Publications by authors named "Tom G W Letteboer"

19 Publications

  • Page 1 of 1

The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect.

Cancer Epidemiol Biomarkers Prev 2019 06 1;28(6):1010-1014. Epub 2019 Mar 1.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

Background: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families.

Methods: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias.

Results: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively].

Conclusions: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome.

Impact: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0576DOI Listing
June 2019

Cancer Risks for PMS2-Associated Lynch Syndrome.

J Clin Oncol 2018 10 30;36(29):2961-2968. Epub 2018 Aug 30.

Sanne W. ten Broeke, Heleen M. van der Klift, Carli M.J. Tops, Manon Suerink, Frederik J. Hes, Hans F.A. Vasen, Juul T. Wijnen, and Maartje Nielsen, Leiden University Medical Center, Leiden; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Tom G.W. Letteboer, University Medical Center, Utrecht; Theo A.M. van Os and Egbert J.W. Redeker, Academic Medical Center, Amsterdam; Maran J.W. Olderode-Berends and Yvonne J. Vos, University of Groningen; University Medical Center Groningen, Groningen; Anja Wagner, Erasmus Medical Center, Rotterdam, the Netherlands; Stefan Aretz, University of Bonn; University Hospital Bonn, Bonn; Christoph Engel, Leipzig University; Medizinisch Genetisches Zentrum Bayerstr, Leipzig; Magnus von Knebel Doeberitz, University of Heidelberg; German Cancer Research Center, Heidelberg; Pål Møller, University of Witten-Herdecke, Wuppertal; Nils Rahner, Heinrich-Heine-University, Düsseldorf; Hans K. Schackert, Technische Universität Dresden, Dresden; Verena Steinke-Lange, Medizinische Klinik und Poliklinik IV Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Pål Møller, The Norwegian Radium Hospital; Oslo University Hospital, Oslo, Norway; Inge Bernstein, Hvidovre Hospital, Hvidovre, and Aalborg University Hospital, Aalborg, Denmark; Daniel D. Buchanan, Mark Clendenning, John L. Hopper, Mark A. Jenkins, Christophe Rosty, Ingrid Winship, and Aung Ko Win, The University of Melbourne; Daniel D. Buchanan, Ingrid Winship, and Aung Ko Win, Royal Melbourne Hospital, Parkville, Melbourne, Victoria; Rodney Scott, University of Newcastle, Newcastle, New South Wales, Australia; Albert de la Chapelle, Heather L. Hampel, Rachel Pearlman, and Leigha Senter, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Gabriel Capella and Marta Pineda, Institut d'Investigació Biomédica de Bellvitge, Barcelona, Spain; Steven Gallinger, Mount Sinai Hospital, Toronto, Ontario, Canada; Jane C. Figueiredo and Robert Haile, Cedars-Sinai Medical Center, Los Angeles, CA; Loic Le Marchand, University of Hawaii Cancer Center, Honolulu, HI; Annika Lindblom, Karolinska Institutet; Karolinska University Hospital, Stockholm, Sweden; Noralane M. Lindor, Mayo Clinic Arizona, Scottsdale, AZ; Polly A. Newcomb, Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA; and Stephen Thibodeau, Mayo Clinic, Rochester, MN.

Purpose: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.

Methods: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance.

Results: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.

Conclusion: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
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http://dx.doi.org/10.1200/JCO.2018.78.4777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349460PMC
October 2018

Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2.

Gastroenterology 2018 09 29;155(3):844-851. Epub 2018 Jul 29.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

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-β gene (CTNNB1), which encodes β-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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http://dx.doi.org/10.1053/j.gastro.2018.05.020DOI Listing
September 2018

SNP association study in PMS2-associated Lynch syndrome.

Fam Cancer 2018 10;17(4):507-515

Department of Clinical Genetics, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2-3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5-4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients.
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http://dx.doi.org/10.1007/s10689-017-0061-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182583PMC
October 2018

Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation.

Eur J Cancer 2017 07 23;80:48-54. Epub 2017 May 23.

Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address:

Introduction: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation.

Methods: We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist.

Results: The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS.

Conclusion: We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour.
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http://dx.doi.org/10.1016/j.ejca.2017.04.021DOI Listing
July 2017

Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.

Hum Mutat 2016 11 21;37(11):1162-1179. Epub 2016 Aug 21.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

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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http://dx.doi.org/10.1002/humu.23052DOI Listing
November 2016

Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

PLoS One 2016 14;11(6):e0157381. Epub 2016 Jun 14.

Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Background And Aims: Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history.

Methods: Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants.

Results: Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1).

Conclusions: This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157381PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907507PMC
July 2017

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers.

Genet Med 2016 Apr 25;18(4):405-9. Epub 2015 Jun 25.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

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.
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http://dx.doi.org/10.1038/gim.2015.83DOI Listing
April 2016

Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14.

