previously completed deletion/duplication analysis did not include the 5' untranslated region. Updated genetic testing in individuals with unexplained polyposis had a very high yield and identified previously undetected PVs. Updated testing enabled more accurate diagnoses and personalized surveillance recommendations as well as identification of at-risk relatives. Given the improved diagnostic yield, it is crucial to consider genetic testing for individuals with unexplained polyposis who have previously undergone limited testing, due to small gene lists and/or outdated technology, ensuring alignment with current standards.
The clinical spectrum of paediatric NF2-SWN is broad and differs from that seen in the cohort of patients presenting over age 30, where symptoms typically relate to enlarging schwannoma, meningioma or ependymoma. Paediat...The clinical spectrum of paediatric NF2-SWN is broad and differs from that seen in the cohort of patients presenting over age 30, where symptoms typically relate to enlarging schwannoma, meningioma or ependymoma. Paediatric cases tend to have a multisystemic presentation with a high tumour burden and significant physical and psychological morbidity. Visual impairment as well as dermatological and non-tumour neurological features are common. Genetic testing characteristically identifies a germline pathogenic variant (often truncating) in the NF2 gene. This review explores the spectrum of clinical disease that arises in NF2-SWN when presenting in childhood.
Schwannomatosis refers to a group of rare genetic syndromes characterized by a predisposition to develop nerve sheath tumors, specifically schwannomas. Although germline and mosaic (described in the NF2 gene) pathogenic...Schwannomatosis refers to a group of rare genetic syndromes characterized by a predisposition to develop nerve sheath tumors, specifically schwannomas. Although germline and mosaic (described in the NF2 gene) pathogenic variants in NF2, SMARCB1, and LZTR1 account for the majority of cases, a subset of affected individuals remains without a definitive molecular diagnosis, including those associated with 22q loss of heterozygosity at the tumor level. The absence of a specific disease cause limits effective risk assessment, clinical surveillance, and genetic counselling. In recent years, advances in sequencing technologies have facilitated the identification of novel candidate driver genes. However, the rarity of these findings makes it challenging to establish their pathogenic relevance. This review aims to evaluate the current knowledge of genetic contributors to schwannomatosis in patients for whom routine genetic testing fails to detect a molecular cause in the known associated genes. On chromosome 22, DGCR8 and SOX10 have emerged as novel susceptibility genes, supported by accumulating molecular and clinical data. In addition, genes such as CDKN2A and SMARCA4 may also contribute to schwannomatosis in the context of broader tumor predisposition syndromes. These emerging genetic associations may help explain a proportion of schwannomatosis cases that currently lack a molecular diagnosis, while there is still room for the discovery of non-coding alleles or mosaic forms of known schwannomatosis-related conditions as well as novel genes that could explain unresolved cases.
Bogdanski AM, Klatte DCF, Laghari SI
… +17 more, Langers AMJ, Das A, Bastiaansen BAJ, Bonsing BA, Dekker E, Van Hooft JE, Samadder JN, Brosens LAA, van der Geest LG, Boardman L, Nielsen M, van Kouwen MCA, Bisseling TM, Wallace MB, Riegert-Johnson D, van Leerdam ME, Dutch Pancreatic Cancer Group
Pancreatic cancer (PDAC) surveillance programs are recommended for individuals with a PDAC lifetime-risk ≥ 5% to improve outcomes. While familial adenomatous polyposis (FAP) is linked to increased PDAC risk, robust data...Pancreatic cancer (PDAC) surveillance programs are recommended for individuals with a PDAC lifetime-risk ≥ 5% to improve outcomes. While familial adenomatous polyposis (FAP) is linked to increased PDAC risk, robust data to guide surveillance recommendations is lacking. This study evaluates PDAC risk in a large FAP-cohort.Data were collected from FAP cohorts in the United States (US) and the Netherlands (NL), including individuals (≥ 18 years) with a confirmed (likely) pathogenic APC variant. Cumulative PDAC incidence, adjusted for death as competing risk, was compared with control data from the Netherlands Cancer Registry and Statistics Netherlands. Data were collected from FAP cohorts in the United States (US) and the Netherlands (NL), including individuals (≥ 18 years) with a confirmed (likely) pathogenic APC variant. Cumulative PDAC incidence, adjusted for death as competing risk, was compared with control data from the Netherlands Cancer Registry and Statistics Netherlands. The US-cohort (n = 357) and NL-cohort (n = 1000) had a median age at the end of follow-up of 46 years (IQR, 32.0-60.0) and 60 years (IQR, 47.5-72.5), respectively. The cumulative risk of PDAC by age 70 was 1.3% (95% CI, 0.2-8.4) in the US cohort and 0.6% (95% CI 0.2-1.7) in the NL cohort. When combining both FAP-cohorts, the cumulative risk of PDAC by age 70 was 0.7% (95% CI, 0.3-1.8). For comparison, the cumulative incidence of PDAC in the general population at age 70 was 0.3% (95% CI 0.3-0.3), corresponding to a relative risk of 2.2 (95% CI, 0.9-5.7). Our findings indicate that PDAC risk in FAP patients is not statistically significantly higher than in the general population. As the cumulative incidence remains below the 5% threshold, PDAC surveillance is not recommended.
