Multi-cancer predisposition gene panel testing (MCPGT) enables simultaneous deep-coverage genotyping of multiple CPGs (cancer predisposing genes) and detects germline pathogenic sequence variants (PSVs). Reported PSV car...Multi-cancer predisposition gene panel testing (MCPGT) enables simultaneous deep-coverage genotyping of multiple CPGs (cancer predisposing genes) and detects germline pathogenic sequence variants (PSVs). Reported PSV carrier rates among pediatric and adolescent cancer patients range from 8 to 17.6%, with variability attributed to ethnic background, the number of genes tested, cancer phenotypes, and patient selection criteria. This study aimed to assess the rate and spectrum of germline PSVs in consecutive pediatric and adolescent cancer patients treated at the Sheba Medical Center, a tertiary medical center. All cancer patients aged 0–18 years treated between 01.2021 and 12.2022 were offered MCPGT. Overall, 257 eligible cancer patients were treated during the study period, of whom 116 Israeli patients underwent MCGPT (Invitae, San Francisco, CA), with complete data available for 108. The range of malignancies included central nervous system (CNS) tumors (n = 45), solid tumors (n = 37), hematological malignancies (n = 14), and retinoblastoma (RB) (n = 12). PSVs were detected in 17/108—15.7% of patients, with the highest rates in patients with RB (7/12, 58.3%) and CNS tumors (6/45, 13.3%). A significant association was found between younger age at diagnosis and PSV carrier status (4.7 years in carriers vs. 9.3 years in non-carriers, p = 0.003). Fulfilling Jongmans' criteria was correlated with PSV detection. The study highlights the importance of genetic testing in children meeting specific clinical criteria, particularly those diagnosed with RB and CNS tumors. Further studies with larger, ethnically diverse cohorts are needed to validate these findings to expand the scientific basis for personalized care strategies.
Von Hippel–Lindau (VHL) disease is an inherited tumor syndrome characterized by tumors and cysts in various organs, such as the eyes, pancreas, adrenal glands, and kidneys. VHL is caused by pathogenic variants in the VHL...Von Hippel–Lindau (VHL) disease is an inherited tumor syndrome characterized by tumors and cysts in various organs, such as the eyes, pancreas, adrenal glands, and kidneys. VHL is caused by pathogenic variants in the VHL gene, which plays a critical role in blood vessel formation. Although direct sequencing is effective for detecting VHL gene variants, approximately 30% of patients with VHL disease harbor large deletions, necessitating alternative detection techniques such as multiplex ligation-dependent probe amplification (MLPA) and comparative genomic hybridization (CGH) arrays. In this study, we evaluated the clinical utility of droplet digital polymerase chain reaction (ddPCR) and targeted adaptive sampling long-read sequencing (TAS-LRS) for VHL gene deletion analysis. In cases of complex deletions, adaptive sampling was shown to be a powerful method capable of precisely identifying the exact sequence alterations. Our findings suggest that these novel techniques enable rapid and accurate detection of gene deletions in clinical genetic testing.
BACKGROUND: BRCA1 and BRCA2 carriers without prior breast cancer have the option to undergo risk-reducing mastectomy (RRM). The aim of this study was to investigate factors associated with their decision, experiences wit...BACKGROUND: BRCA1 and BRCA2 carriers without prior breast cancer have the option to undergo risk-reducing mastectomy (RRM). The aim of this study was to investigate factors associated with their decision, experiences with the process, and satisfaction with the procedure. MATERIALS AND METHODS: We distributed a cross-sectional survey to 425 women aged 25-70 with a pathogenic BRCA1/2 variant. The survey collected data on sociodemographic factors, family cancer history, reasons for choosing RRM or not, experiences with the decision-making process, support from healthcare, and surgery satisfaction. Multivariate logistic regression analysis identified factors associated with the decision to undergo RRM and satisfaction with having undergone surgery. RESULTS: Of the 272 respondents, 190 (69.9%) had undergone RRM. Having children and being a BRCA1 carrier were both associated with higher probability of choosing RRM, with an OR of 3.5 (p = 0.005 and p < 0.001 respectively). Among those who had undergone RRM, 78.9% (150/190) were satisfied with their decision and would choose the same procedure again. Feeling satisfied with support from the health care system gave an OR of 5.5 for being satisfied with having undergone RRM (p < 0.01). Those who found the decision difficult had lower odds of being satisfied (OR 0.2, p = 0.02). CONCLUSION: Being a BRCA1 carrier and having children were strongly associated with choosing RRM. Most participants felt relieved after RRM, were satisfied with their decision, and would choose the surgery again. Support from healthcare providers during decision-making was linked to higher satisfaction with having undergone surgery while those who struggled with the decision reported lower satisfaction.
