Exploring the Prevalence of Oral Features for Early Detection of PTEN Hamartoma Tumour Syndrome.

AIMS: Patients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene. Early recognition of PHTS facilitates initiation of cancer surveillance which is highly effective in preventing the development of advanced malignancies. PHTS is rare and due to its varied phenotype, even within families, oral abnormalities may be a valuable tool in the identification of these patients at an early stage before cancer development. MATERIALS AND METHODS: Between 1997 and 2020, phenotypic characteristics were evaluated in 81 paediatric (median age: 9 years) and 86 adult (median age: 40 years) PHTS patients by one of 2 medical experts during yearly surveillance visits at a Dutch PHTS expertise centre. Oral features evaluated included gingival hypertrophy, oral papillomas, and high palate (in adults). RESULTS: Within adults, gingival hypertrophy was present in 94%, oral papillomas in 88%, and a high palate in 89%. All adult patients had at least one of these oral features, and 99% showed at least 2 oral features. Oral features were less common in paediatric patients, especially under 11 years of age. Gingival hypertrophy was observed in 44% and oral papillomas in 54% of paediatric patients. CONCLUSIONS: The presence of 2 or 3 oral features may indicate PHTS in adults or adolescents, especially if macrocephaly is present. Dental professionals are well-positioned to recognise these oral manifestations could be related to PHTS. They can initiate an overall clinical assessment of the patient by alerting the patient's medical practitioner of the findings and the possible need for genetic testing. This could significantly improve outcomes, including life expectancy, for patients and possibly for their relatives. CLINICAL RELEVANCE: Dental professionals are ideally placed to recognise oral features and initiate early assessment of PHTS which could significantly improve patient outcomes.

Neuropsychological functioning of adults with PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) might be associated with a distinct cognitive and psychological profile. However, previous studies are limited, predominantly based on small and pediatric cohorts, likely affected by selection bias, and show a broad range of findings. We aimed to characterize the neuropsychological functioning of adults with PHTS. A total of 40 participants, with intellectual disability as exclusion criterium, completed an extensive clinical neuropsychological assessment including cognitive tasks, questionnaires, and a clinical diagnostic interview. The cognitive tasks and questionnaire data were categorized as below and above average based on 1.5 SD. About 80% of participants showed an average level of intelligence. In addition, 30% and 24% of participants scored below average on immediate memory recall and speed of information processing, respectively. Furthermore, about 25% reported above average scores on the majority of the questionnaires, indicating psychological distress, signs of alexithymia, and cognitive complaints. Personality of participants was characterized by inflexibility, social withdrawal, and difficulties in recognizing and describing their own emotions. Adults with PHTS demonstrate a heterogeneous yet distinct neuropsychological profile that is characterized by slower information processing, psychological problems, and specific personality traits. These findings provide directions on how to optimize the care and daily lives of adults with PHTS.

Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS).

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0-1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3-2.6); consumed daily about 1.2-1.8 times more often ≥1 than 0-1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4-4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4-6.9); were about 1.04-1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4-2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4-4.2)); and overweight or obesity (72%) was about 1.02-1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4-2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3-2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important.

The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.

PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291). RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.

Detection and yield of thyroid cancer surveillance in adults with PTEN hamartoma tumour syndrome.

Thyroid cancer surveillance (TCS) with ultrasound (US) is advised for PTEN hamartoma tumour syndrome (PHTS) patients due to increased thyroid cancer (TC) risk. However, data supporting TCS guidelines are scarce. We aimed to assess the detection and yield of annual TCS with US in adult PHTS patients without a TC history and to evaluate the impact of a reduced US interval on the TCS yield. A retrospective cohort study was conducted, including adult PHTS patients and medical record data between 2005 and 2021. The yield from annual TCS was compared with hypothetical biennial and triennial TCS after two initial US with annual interval by counting delayed detection of nodular growth, thyroid adenoma, and TC. During 279 follow-up years, 84 patients (median age 40 years) underwent 349 US. Thyroidectomy was performed in 6/84 (7%) patients, revealing a minimally invasive follicular TC in one patient aged 22 and a thyroid adenoma in two patients aged 21 and 53. Multiple thyroid nodules were diagnosed in 73/84 (87%) patients (median age 36 years). Nodular growth was detected in 9/56 (16%) patients, and its detection would have been delayed in 4-7% US rounds with biennial TCS, and in 2-6% US rounds with triennial TCS. US-based thyroiditis and indeterminate non-malignant lymph nodes were found in 8/74 (11%) and 7/72 (10%) patients, respectively. Following our findings combined with the literature, we propose starting TCS before age 18 and reducing the follow-up frequency after the initial two US from annual to biennial if no suspicious findings are detected.

