RESUMEN
BACKGROUND: Among the 10% of pancreatic cancers that occur in a familial context, around a third carry a pathogenic variant in a cancer predisposition gene. Genetic studies of pancreatic cancer predisposition are limited by high mortality rates amongst index patients and other affected family members. The genetic risk for pancreatic cancer is often shared with breast cancer susceptibility genes, most notably BRCA2, PALB2, ATM and BRCA1. Therefore, we hypothesized that additional shared genetic etiologies might be uncovered by studying families presenting with both breast and pancreatic cancer. METHODS: Focusing on a multigene panel of 276 DNA Damage Repair (DDR) genes, we performed next-generation sequencing in a cohort of 41 families with at least three breast cancer cases and one pancreatic cancer. When the index patient with pancreatic cancer was deceased, close relatives (first or second-degree) affected with breast cancer were tested (39 families). RESULTS: We identified 27 variants of uncertain significance in DDR genes. A splice site variant (c.1605 + 2T > A) in the RAD17 gene stood out, as a likely loss of function variant. RAD17 is a checkpoint protein that recruits the MRN (MRE11-RAD50-NBS1) complex to initiate DNA signaling, leading to DNA double-strand break repair. CONCLUSION: Within families with breast and pancreatic cancer, we identified RAD17 as a novel candidate predisposition gene. Further genetic studies are warranted to better understand the potential pathogenic effect of RAD17 variants and in other DDR genes.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Neoplasias Pancreáticas , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas Nucleares , Neoplasias Pancreáticas/genética , LinajeRESUMEN
BACKGROUND: Pathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants. METHODS: Using the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families. RESULTS: We identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%). CONCLUSIONS: Our results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk.
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Neoplasias del Sistema Biliar/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Melanoma/genética , Neoplasias Pancreáticas/genética , Adulto , Anciano , Neoplasias del Sistema Biliar/epidemiología , Neoplasias del Sistema Biliar/patología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Melanoma/epidemiología , Melanoma/patología , Persona de Mediana Edad , Países Bajos/epidemiología , Páncreas/patología , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/patología , Factores de RiesgoRESUMEN
BACKGROUND: Pathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype. METHODS: Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes. RESULTS: Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001). CONCLUSIONS: SDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.
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Proteínas de la Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Adulto , Femenino , Mutación de Línea Germinal/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Heterocigoto , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Paraganglioma/patología , Feocromocitoma/patologíaRESUMEN
PURPOSE: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. METHODS: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. RESULTS: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). CONCLUSION: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.
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Poliposis Intestinal , Síndromes Neoplásicos Hereditarios , Adulto , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Mutación de Línea Germinal , Humanos , Poliposis Intestinal/congénito , Poliposis Intestinal/diagnóstico , Poliposis Intestinal/epidemiología , Poliposis Intestinal/genética , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/genética , Estudios Retrospectivos , Proteína Smad4/genética , Encuestas y CuestionariosRESUMEN
Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In our study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1-families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.
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Quinasa 4 Dependiente de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal/genética , Melanoma/genética , Estudios de Cohortes , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Mesotelioma/genética , Mesotelioma Maligno , Factor de Transcripción Asociado a Microftalmía/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
BACKGROUND & AIMS: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with variants in other mismatch repair genes. METHODS: We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3,000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher exact test. RESULTS: None of the PMS2-associated CRCs contained any somatic variants in the catenin-ß1 gene (CTNNB1), which encodes ß-catenin, whereas 14 of 24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half the PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%; P = .44) and MSH2 (71.4%; P = .035) than in those associated with variants in PMS2. CONCLUSIONS: In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence.
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Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Mutación de Línea Germinal , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Adulto , Anciano , Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/genética , Molécula de Adhesión Celular Epitelial/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , beta Catenina/genéticaRESUMEN
BACKGROUND: Several factors have been reported that influence the probability of a germline CDKN2A mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family. METHODS: Five clinical features and their association with CDKN2A mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with CDKN2A mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (CDKN2A Mutation(CM)-Score) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with CDKN2A mutation). RESULTS: All five features were significantly associated (p<0.05) with a CDKN2A mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to >90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98). CONCLUSION: We developed a practical scoring system to predict CDKN2A mutation status among melanoma-prone families. We suggest that CDKN2A analysis should be recommended to families with a CM-Score of ≥16 points.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Melanoma/genética , Neoplasias Pancreáticas/genética , Adulto , Estudios de Cohortes , Europa (Continente) , Femenino , Mutación de Línea Germinal , Humanos , Modelos Logísticos , Masculino , Melanoma/diagnóstico , Persona de Mediana Edad , Países Bajos , Neoplasias Pancreáticas/diagnóstico , Proyectos de Investigación , Suecia , Adulto JovenRESUMEN
BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. CONCLUSIONS: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
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Antígenos CD/genética , Cadherinas/genética , Quinasas Quinasa Quinasa PAM/genética , Factor 88 de Diferenciación Mieloide/genética , Neoplasias Gástricas/genética , alfa Catenina/genética , Adulto , Anciano , Estudios de Cohortes , Europa (Continente) , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Adulto JovenAsunto(s)
Poliposis Adenomatosa del Colon , Neoplasias Colorrectales , Humanos , Mosaicismo , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Genes APC , Proteína de la Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , Mutación de Línea Germinal , MutaciónRESUMEN
Mutations in SDHD and SDHAF2 (both located on chromosome 11) give rise to hereditary paraganglioma almost exclusively after paternal transmission of the mutation, and tumours often show loss of the entire maternal copy of chromosome 11. The 'Hensen' model postulates that a tumour modifier gene located on chromosome 11p15, a region known to harbour a cluster of imprinted genes, is essential to tumour formation. We observed decreased protein expression of the 11p15 candidate genes CDKN1C, SLC22A18 and ZNF215 evaluated in 60 SDHD-mutated tumours compared to normal carotid body tissue and non-SDH mutant tumours.We then created stable knockdown in vitro models, reasoning that the simultaneous knockdown of SDHD and a maternally expressed 11p15 modifier gene would enhance paraganglioma-related cellular characteristics compared to SDHD knockdown alone. Knockdown of SDHD in SNB19 and SHSY5Y cells resulted in the accumulation of succinate, the stabilization of HIF1 protein and a reduction in cell proliferation.Compared to single knockdown of SDHD, knockdown of SDHD together with SLC22A18 or with CDKN1C led to small but significant increases in cell proliferation and resistance to apoptosis, and to a gene expression profile closely related to the known transcriptional profile of SDH-deficient tumours. Of the 60 SDHD tumours investigated, four tumours showing retention of chromosome 11 showed SLC22A18 and CDKN1C expression levels comparable to levels in tumours showing loss of chromosome 11, suggesting loss of protein expression despite chromosomal retention.Our data strongly suggest that SLC22A18 and/or CDKN1C are tumour modifier genes involved in the tumourigenesis of SDHD-linked paraganglioma.