The MLH1 synonymous variant c.27G>A (p.Arg9 =) has been reported in four index cases with suspected Lynch syndrome, but is variably classified as "likely pathogenic" or "variant of uncertain significance" due to insubsta...The MLH1 synonymous variant c.27G>A (p.Arg9 =) has been reported in four index cases with suspected Lynch syndrome, but is variably classified as "likely pathogenic" or "variant of uncertain significance" due to insubstantial clinical and functional evidence. We report three new MLH1 c.27G>A index cases with family histories fulfilling Amsterdam criteria for Lynch syndrome and reassessed collective evidence for pathogenicity. Two are European families from the UK (two siblings) and Spain (three members spanning three generations), and the third is a proband from Mongolia, the first non-European reported with this variant. Blood-based constitutional MLH1 methylation testing in six heterozygotes from the three families revealed varying levels of mosaic methylation, even within the same family, ranging from extremely low (≤ 1%) to ~ 16%. Two heterozygotes with blood methylation ≤ 1% had elevated methylation (5-8%) in normal colon distant from their colon cancers. Mosaic constitutional MLH1 methylation was linked in cis to the variant c.27A allele in all six heterozygotes and segregated together across generations. Three archived early-onset colon cancers available from three heterozygotes (UK siblings, Mongolian proband) each displayed MLH1 loss, MLH1 hypermethylation, and loss-of-heterozygosity of the wild-type c.27G allele, consistent with methylated c.27A alleles within a fraction of colon cells predisposing to tumorigenesis. Nanopore sequencing in the two European families found no significant shared ancestry and no other candidate variants. Multifactorial data collated from these and prior observational studies now provide sufficient evidence for the classification of MLH1 c.27G>A as likely/pathogenic via a functional mechanism of variably mosaic "secondary" constitutional MLH1 epimutation.
We present the first documented case of gastric-type endocervical adenocarcinoma in situ in a mosaic STK11 pathogenic variant carrier, who delivered a child with classic Peutz-Jeghers syndrome (PJS). A 53-year-old woman...We present the first documented case of gastric-type endocervical adenocarcinoma in situ in a mosaic STK11 pathogenic variant carrier, who delivered a child with classic Peutz-Jeghers syndrome (PJS). A 53-year-old woman presented with persistent watery vaginal discharge for 2 years. Histopathology confirmed gastric-type endocervical adenocarcinoma in situ. Familial genetic investigation was initiated after her son's diagnosis of PJS with an apparent de novo STK11 germline variant [NM_000455.4:c.842del (p.Pro281Argfs*6)]. Comprehensive STK11 screening via Sanger sequencing of peripheral blood from both parents showed no pathogenic variants. Following multidisciplinary tumor board review, ultra-deep next-generation sequencing was performed on multiple tissue specimens. Molecular analysis revealed low-level mosaicism for the familial STK11 variant in cervical tissue with no detectable mutations in blood, saliva, urine, or ovarian stroma. This case demonstrates three key clinical insights: (1) parental mosaicism may underlie apparent de novo PJS cases, (2) tissue-specific STK11 mosaicism can manifest as localized neoplastic transformation without classic PJS manifestations, and (3) ultra-deep sequencing may be considered in genetic counseling paradigms for parents of children with "de novo" cancer predisposition syndromes. These findings highlight the importance of considering mosaic phenomena in tumor prevention for hereditary cancer syndrome families.