Front Genet 2015 12;6:67. Epub 2015 Mar 12.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco San Francisco, CA, USA ; Institute of Human Genetics, University of California, San Francisco San Francisco, CA, USA ; Department of Anatomy, University of California, San Francisco San Francisco, CA, USA.

HHT shows clinical variability within and between families. Organ site and prevalence of arteriovenous malformations (AVMs) depend on the HHT causative gene and on environmental and genetic modifiers. We tested whether variation in the functional ENG allele, inherited from the unaffected parent, alters risk for pulmonary AVM in HHT1 mutation carriers who are ENG haploinsufficient. Genetic association was found between rs10987746 of the wild type ENG allele and presence of pulmonary AVM [relative risk = 1.3 (1.0018-1.7424)]. The rs10987746-C at-risk allele associated with lower expression of ENG RNA in a panel of human lymphoblastoid cell lines (P = 0.004). Moreover, in angiogenically active human lung adenocarcinoma tissue, but not in uninvolved quiescent lung, rs10987746-C was correlated with expression of PTPN14 (P = 0.004), another modifier of HHT. Quantitative TAQMAN expression analysis in a panel of normal lung tissues from 69 genetically heterogeneous inter-specific backcross mice, demonstrated strong correlation between expression levels of Eng, Acvrl1, and Ptpn14 (r2 = 0.75-0.9, P < 1 × 10(-12)), further suggesting a direct or indirect interaction between these three genes in lung in vivo. Our data indicate that genetic variation within the single functional ENG gene influences quantitative and/or qualitative differences in ENG expression that contribute to risk of pulmonary AVM in HHT1, and provide correlative support for PTPN14 involvement in endoglin/ALK1 lung biology in vivo. PTPN14 has been shown to be a negative regulator of Yap/Taz signaling, which is implicated in mechanotransduction, providing a possible molecular link between endoglin/ALK1 signaling and mechanical stress. EMILIN2, which showed suggestive genetic association with pulmonary AVM, is also reported to interact with Taz in angiogenesis. Elucidation of the molecular mechanisms regulating these interactions in endothelial cells may ultimately provide more rational choices for HHT therapy.
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http://dx.doi.org/10.3389/fgene.2015.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357294PMC
March 2015

Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

J Clin Oncol 2015 Feb 15;33(4):319-25. Epub 2014 Dec 15.

Sanne W. ten Broeke, Carli M. Tops, Heleen M. van der Klift, Manon Suerink, Frederik J. Hes, Hans F. Vasen, Maartje Nielsen, and Juul T. Wijnen, Leiden University Medical Center; Hans F. Vasen, The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden; Richard M. Brohet, Research Center Linnaeus Institute, Spaarne Hospital, Hoofddorp; Mary E. Velthuizen and Tom G.W. Letteboer, University Medical Center Utrecht, Utrecht; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Fred H. Menko, Vrije Universiteit, University Medical Center; Theo A. van Os and Bert J.W. Redeker, Academic Medical Center, Amsterdam; Rolf H. Sijmons and Yvonne J. Vos, University of Groningen, University Medical Center Groningen, Groningen; Anja Wagner, Erasmus University Medical Center, Rotterdam, the Netherlands; Inge Bernstein, Aalborg University Hospital, Aalborg; Inge Bernstein, Danish Hereditary Nonpolyposis Colorectal Cancer Registry, Hvidovre University Hospital Copenhagen, Denmark; Gabriel Capellá Munar, Hereditary Cancer Program, Catalan Institute of Oncology-Institut D'Investigació Biomèdica de Bellvitge, l'Hospitalet de Llobregat, Spain; Annika Lindblom, Karolinska Institutet, Karolinska University Hospital, Solna; Pal Moller, Research Group Inherited Cancer, Oslo University Hospital, Oslo, Norway; and Nils Rahner, Institute of Human Genetics, University of Dusseldorf, Dusseldorf, Germany.

Purpose: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers.

Methods: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.

Results: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.

Conclusion: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.
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http://dx.doi.org/10.1200/JCO.2014.57.8088DOI Listing
February 2015

Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans.

Proc Natl Acad Sci U S A 2014 May 8;111(21):7723-8. Epub 2014 May 8.

Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;Department of Anatomy, andInstitute of Human Genetics, University of California, San Francisco, CA 94143

