Publications by authors named "Arjen Mensenkamp"

The development of multiple primary tumors is one of the hallmarks of hereditary cancer. The phenotypic presentation of individuals with multiple primary tumors is often heterogeneous, which hampers the establishment of a genetic diagnosis. The absence of a genetic diagnosis may lead to inappropriate surveillance advices and treatment choices.

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Approximately 10% of affected individuals have an inherited component. Deleterious germline variants increase the lifetime risk for PDAC and are often associated with an elevated risk for extra-pancreatic malignancies.

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Purpose: Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.

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Article Synopsis
  • Researchers found that changes in a specific part of the p53 gene, called p53β, might be important in causing some types of cancer.
  • They discovered a special change (stop-lost variant) in this gene in four families with a history of certain cancers like colorectal, breast, and thyroid cancer.
  • This change affects how p53β works and can increase cancer risk, showing that we need to look closely at all parts of the p53 gene to better understand cancer and who might be at risk.
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  • Wilms tumor is the most common kidney cancer in children, mainly caused by non-genetic factors, but can also be linked to specific genes.
  • Familial cases of Wilms tumors are rare, with four previously described families linked to pathogenic variants in the CTR9 gene, often inherited from unaffected fathers.
  • The report introduces female siblings, one with a bilateral Wilms tumor, who have a new splice site variant in the CTR9 gene leading to exon 9 deletion, confirming that CTR9 variants are a rare cause of Wilms tumors typically seen in families.
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  • The ENIGMA research consortium focuses on determining the clinical significance of variants in hereditary breast and ovarian cancer genes, specifically BRCA1 and BRCA2, and evolved from an external expert panel to an internal Variant Curation Expert Panel (VCEP) to enhance alignment with FDA recognized classification processes.
  • The VCEP reviewed existing classification criteria and utilized statistical methods to assess evidence strength, testing new specifications on variants and updating documentation for better user clarity.
  • Analysis led to refined classifications for variants—resolving uncertainties and maintaining confidence in others—while revealing gaps in both ENIGMA's research and ACMG/AMP criteria, ultimately improving the classification process for BRCA1 and BRCA2 variants.
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  • * Analysis of data from over 55,000 breast cancer patients showed that co-observation of variants in BRCA1, BRCA2, and PALB2 with other breast cancer genes occurred less frequently than expected, suggesting a potential correlation with pathogenicity.
  • * The findings indicate that identifying a variant of uncertain significance alongside a known pathogenic variant supports evidence against the variant's pathogenicity, which could improve variant classification in clinical settings and for other genetic conditions.
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Background: Individuals with germline pathogenic variants in BRCA1 or BRCA2 are at a high risk of breast and ovarian carcinomas with BRCA1/2 deficiency and homologous recombination deficiency that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. Malignancies with homologous recombination deficiency are more sensitive to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors. We investigated the fraction of non-breast or ovarian malignancies that have BRCA1/2 deficiency and genomic instability features.

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PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition.

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  • CHEK2 plays a role in homologous recombination repair (HRR) and individuals with harmful variants in this gene are at higher risk for developing breast cancer and potentially other cancers.
  • PARP inhibitors (PARPi) are effective for cancers with HRR deficiencies, such as those caused by BRCA1/2 mutations, but they have shown little success in treating cancers linked to CHEK2 variants.
  • Research indicates that cancers from individuals with biallelic CHEK2 variants do not exhibit traits associated with HRR deficiency, explaining the lack of efficacy of PARPi treatment for these patients.
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Purpose: Female CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported.

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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.

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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.

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  • Rapid exome sequencing (rES) is becoming the go-to genetic test for critically ill patients, especially neonates and young infants, helping quickly identify genetic causes of rare diseases to guide treatment.
  • A study evaluated rES on 575 patients over four years, revealing a significant increase in referrals and a decrease in turnaround time for results, with an overall diagnostic yield of 30.4%.
  • Even when no genetic diagnosis was found, rES still influenced clinical decision-making, highlighting its value for patients of all ages and various rare conditions.
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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.

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Background: Germline pathogenic variants in are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) Variant Curation Expert Panel (VCEP) developed specifications for variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.

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Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD.

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  • Pathogenic PTEN germline variants lead to PTEN Hamartoma Tumor Syndrome (PHTS), which exhibits a range of symptoms and genetic mutations, underscoring the importance of understanding these associations for better diagnostics and personalized treatment.
  • A study involving 510 patients identified 268 pathogenic variants, revealing trends such as adults having more truncating variants and children more often presenting with macrocephaly and developmental delays.
  • Findings suggest that the type of PTEN variant (missense vs. truncating) correlates with the age of disease onset and specific phenotypes, indicating that genetic variation influences the clinical features of PHTS.
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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.

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Article Synopsis
  • - The study investigated how a 313-variant Polygenic Risk Score (PRS) could enhance breast cancer (BC) risk predictions in non-Dutch families, beyond standard genetic testing.
  • - It included data from nearly 4,000 BC cases and analyzed the relationship between the PRS and BC occurrence, revealing a significant link that could adjust screening recommendations for up to 58% of individuals across different guidelines.
  • - The findings suggest that incorporating the PRS could be beneficial for managing BC risk in families with unknown genetic predispositions and those with known moderate-risk gene variants.
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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.

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In a subset of pediatric cancers, a germline cancer predisposition is highly suspected based on clinical and pathological findings, but genetic evidence is lacking, which hampers genetic counseling and predictive testing in the families involved. We describe a family with two siblings born from healthy parents who were both neonatally diagnosed with atypical teratoid rhabdoid tumor (ATRT). This rare and aggressive pediatric tumor is associated with biallelic inactivation of SMARCB1, and in 30% of the cases, a predisposing germline mutation is involved.

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Background: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

Methods: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes.

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