The Danish Hereditary Non-Polyposis Colorectal Cancer Register (HNPCC-R) has formed the basis for many epidemiologic studies supporting risk stratification and both national and international guidelines on surveillance....The Danish Hereditary Non-Polyposis Colorectal Cancer Register (HNPCC-R) has formed the basis for many epidemiologic studies supporting risk stratification and both national and international guidelines on surveillance. However, the HNPCC-R is based on voluntary reporting and the completeness of registration is unknown. Hence, we aimed to assess the validity and completeness of the colorectal cancer (CRC) registrations in the HNPCC-R. We combined the registrations in the HNPCC-R with the registrations in the national Danish Cancer Registry (DCR), which is validated and based on mandatory reporting, and matched the cases from each register using a 13-step algorithm based on unique, national Central Population Registration number, date of diagnosis, location, and morphology thus identifying 9160 verified CRCs in 49,799 individuals. The overall agreement between the registers was 85%, and the completeness of the HNPCC-R was 95%. The DCR had the highest number of registrations before 1975, and the HNPCC-R had the highest number of registrations after 1985-especially more synchronous and metachronous cases. In conclusion, data from the HNPCC-R on CRC are valid and should be preferred for studies on CRC in families with a heritable increased risk of colorectal cancer-especially in Lynch syndrome, which is known for multiple CRCs, though a combination of both registers would secure the most optimal dataset.
Cancer remains a leading cause of death in children/adolescents. Approximately 8-18% of children/adolescents with cancer have an underlying pediatric Genetic Cancer Risk (p-GCR). P-GCR clinics offer surveillance aimed at...Cancer remains a leading cause of death in children/adolescents. Approximately 8-18% of children/adolescents with cancer have an underlying pediatric Genetic Cancer Risk (p-GCR). P-GCR clinics offer surveillance aimed at improving survival outcomes. Yet children/adolescents require more than surveillance protocols to support holistic health. A multidisciplinary model of care (MoC), including Advanced Practice Nurses (APN) is needed. Yet a MoC and formal description of the APN is lacking in p-GCR clinics. To explore existing evidence of holistic, multidisciplinary approaches to care for children/adolescents and families with a p-GCR; to identify how Advanced Practice Nurses (APN) contribute to care delivery in p-GCR services. A scoping review was conducted in three databases: MEDLINE (Ovid), Embase (Ovid) and CINAHL Complete. JBI methodology for conducting and reporting scoping reviews was used to search MEDLINE, Embase and CINAHL Complete. Gray and white literature was considered from 1991 to 2023. Thirty two studies met inclusion criteria. Thirteen aspects of a MoC in p-GCR were identified including: clinic scope, clinic locality, clinicians involved, care coordination, clinic activity, geography, centralisation of care, psychosocial aspects, shared decision making, education, referrals, transition to adult services and research. There were 10 APN roles described that supported the service/organisation and the delivery of holistic care to children/adolescents with a p-GCR. Using a systematic approach, this review identified how services provide care to children/adolescents with a p-GCR and the APN role in these services. A multidisciplinary MoC with dedicated care coordination can enable child and family centred care with a holistic healthcare approach.
