Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the ...MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up.
This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population.
A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001).
Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetic analysis of von Hippel-Lindau disease Nordstrom-O'Brien, Morgan; van der Luijt, Rob B; van Rooijen, Ellen ...
Human mutation,
20/May , Letnik:
31, Številka:
5
Journal Article
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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed ...throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537, 2010.
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The ...Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease‐associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population‐specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad‐based oncogenetic testing in some populations.
The prevalence and spectrum of germline mutations in BPCA1/2 have been reported in single populations, with the majority of reports focused on Caucasians in, Europe and North America. This study comprehensively describes the characteristics of worldwide disease‐associated BPCA1/2 mutations. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. Knowledge of the population‐specific mutational spectrum in BPCA1/2 could inform efficient strategies' or genetic testing and may justify a more broad‐based oncogenetic testing in some populations.
We previously showed that the
variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer ...risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female
*R1699Q carriers.
Data were collected from 129
*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.
In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).
Our results confirm that
*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.
Abstract Context The underlying genetic cause of nonmedullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical ...management. Objective Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date. Methods Nationwide retrospective cohort study in tertiary referral centers. In total, 97 patients diagnosed with pediatric NMTC between 1970 and 2020 were included in this study. Patients underwent germline whole genome sequencing. The main outcome measures were mutation detection yield in (1) clinically relevant tumor predisposition genes and (2) genes previously associated with NMTC. Results In total, 13 of 97 patients (13%) carried a germline (likely) pathogenic variant in a well-known tumor predisposition gene: APC (n = 1), BRCA2 (n = 2), CHEK2 (n = 4), DICER1 (n = 4), HOXB13 (n = 1), and MITF (n = 1). In addition, 1 patient was diagnosed with Pendred syndrome (SLC26A4) and 9 variants of high interest were found in other NMTC candidate susceptibility genes. Conclusion The reported prevalence (13%) of germline variants in well-known tumor predisposing genes and the added value of a revised personal/family history and histology led us to recommend genetic counseling for all patients with childhood NMTC. The detected tumor predisposition syndromes are associated with a risk for second cancers which necessitates additional surveillance of the index patients and presymptomatic genetic testing of at risk family members.
To identify the optimal surgical strategy for multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism (pHPT). To describe the course of postoperative hypoparathyroidism and to ...assess whether genotype is associated with persistent/recurrent pHPT.
Surgery is the preferred treatment in MEN1-related pHPT, but the surgical procedure of choice is still uncertain.
This retrospective cohort study was performed at the Departments of Endocrinology of the University Medical Centers of Utrecht and Nijmegen, the Netherlands. Patients were selected from the Dutch MEN1 database, including all patients 16 years or older treated for MEN1 from 1990 to 2009. Data were collected by medical record review.
Seventy-three patients underwent parathyroid surgery. Persistent/recurrent pHPT occurred in 53% after less than 3 parathyroids resected (<SPTX), 17% after subtotal resection (SPTX), and 19% after total resection with autotransplantation (TPTX). Persistent (≥6 months) postoperative hypoparathyroidism occurred in 24% after <SPTX, 39% after SPTX, and 66% after TPTX. Median duration of hypoparathyroidism was 1.5 years, in 65% successful cessation of vitamin D/calcium was possible, even after more than 10 years. After <SPTX, patients with nonsense or frameshift mutations in exons 2, 9, and 10 had a significantly lower risk of persistent/recurrent pHPT than patients with other mutations. After SPTX/TPTX persistence/recurrence did not differ with genotype. After SPTX/TPTX persistence/recurrence was more frequent (P = 0.07) in patients without bilateral transcervical thymectomy (TCT).
SPTX with bilateral TCT is the procedure of choice for MEN1-related pHPT. Genotype seems to affect the chance of recurrence. Postoperative hypoparathyroidism lasting 6 months or more should not be considered permanent in MEN1.
This observational study aimed to investigate whether the reported association between family history (FH) of breast cancer (BC) or ovarian cancer (OC) and OC risks in BRCA1/2 mutation carriers can ...be explained by mutation position on the gene. In total, 3310 female BRCA1/2 mutation carriers participating in a nationwide prospective cohort (Hereditary Breast and Ovarian Cancer in the Netherlands) were included. FH was classified according to cancer occurrence in first-degree relatives (BC only, OC only, both, neither) and mutations were classified according to their position on the gene (OC cluster region (OCCR), BC cluster region, neither). The main outcome was OC occurrence. Cox proportional-hazard models were applied to investigate the association between FH and OC risks before and after adjusting for mutation position. Of all women included, 202 were diagnosed with OC. A BC-only FH tended to be associated with lower OC risks when compared with a FH without BC/OC (HR: 0.79, 95% CI: 0.52-1.17; HR: 0.59, 95% CI: 0.33-1.07 for BRCA1 and BRCA2, respectively) while an OC-only FH tended to be associated with higher risks (HR: 1.58, 95% CI: 0.90-2.77; HR: 1.75, 95% CI: 0.70-4.37 for BRCA1 and BRCA2, respectively). After adjusting for mutation position, association between FH and OC risks was slightly smaller in magnitude (HR: 0.85, 95% CI: 0.55-1.30; HR: 0.64, 95% CI: 0.34-1.21 for BC-only FH in BRCA1 and BRCA2, respectively; HR: 1.46, 95% CI: 0.80-2.68; HR: 1.49, 95% CI: 0.44-4.02 for OC-only FH in BRCA1 and BRCA2, respectively), indicating that mutation position explains only part of the association. Considering the magnitude of the observed trend, we do not believe FH should be used to change counseling regarding OC prevention.
Pituitary adenomas are common neoplasms of the anterior pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition ...(PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of pituitary adenomas. To evaluate the role of AIP in pituitary adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of pituitary adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants ...identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1α (HIF-1α), the key regulator of the hypoxia ...response. However, the question remained whether hypoxia is a late stage bystander or a true carcinogenetic event in patients with hereditary predisposition. We therefore studied HIF-1α overexpression in ductal carcinoma in situ (DCIS), an established precursor of invasive breast cancer.We used immunohistochemistry to examine the expression of the hypoxia markers HIF-1α, CAIX and Glut-1 in DCIS and available invasive carcinoma lesions of 32 BRCA1, 16 BRCA2 and 77 non-BRCA mutation-related cases. HIF-1α expression was detected in 63% of BRCA1 and 62% of BRCA2 as compared to 34% of non-BRCA mutation-related DCIS cases (p = 0.005). CAIX overexpression was present in 56% of BRCA1 and 44% of BRCA2 as compared to 6% of non-BRCA mutation-related DCIS cases (p = 0.000). Glut-1 overexpression was observed in 59% of BRCA1, 75% of BRCA2 and 67% of non-BRCA mutation-related DCIS cases (p = 0.527). Overall, HIF-1α, CAIX and Glut-1 expression in BRCA mutation-related DCIS matched the expression in the accompanying invasive cancers in 60% or more of cases. In non-BRCA mutation-related cases the expression of the hypoxia markers in DCIS matched the expression in the invasive part in 46% or more of the cases.Although BRCA1 and BRCA2 germline mutation-related invasive breast cancers are different in many ways, the hypoxia-related proteins HIF-1α, CAIX and Glut-1 are expressed in both DCIS and invasive lesions of BRCA1 and BRCA2 mutation carriers. This suggests that hypoxia may already play a role in the DCIS stage of BRCA1 and BRCA2 germline mutation related breast carcinogenesis, and may also drive cancer progression. Hypoxia-related proteins are therefore putative targets for therapy and molecular imaging for early detection and monitoring therapy response in BRCA mutation patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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