Yield of annual endometrial cancer surveillance in women with PTEN Hamartoma Tumor Syndrome.

OBJECTIVE: Expert-opinion based guidelines state that endometrial cancer surveillance (ECS) might be considered for patients with PTEN Hamartoma Tumor Syndrome (PHTS) based on an elevated lifetime risk of endometrial cancer. We aimed to evaluate the yield of ECS by annual transvaginal ultrasound (TVUS) and endometrial biopsy (EMB) in PHTS patients. METHODS: PHTS patients who visited our PHTS expert center between August 2012 and September 2020 and opted for annual ECS were included. Data on surveillance visits, diagnostics, reports of abnormal uterine bleeding and pathology results were retrospectively gathered and analyzed. RESULTS: Surveillance was initiated in 25 women with a total of 93 gynecological surveillance visits during 76 surveillance years. The median age at first visit was 39 years (range 31-60) with a median follow-up duration of 38 months (range 6-96). Hyperplasia with and without atypia was detected six and three times, respectively, in seven (28%) women. The median age at hyperplasia detection was 40 years (range 31-50). In six asymptomatic women hyperplasia was detected during annual surveillance visits, while in one patient hyperplasia with atypia was detected during an additional visit due to abnormal uterine bleeding. In seven out of nine hyperplasias detected with EMB, TVUS beforehand showed no abnormalities. No (interval) carcinomas occurred. CONCLUSIONS: ECS in women with PHTS enables detection of a substantial number of asymptomatic premalignancies, such as hyperplasia with and without atypia, suggesting that ECS may be beneficial with regard to cancer prevention. The addition of EMB to TVUS likely improves the detection of premalignancies.

Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.

BACKGROUND: Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance. METHODS: Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis. RESULTS: We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care. CONCLUSION: In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.

The most efficient and effective BRCA1/2 testing strategy in epithelial ovarian cancer: Tumor-First or Germline-First?

OBJECTIVE: Genetic testing in epithelial ovarian cancer (OC) is essential to identify a hereditary cause like a germline BRCA1/2 pathogenic variant (PV). An efficient strategy for genetic testing in OC is highly desired. We evaluated costs and effects of two strategies; (i) Tumor-First strategy, using a tumor DNA test as prescreen to germline testing, and (ii) Germline-First strategy, referring all patients to the clinical geneticist for germline testing. METHODS: Tumor-First and Germline-First were compared in two scenarios; using real-world uptake of testing and setting implementation to 100%. Decision analytic models were built to analyze genetic testing costs (including counseling) per OC patient and per family as well as BRCA1/2 detection probabilities. With a Markov model, the life years gained among female relatives with a germline BRCA1/2 PV was investigated. RESULTS: Focusing on real-world uptake, with the Tumor-First strategy more OC patients and relatives with a germline BRCA1/2 PV are detected (70% versus 49%), at lower genetic testing costs (€1898 versus €2502 per patient, and €2511 versus €2930 per family). Thereby, female relatives with a germline BRCA1/2 PV can live on average 0.54 life years longer with Tumor-First compared to Germline-First. Focusing on 100% uptake, the genetic testing costs per OC patient are substantially lower in the Tumor-First strategy (€2257 versus €4986). CONCLUSIONS: The Tumor-First strategy in OC patients is more effective in identifying germline BRCA1/2 PV at lower genetic testing costs per patient and per family. Optimal implementation of Tumor-First can further improve detection of heredity in OC patients.

Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

BACKGROUND: Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics. METHODS: We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lynch syndrome and calculated the standardized incidence ratio for all tumor types. MSI status, somatic second hit alterations, and immunohistochemistry-based MMR status were analyzed in 236 noncolorectal and nonendometrial malignant tumors. RESULTS: In individuals with Lynch syndrome MSI-H/dMMR occurred both in Lynch-spectrum and in non-Lynch-spectrum malignancies (85% vs 37%, P < .01). MSI-H/dMMR malignancies were found in nearly all non-Lynch-spectrum tumor types. Almost all breast carcinomas had medullary features, and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be associated with Lynch syndrome (standardized incidence ratio = 38.8, 95% confidence interval = 16.7 to 76.5). CONCLUSIONS: In individuals with Lynch syndrome, MSI-H/dMMR occurs in more than one-half of the malignancies other than colorectal and endometrial carcinomas, including tumor types without increased incidence. The Lynch-spectrum tumors should be expanded to breast carcinomas with medullary features. All malignancies in patients with Lynch syndrome, independent of subtype, should be tested for MSI-H/dMMR in case therapy with immune checkpoint inhibitors is considered. Moreover, Lynch syndrome should be considered an underlying cause of all MSI-H/dMMR malignancies other than colorectal and endometrial carcinomas.

[Genetic testing in epithelial ovarian cancer: implementation of the 'Tumor-First' workflow]. / Erfelijkheidsonderzoek bij ovariumcarcinoom.

The new 'Tumor-First' workflow for genetic testing in epithelial ovarian cancer detects women with a genetic predisposition effectively and efficiently. 'Tumor-First' indicates that the tumor DNA of all patients diagnosed with epithelial ovarian cancer is examined for the presence of pathogenic variants in, amongst others, BRCA1 and BRCA2 genes. Women with an aberrant tumor DNA test result are eligible for genetic testing using a sample of blood to detect heredity. Simultaneously, the tumor DNA test provides information on the effectiveness of additional treatment with PARP inhibitors. Thereby, the Tumor-First workflow saves time and healthcare costs. This workflow is currently implemented on a national level. The focus of implementation is transferring knowledge to healthcare professionals on requesting, interpreting and reporting the tumor DNA test and providing adequate support. This nationwide implementation of Tumor-First can improve the recognition of heredity in epithelial ovarian cancer.

Healthcare professionals' perspectives on implementation of universal tumor DNA testing in ovarian cancer patients: multidisciplinary focus groups.

Universal tumor DNA testing in epithelial ovarian cancer patients can function not only as an efficient prescreen for hereditary cancer testing, but may also guide treatment choices. This innovation, introduced as Tumor-First workflow, offers great opportunities, but ensuring optimal multidisciplinary collaboration is a challenge. We investigated factors that were relevant and important for large-scale implementation. In three multidisciplinary online focus groups, healthcare professionals (gynecologic oncologists, pathologists, clinical geneticists, and clinical laboratory specialists) were interviewed on factors critical for the implementation of the Tumor-First workflow. Recordings were transcribed for analysis in Atlas.ti according to the framework of Flottorp that categorizes seven implementation domains. Healthcare professionals from all disciplines endorse implementation of the Tumor-First workflow, but more detailed standardization and advice regarding the logistics of the workflow were needed. Healthcare professionals explored ways to stay informed about the different phases of the workflow and the results. They emphasized the importance of including all epithelial ovarian cancer patients in the workflow and monitoring this inclusion. Overall, healthcare professionals would appreciate supporting material for the implementation of the Tumor-First workflow in the daily work routine. Focus group discussions have revealed factors for developing a tailored implementation strategy for the Tumor-First workflow in order to optimize care for epithelial ovarian cancer patients. Future innovations affecting multidisciplinary oncology teams including clinical geneticists can benefit from the lessons learned.

Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome.

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

The yield and effectiveness of breast cancer surveillance in women with PTEN Hamartoma Tumor Syndrome.