The three major schwannomatosis genes, NF2, LZTR1 and SMARCB1, are all located within approximately 9 megabases on chromosome 22 and cause three genetically distinct conditions with significant clinical phenotypic overla...The three major schwannomatosis genes, NF2, LZTR1 and SMARCB1, are all located within approximately 9 megabases on chromosome 22 and cause three genetically distinct conditions with significant clinical phenotypic overlap. All forms of schwannomatosis predispose to the development of multiple schwannomas, but display differences in tumour location and long-term prognosis. In addition, high levels of mosaic disease can complicate clinical diagnosis. Genetic diagnosis can be critical for distinguishing between the three conditions to optimise clinical management, especially in cases of mosaic disease. This review summarises the distinctions between the clinical and genetic characteristics of each form of schwannomatosis and discusses the genetic analytic tools that are typically used to detect the variants found in these conditions.
BACKGROUND: Lynch Syndrome (LS) is a common condition that increases risk of multi-organ cancers. Risk-reduction care is complex and challenging, resulting in suboptimal adherence care despite patient motivation. There i...BACKGROUND: Lynch Syndrome (LS) is a common condition that increases risk of multi-organ cancers. Risk-reduction care is complex and challenging, resulting in suboptimal adherence care despite patient motivation. There is a need for an accessible, centralized, evidence-based platform that provides up-to-date medical information to patients and clinicians to navigate their complex care. The aim of this study was to understand how a mobile health application (mHealth app) could meet these needs. METHODS: Semi-structured interviews were conducted with a purposefully recruited stratified sample of adult patients with LS and clinicians across different specialties. Qualitative content analysis was used to explore experiences with LS care and perspectives on potential mHealth solutions, with triangulation of participant data to inform key components of mHealth app design. FINDINGS: Three core themes were identified, capturing the challenges LS patients face in managing their care and how an mHealth app can potentially overcome these challenges: (1) the importance of accurate and up-to-date information about LS, (2) the need for streamlined and centralized care management, and (3) the value of building connections to overcome isolation. Our study also identified key features of an mHealth app to address these challenges while optimizing usability and accessibility per patient/provider preference. INTERPRETATION: LS patients and clinicians experience multifaceted barriers to LS management that an mHealth app can help overcome. This application can support LS patients and providers by empowering patients with vetted, up-to-date information, serving as a centralized location to store and organize their medical care, and providing opportunities to build connections.
Hybrid neurofibroma/schwannoma tumors (HNS) represent a still underrecognized, yet clinically and diagnostically significant entity within the spectrum of schwannomatosis (SWN). While classical schwannomas have been well...Hybrid neurofibroma/schwannoma tumors (HNS) represent a still underrecognized, yet clinically and diagnostically significant entity within the spectrum of schwannomatosis (SWN). While classical schwannomas have been well known for decades, HNS have only recently been described as a distinct histological pattern, composed of intermixed features typical of both schwannomas and neurofibromas. Differentiating HNS from pure neurofibroma (Nf) is critical, as misclassification may lead to an incorrect diagnosis of neurofibromatosis type 1 rather than SWN. The distinction of hybrid tumors (more precisely HNS) is especially important in SWN forms outside the neurofibromatosis type 2 (NF2) spectrum (NF2-SWN), where major diagnostic criteria are less well defined, making histological differentiation even more significant. At the molecular level, HNS frequently show alterations in the genes NF2, LZTR1, and SMARCB1, often accompanied by characteristic losses of chromosome 22q. In addition, recurrent somatic mutations have been identified in genes such as ERBB2, RET, KMT2A, and CTNNA3. Methylation profiling classifies HNS within the schwannoma spectrum, supporting the hypothesis that they may be a morphological variant rather than a distinct entity, although this has not yet been conclusively confirmed. Histologically, HNS are characterized by a combination of mostly schwannoma-associated Antoni A patterns, collagen-rich neurofibroma-like areas, lymphocytic infiltrates, and, in some cases, plexiform growth. Given the diagnostic challenges, artificial intelligence-based image analysis, such as whole-slide imaging and radiomics, may offer valuable tools for more accurate identification of these tumors in the future. Initial studies in related fields have shown that such approaches can even surpass human-level accuracy. Nevertheless, an accurate histological and, if necessary, molecular evaluation remains essential-particularly for the correct classification as SWN and for ensuring appropriate genetic counseling to affected individuals.