Desmoids are rare non-cancerous fibrous growths with variable behavior ranging from slow indolent growth or even regression, to locally aggressive and progressive tumors that can cause significant morbidity or mortality....Desmoids are rare non-cancerous fibrous growths with variable behavior ranging from slow indolent growth or even regression, to locally aggressive and progressive tumors that can cause significant morbidity or mortality. Approximately 10-15% of patients with familial adenomatous polyposis (FAP) develop desmoid disease, most commonly located in the abdomen, on the abdominal wall, or in limbs. The majority of desmoids in FAP occur after abdominal surgery. Management is quite challenging and employing a multidisciplinary team at a specialized center is important for success. New treatment modalities have emerged, including tyrosine kinase inhibitors, γ-secretase inhibitors, and ablation techniques, complementing the existing repertoire of therapies such as NSAIDs, anti-hormonal therapy, chemotherapy, radiotherapy, and surgical interventions. Surgery remains the treatment of choice for easily resectable abdominal wall desmoids and intra-abdominal desmoids that cause intractable symptoms, or progressive disease despite alternate therapies, or complications from the invasion of nearby organs. When considering prophylactic colectomies in FAP patients, it's essential to account for the desmoidogenic potential of surgical interventions, especially in high-risk individuals with a positive family history of desmoids, presence of extracolonic manifestations and carriers of certain genotypes. Given the rarity of the disease and the variability in both anatomical presentation and clinical course, desmoids should be managed by a multidisciplinary team capable of coordinating patient specific care and optimizing treatment options.
Limited data exist on hereditary breast cancer characteristics and treatment driven by germline mutations beyond BRCA. Our primary aim is to describe the tumour and patient characteristics, treatment patterns and outcome...Limited data exist on hereditary breast cancer characteristics and treatment driven by germline mutations beyond BRCA. Our primary aim is to describe the tumour and patient characteristics, treatment patterns and outcomes in patients with non-BRCA hereditary breast cancer with a focus on CHEK2, ATM, PALB2 and TP53 variants. This is a retrospective single centre hospital-based cohort study of adult patients with a known (likely) pathogenic germline mutation and breast cancer diagnosis in UZ Leuven before April 2022. Data collection included baseline demographics, breast cancer characteristics, treatment patterns and disease outcome variables. Cohorts of patients with variants in different genes will be compared. We retrieved 185 patients with variants in ATM (N = 40), CHEK2 (N = 114), PALB2 (N = 8) and TP53 (N = 23). Median age was significantly lower in the TP53 group (36 years, p = 0.001). Only estrogen receptor (ER) status (p = 0.005) and breast cancer subtype (p < 0.001) differed significantly across the defined gene cohorts. HER2-positive disease was more frequent in the TP53 subgroup (59.1%, p < 0.001). Neoadjuvant chemotherapy was more commonly administered in the PALB2 and TP53 cohorts (p = 0.011). Univariate and multivariate survival analysis by gene cohort showed no significant difference in survival outcomes. In our series, we confirm that TP53 carriers are younger at breast cancer diagnosis and have more often HER2-positive breast cancer. Triple-negative breast cancer is more frequent in the PALB2 carriers, while ER-positivity is most common in ATM and CHEK2 carriers. Survival outcomes were similar across different gene cohorts in this study.
Familial adenomatous polyposis (FAP) is a hereditary disorder caused by constitutional pathogenic variants in the APC gene, leading to the development of up to hundreds of colorectal adenomas and a near-inevitable risk o...Familial adenomatous polyposis (FAP) is a hereditary disorder caused by constitutional pathogenic variants in the APC gene, leading to the development of up to hundreds of colorectal adenomas and a near-inevitable risk of colorectal cancer (CRC) if untreated. Traditional management relies on prophylactic colectomy, but advances in endoscopic techniques and chemoprevention offer alternative strategies to delay or even avoid surgery. This review explores the role of endoscopic surveillance, polypectomy strategies, and chemopreventive agents in FAP management, evaluating their efficacy, limitations, and the need for personalized approaches.
The Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) is an organization of healthcare providers, researchers, and advocates whose mission is to be a leading global authority in advancing...The Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) is an organization of healthcare providers, researchers, and advocates whose mission is to be a leading global authority in advancing the science and clinical management of hereditary gastrointestinal cancer syndromes. In 2024, the Executive Council developed a Strategic Plan, outlined here, to guide the organization's work over the next 3 years. The Strategic Plan is based on the four pillars of Education, Discovery & Innovation, Community & Collaboration, and Organizational Vitality, with associated goals, action plans, and metrics for each pillar. Ultimately, the Strategic Plan will help CGA-IGC fulfill its vision and mission to advance the science and clinical management of hereditary gastrointestinal cancers.
Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome characterized by germline mutations in the APC gene that result in the development of hundreds of premalignant adenomas throughout the colon and rectum...Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome characterized by germline mutations in the APC gene that result in the development of hundreds of premalignant adenomas throughout the colon and rectum. Prophylactic surgery remains the primary intervention strategy, as there are currently no pharmacological treatment options for FAP patients. Previous therapeutic approaches have predominantly focused on reducing polyp size rather than preventing their initiation, thereby missing a key opportunity for early intervention. Crucially, to effectively target the earliest stages of tumour development requires a deeper understanding of the molecular mechanisms underlying adenoma formation. In this review, we evaluate the latest models and methods employed to investigate the origin of FAP adenomas. We describe how mutant cells expand from their initial emergence within the intestinal epithelium and how they compete with normal cells within intestinal crypts. In addition, we discuss how multiple mutant crypts cooperate to collectively form polyclonal adenomas, and how these polyclonal lesions gradually transition towards monoclonality as adenomas progress towards colorectal cancer. Finally, we highlight how these insights inform the development of targeted cancer prevention strategies for individuals with FAP.
BACKGROUND: Tatars and Bashkirs are large and closely related ethnic communities that reside in the territory of the Russian Federation but have managed to preserve their national identity through the course of history....BACKGROUND: Tatars and Bashkirs are large and closely related ethnic communities that reside in the territory of the Russian Federation but have managed to preserve their national identity through the course of history. METHODS: This study included 446 Tatars, 53 Bashkirs, and 26 women of mixed Tatar-Bashkir ethnicity. Germline DNA analysis was performed for 349 breast cancer (BC) patients with clinical features of hereditary disease (family history, or young onset (</= 50 years), or BC bilaterality, or triple-negative receptor status (lack of expression of ER, PgR, and HER2) and 176 subjects with high-grade serous ovarian cancer (HGSOC). RESULTS: BRCA1 pathogenic variants (PVs) were detected in 63 women; surprisingly, five Slavic founder alleles accounted for 30 (48%) of the BRCA1 PVs. The genuine Tatar BRCA1 allele, c.5161C > T, was observed in 11 subjects. Among 27 women with BRCA2 PVs, six and five women were carriers of the c.-39-1_-39del and c.468dup variants, respectively. The loss-of-heterozygosity (LOH) test confirmed the pathogenic nature of the c.-39-1_-39del [rs758732038] allele, which is located in the 5'UTR of BRCA2. Analysis of other BC-associated genes revealed single instances of PVs affecting PALB2, TP53, ATM, RAD51, and RAD51D genes. CONCLUSION: Tatars and Bashkirs, which are ethnically and religiously separated from Russians, carry an unexpectedly high proportion of Slavic BRCA1/2 founder alleles. The identification of recurrent Tatar/Bashkir BRCA2 pathogenic 5'UTR variant c.-39-1_-39del calls for a systematic analysis of regulatory regions of cancer-predisposing genes in patients with missing heritability.
Colorectal cancer can be prevented in most patients with FAP by performing (procto)colectomy and lifelong endoscopic surveillance. Subsequently, the challenge is to prevent duodenal and gastric cancer. Duodenal cancer is...Colorectal cancer can be prevented in most patients with FAP by performing (procto)colectomy and lifelong endoscopic surveillance. Subsequently, the challenge is to prevent duodenal and gastric cancer. Duodenal cancer is one of the most common FAP-related causes of death and, in the last decade, the incidence of gastric cancer has increased. Performing frequent endoscopic surveillance with removal of neoplasia is important to prevent cancer especially since cancers in the upper GI tract generally have a poor prognosis. Moreover, the goal is to prevent upper GI surgery as these procedures are associated with substantial morbidity. In this review, we provide the prevalence of upper GI polyposis and cancer, describe endoscopic and histologic features, and discuss strategies for surveillance and treatment.