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Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Paraganglioma/genética , Succinato Deshidrogenasa/genética , Línea Celular Tumoral , Proliferación Celular , Cromosomas Humanos Par 11/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Modelos Genéticos , Impresión Molecular , Paraganglioma/metabolismo , Ácido Succínico/metabolismoRESUMEN
We investigated the presence and patterns of mosaicism in the APC gene in patients with colon neoplasms not associated with any other genetic variants; we performed deep sequence analysis of APC in at least 2 adenomas or carcinomas per patient. We identified mosaic variants in APC in adenomas from 9 of the 18 patients with 21 to approximately 100 adenomas. Mosaic variants of APC were variably detected in leukocyte DNA and/or non-neoplastic intestinal mucosa of these patients. In a comprehensive sequence analysis of 1 patient, we found no evidence for mosaicism in APC in non-neoplastic intestinal mucosa. One patient was found to carry a mosaic c.4666dupA APC variant in only 10 of 16 adenomas, indicating the importance of screening 2 or more adenomas for genetic variants.
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Adenoma/genética , Poliposis Adenomatosa del Colon/genética , Carcinoma/genética , Neoplasias Colorrectales/genética , Genes APC , Mosaicismo , Neoplasias Primarias Múltiples/genética , Adulto , Anciano , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Vía de Señalización WntRESUMEN
BACKGROUND: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. METHODS: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level. RESULTS: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues. CONCLUSIONS: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.
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Poliposis Adenomatosa del Colon/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Cromosomas Humanos Par 1/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Proteínas de Neoplasias/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Mapeo Cromosómico , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Ligamiento Genético , Genotipo , Homocigoto , Humanos , Repeticiones de Microsatélite , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleótido Simple , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , ARN Mensajero/metabolismoAsunto(s)
Pólipos Adenomatosos/patología , ADN Glicosilasas/genética , Neoplasias Duodenales/epidemiología , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/genética , Neoplasias Duodenales/patología , Duodenoscopía/estadística & datos numéricos , Duodeno/diagnóstico por imagen , Duodeno/patología , Femenino , Humanos , Mucosa Intestinal/diagnóstico por imagen , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Adulto JovenRESUMEN
Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers.
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Neoplasias Encefálicas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN/métodos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Encefálicas/metabolismo , Estudios de Cohortes , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Predisposición Genética a la Enfermedad , Variación Genética , Mutación de Línea Germinal , Humanos , Inestabilidad de Microsatélites , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Síndromes Neoplásicos Hereditarios/metabolismo , Países BajosRESUMEN
BACKGROUND & AIMS: Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. METHODS: We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations. RESULTS: In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P = .014 for comparative survival analysis between patients with and without a CDH1 mutation). CONCLUSIONS: All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.
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Neoplasias de la Mama/genética , Cadherinas/genética , Carcinoma Lobular/genética , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Gástricas/genética , Adulto , Anciano , Antígenos CD , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Lobular/mortalidad , Carcinoma Lobular/patología , Carcinoma Lobular/terapia , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/mortalidad , Síndromes Neoplásicos Hereditarios/patología , Síndromes Neoplásicos Hereditarios/terapia , Países Bajos , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.
Asunto(s)
Heterocigoto , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Mutación , Neoplasias/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , RiesgoRESUMEN
BACKGROUND: Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. METHODS: We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). RESULTS: We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. CONCLUSIONS: These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
Asunto(s)
Poliposis Adenomatosa del Colon/complicaciones , Poliposis Adenomatosa del Colon/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 15 , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/genética , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Mutación , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple , Riesgo , Adulto JovenRESUMEN
BACKGROUND: The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations. METHODS: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis. RESULTS: We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm. CONCLUSIONS: Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/patología , Cromosomas Humanos Par 11 , Femenino , Genes Mitocondriales , Humanos , Masculino , Repeticiones de Microsatélite , Paraganglioma/patología , Linaje , Feocromocitoma/patología , Succinato Deshidrogenasa/metabolismoRESUMEN
Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.