BACKGROUND: Women with PTEN Hamartoma Tumor Syndrome (PHTS) are offered breast cancer (BC) surveillance because of an increased BC lifetime risk. Surveillance guidelines are, however, expert opinion-based because of a lack of data. We aimed to assess the yield and effectiveness of BC surveillance and the prevalence and type of breast disease in women with PHTS. METHODS: Sixty-five women with PHTS who visited our center between 2001 and 2021 were included. Surveillance consisted of annual magnetic resonance imaging (MRI) and mammography from ages 25 and 30 years, respectively. RESULTS: Thirty-nine women enrolled in the BC surveillance program (median age at first examination, 38 years [range, 24-70]) and underwent 156 surveillance rounds. Surveillance led to detection of BC in 7/39 women (cancer detection rate [CDR], 45/1000 rounds) and benign breast lesions (BBLs) in 11/39 women. Overall sensitivity2 (which excludes prophylactic-mastectomy detected BCs) was 100%, whereas sensitivity2 of mammography and MRI alone was 50% and 100%, respectively. Overall specificity was higher in follow-up rounds (86%) versus first rounds (71%). Regardless of surveillance, 21/65 women developed 35 distinct BCs (median age at first diagnosis, 40 years [range, 24-59]) and 23/65 developed 89 BBLs (median age at first diagnosis, 38 years [range, 15-61]). Surveillance-detected BCs were all T1 and N0, whereas outside surveillance-detected BCs were more often ≥T2 (60%) and N+ (45%) (p < .005). CONCLUSIONS: The findings show that annual BC surveillance with MRI starting at age 25 years enables detection of early-stage BCs. Performance measures of surveillance and CDR were both high. BBLs were commonly present, underlining the importance of evaluation of all lesions independently. LAY SUMMARY: Breast cancer surveillance leads to decreased tumor stage and improved survival. Breast cancer surveillance with breast magnetic resonance imaging from age 25 years onward is recommended.

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort.

BACKGROUND: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. METHODS: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. RESULTS: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. CONCLUSION: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.

Detection and Yield of Colorectal Cancer Surveillance in Adults with PTEN Hamartoma Tumour Syndrome.

Colorectal cancer surveillance (CCS) with colonoscopy every five years is advised for PTEN Hamartoma Tumour Syndrome (PHTS) patients aged ≥40 due to an increased colorectal cancer (CRC) risk. However, data to support CCS guidelines are scarce and available CRC risks are low (0-5% at age 50) and likely overestimated. We aimed to assess the detection and yield of CCS for PHTS patients without a CRC history. A retrospective cohort study including PHTS patients aged ≥40 with CCS at a PHTS expertise centre between 2011 and 2022. Adenomas with a ≥10 mm size, (tubulo)villous histology, or high-grade dysplasia were considered advanced. During 67 follow-up years, 37 patients (median age 47 years) underwent 61 colonoscopies. CCS yielded no CRCs. Adenomas were diagnosed in 13/37 (35%) patients during 23/100 colonoscopies (95% CI: 14-36), including one advanced adenoma. Baseline adenoma detection rates were similar to follow-up and higher in patients aged above 50 (50/100, 95% CI: 24-76) vs. age 50 or below (11/100, 95% CI: 3-30; p = 0.021). The low CRC and advanced adenoma yield allow for a more personalised surveillance program. Following our findings combined with literature on CRC risk and progression, we suggest starting CCS at age 40 with variable follow-up intervals between 1 and 10 years depending on previous colonoscopy findings.

Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review.

PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy.

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis.

PURPOSE: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. METHODS: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. RESULTS: From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. CONCLUSION: BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.

Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes- a collaborative multicentre endeavour within the project Solve-RD.

BACKGROUND: Patients and families with suspected, but genetically unexplained (unsolved) genetic tumour risk syndromes lack appropriate treatment and prevention, leading to preventable morbidity and mortality. To tackle this problem, patients from the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) are analysed in the European Commission's research project "Solving the unsolved rare diseases" (Solve-RD). The aim is to uncover known and novel cancer predisposing genes by reanalysing available whole-exome sequencing (WES) data of large cohorts in a combined manner, and applying a multidimensional omics approach. APPROACH: Around 500 genetically unsolved cases with suspected hereditary gastrointestinal tumour syndromes (polyposis, early-onset/familial colorectal cancer and gastric cancer) from multiple European centres are aimed to be included. Currently, clinical and germline WES data from 294 cases have been analysed. In addition, an extensive molecular profiling of gastrointestinal tumours from these patients is planned and deep learning techniques will be applied. The ambitious, multidisciplinary project is accompanied by a number of methodical, technical, and logistic challenges, which require the development and implementation of new analysis tools, the standardisation of bioinformatics pipelines, and strategies to exchange data and knowledge. RESULTS: and Outlook. The first re-analysis of 229 known and proposed cancer predisposition genes allowed solving 2-3% of previously unsolved GENTURIS cases. The integration of expert knowledge and new technologies will help to identify the genetic basis of additional unsolved cases within the ongoing project. The ERN GENTURIS approach might serve as a model for other genomic initiatives.