Germline pathogenic variants (GPVs) in RB1 are associated with the pediatric-onset intra-ocular malignancy retinoblastoma and typically present in infancy as multi-focal or bilateral disease. Survivors of retinoblastoma...Germline pathogenic variants (GPVs) in RB1 are associated with the pediatric-onset intra-ocular malignancy retinoblastoma and typically present in infancy as multi-focal or bilateral disease. Survivors of retinoblastoma are at high risk for developing subsequent malignant neoplasms (SMNs); indeed, these are the leading cause of death for individuals cured of their retinoblastoma. With the exception of sarcomas, typically occurring at the site of antecedent radiation therapy for the original retinoblastoma diagnosis, and melanoma, little is known of other SMNs in retinoblastoma survivors. Here, we describe a unique case of pancreatic adenocarcinoma (PDAC) in a patient with a RB1 GPV who was diagnosed with retinoblastoma as an infant. At age 57, he was diagnosed with PDAC. Sequence analysis of the PDAC revealed the acquisition of a somatic second-hit in RB1 in the PDAC. Multispectral immunofluorescence analyses of the PDAC tumor illustrated selective loss of the RB protein in the tumor that was accompanied by the continued expression of p16, encoded by the CDKN2A gene. In PDAC, CDKN2A loss is a common early event that contributes to carcinogenesis. This case may suggest that PDAC is a rare late component of RB1-associated tumor predisposition and illustrates that biallelic loss of RB1 is an alternative mechanism by which the RB1-pathway can be disrupted in PDAC independent of CDKN2A inactivation.
Efficient use of genetic biobank data in support of clinical care would enhance the adoption of personalized medicine. Identification of carriers of medically actionable variants that predispose to cancer enables intensi...Efficient use of genetic biobank data in support of clinical care would enhance the adoption of personalized medicine. Identification of carriers of medically actionable variants that predispose to cancer enables intensified screening and follow-up to decrease disease risk. Pathogenic variants of the MLH1 gene cause Lynch syndrome with a significant risk of developing cancer. Here, we introduce a novel approach for the large-scale screening of biobank SNP-array-based genotyping data to analyze copy-number variants (CNVs). With the method developed, we analyzed the Helsinki Biobank cohort of 121 073 samples and identified 29 MLH1 exon 16 deletion (MLH1∆Ex16) carriers, of which five (17%) had not been previously identified in healthcare. Our results demonstrate a high positive predictive value for the identification of MLH1∆Ex16 carriers from genotyping data. The cost-efficient method for detection of CNV carriers from large biobank genotyping cohorts described here facilitates intensified screening and follow-up aiming to cancer prevention.
Since panel genetic testing has become widely available, national guidelines recommend that individuals who previously underwent BRCA1/2-only testing should undergo updated testing to include other hereditary breast and...Since panel genetic testing has become widely available, national guidelines recommend that individuals who previously underwent BRCA1/2-only testing should undergo updated testing to include other hereditary breast and ovarian cancer predisposition genes. Our study assessed the yield of additional hereditary cancer predisposition testing in patients who previously underwent negative BRCA1/2 testing. Additionally, our study included a small pilot to evaluate whole exome sequencing in patients with a strong family history. Patients enrolled in a registry study who previously underwent negative BRCA1/2 testing were included and stratified into three categories based on personal and family cancer history-strongly suggestive, moderately suggestive, and possibly suggestive. Updated testing with a 36-gene pan-cancer panel was performed on most participants. A selected set of participants had whole exome sequencing. Patients with a pathogenic variant identified were offered clinical confirmatory testing. Rates of positive test results were compared among the three groups. Clinically relevant pathogenic variants in non-BRCA1/2 genes from the 36-gene panel test were identified in 8.1% of participants, most commonly in PALB2 (1.9%), ATM (1.2%), and MSH6 (1.2%). Positive findings were more common in patients with strongly suggestive history, but the differences were not statistically significant. Exome testing in individuals with a strongly suggestive personal and family history did not yield novel findings. Our findings aligned with previous studies and support the use of expanded gene panel testing in all patients meeting testing criteria who previously underwent negative BRCA1/2 testing. Our small pilot whole exome sequencing did not identify any novel finding.
Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increas...Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004-12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66%) and white (93.1%). The median age at first colonoscopy was 47 years. The adenoma detection rate (ADR) was 29.4% (95% CI:19.9-41.1%) in the German cohort and 48.6% (95% CI: 33.0-64.4%) in the Cleveland cohort (p = 0.055) and significantly correlated with age (< 45 years, 13.6% (95% CI: 6.40-26.7%); 45-49 years, 52.4% (95% CI: 32.4-71.7%); ≥50 years, 52.6% (95% CI: 37.3-67.5%); p < 0.001). The ADR in Cleveland was higher than the U.S. average ADR but the difference was not statistically significant (48.6% vs. 35.6%, p = 0.08), and the ADR in the German cohort (29.4%) was similar to the national German average risk screening cohort (31.3% in men, p = 0.84; 20.1% in women, p = 0.08). In our screening cohort with CDH1 PV carriers, we demonstrated an ADR of 13.5% in individuals under 45 years, similar to the ADR in patients aged 25-40 years with a family history of CRC. Overall, SSL detection rate was 9.7%. Colorectal cancer was diagnosed in 3 patients (3.2%), 2/3 with an early age of onset before the age of 50 years. This first international study provides preliminary evidence of a higher ADR in U.S. CDH1 PV carriers compared to the general population, with a high number of adenomas detected before the age of 50. This may indicate an increased CRC risk that should be explored in larger studies.
Lanjouw L, Kramer CJH, Elst AT
… +14 more, de Bock GH, Gaarenstroom KN, Yigit R, Berger LPV, van Asperen CJ, Commandeur-Jan SZ, van der Hall DMX, Jalving M, Kagie MJ, van der Stoep N, van Wezel T, Mourits MJE, Bosse T, Bart J
Identification of somatic and germline BRCA1/2 pathogenic variants in epithelial ovarian cancer (EOC) patients is essential for determining poly-(ADP-ribose)-polymerase (PARP) inhibitor sensitivity and genetic predisposi...Identification of somatic and germline BRCA1/2 pathogenic variants in epithelial ovarian cancer (EOC) patients is essential for determining poly-(ADP-ribose)-polymerase (PARP) inhibitor sensitivity and genetic predisposition. In the Netherlands, BRCA1/2 testing changed to a tumor-first approach to efficiently identify both somatic and germline pathogenic variants in all patients. Here, we performed an in-depth evaluation of the first four years of the tumor-first test-pathway. Data of consecutive series of patients diagnosed with EOC in two regions were obtained from the Netherlands Cancer Registry. Tumor and/or germline test data were retrieved from hospital databases. The primary outcome was the percentage of patients completing the BRCA1/2 test-pathway, defined as having a negative tumor test or a referral for a germline test in case of a positive tumor test or no tumor test. Factors associated with test-pathway completion were identified through multivariable logistic regression analysis. In total, 69.8% (757/1085) completed the test-pathway. This was 74.4% in the most recent year. Younger patients, patients diagnosed in year three or four, patients with high-grade serous/high-grade endometrioid carcinoma, advanced stage disease, middle or high socioeconomic status, and patients who underwent surgery or chemotherapy, were more likely to complete the test-pathway. We report inequalities in genetic testing access in EOC patients, which highlight the need for better guideline adherence, particularly in older patients, those with low socioeconomic status, low-grade histotypes, early-stage disease and those without surgery or chemotherapy. Additionally, timely testing of patients, and testing relatives if patients cannot be tested, are crucial to increase test uptake.