Outcome of TGFβ1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced TGFβ1 signaling, we dissected the modifier locus Tgfbm3, on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b(C57) haplotype suppresses prenatal lethality of Tgfb1(-/-) embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFβRI, and we show that the C57 variant is hypomorphic for down-regulation of Smad2/3-driven transcription. Genetic variation at Tgfbm3 or pharmacological inhibition of ADAM17, modulates postnatal circulating endothelial progenitor cell (CEPC) numbers via effects on TGFβRI activity. Because CEPC numbers correlate with angiogenic potential, this suggests that variant Adam17 is an innate modifier of adult angiogenesis, acting through TGFβR1. To determine whether human ADAM17 is also polymorphic and interacts with TGFβ signaling in human vascular disease, we investigated hereditary hemorrhagic telangiectasia (HHT), which is caused by mutations in TGFβ/bone morphogenetic protein receptor genes, ENG, encoding endoglin (HHT1), or ACVRL1 encoding ALK1 (HHT2), and considered a disease of excessive abnormal angiogenesis. HHT manifests highly variable incidence and severity of clinical features, ranging from small mucocutaneous telangiectases to life-threatening visceral and cerebral arteriovenous malformations (AVMs). We show that ADAM17 SNPs associate with the presence of pulmonary AVM in HHT1 but not HHT2, indicating genetic variation in ADAM17 can potentiate a TGFβ-regulated vascular disease.
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http://dx.doi.org/10.1073/pnas.1318761111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040598PMC
May 2014

Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis.

J Med Genet 2014 Jan 19;51(1):55-60. Epub 2013 Nov 19.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

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.
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http://dx.doi.org/10.1136/jmedgenet-2013-102000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889192PMC
January 2014

Hereditary hemorrhagic telangiectasia: how accurate are the clinical criteria?

Am J Med Genet A 2013 Mar 8;161A(3):461-6. Epub 2013 Feb 8.

Department of Cardiology, St. Antonius Hospital, Koekoekslaan, Nieuwegein, The Netherlands.

The clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria. Three out of four criteria are required for a definite clinical diagnosis HHT, two criteria are considered "possible" HHT, and 0 or 1 criterion makes the diagnosis unlikely. However, these consensus diagnostic criteria have not been validated. We report on the diagnostic accuracy of the clinical criteria. A total of 450 consecutive persons ≥16 years of age were screened for HHT between May 2004 and September 2009, including a chest CT to screen for pulmonary arteriovenous malformations (AVMs). We selected 263 first-degree relatives of disease-causing mutation carriers who underwent mutation analysis. Genetic test results were considered the gold standard. The family mutation was present in 186 patients (mean age 42.9 ± 14.6 yr; 54.8% female). A clinical diagnosis was definite, "possible", and unlikely in 168 (90.3%), 17 (9.1%), and 1 (0.5%) patient, respectively. In 77 persons the family mutation was absent (mean age 37.1 ± 12.3 yr, 59.7% female). In this group a clinical diagnosis was definite, possible, and unlikely in 0, 35 (45.5%), and 42 (54.5%) persons, respectively. The positive predictive value of a definite clinical diagnosis was 100% (95% CI 97.8-100), the negative predictive value of an unlikely diagnosis 97.7% (95% CI 87.9-99.6). Of 52 patients with "possible" HHT, 17 (32.7%) displayed an HHT-causing mutation. The Curaçao clinical criteria have a good diagnostic performance. Genetic testing is particularly helpful in patients with a "possible" clinical diagnosis HHT.
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http://dx.doi.org/10.1002/ajmg.a.35715DOI Listing
March 2013

Risks of less common cancers in proven mutation carriers with lynch syndrome.

J Clin Oncol 2012 Dec 22;30(35):4409-15. Epub 2012 Oct 22.

University of Leipzig, Leipzig, Germany.

Purpose: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6.

Patients And Methods: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk.

Results: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers.

Conclusion: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
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http://dx.doi.org/10.1200/JCO.2012.43.2278DOI Listing
December 2012

Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.

Nat Commun 2012 Jan 10;3:616. Epub 2012 Jan 10.

UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC), San Francisco, California 94158-9001, USA.

Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-β pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general.
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http://dx.doi.org/10.1038/ncomms1633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509798PMC
January 2012

[Diagnosis of fetal alcohol spectrum disorders].

Ned Tijdschr Geneeskd 2010 ;154:A331

St. Antoniusziekenhuis, afd. Kindergeneeskunde, Nieuwegein, the Netherlands.

Prenatal alcohol exposure may cause decreased growth of the child, congenital abnormalities, specific facial characteristics, and, most importantly, mental retardation and behavioural disorders, all known as fetal alcohol spectrum disorders (FASD). A significant number of pregnant women in the Netherlands drink alcohol, but the prevalence of FASD in our country is unknown. Repeated and high peak blood alcohol concentrations, for example in the case of binge drinking by the mother, result in more severe abnormalities; a safe limit for alcohol consumption in pregnancy cannot be defined. In 2007 and 2008, Dutch paediatricians reported a total of 56 diagnosed cases of FASD, mostly adopted and foster children. Possibly the condition has not always been diagnosed. Use of international guidelines for diagnosis by the medical profession may improve detection. The guidelines of the Canadian Public Health Agency provide a useful and generally accepted classification, with strict cut-off points to avoid overdiagnosis; attention should always be paid to the broad differential diagnosis.
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October 2010

Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia.

Am J Med Genet A 2008 Nov;146A(21):2733-9

DBG-Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations (AVMs) ranging from telangiectases to larger AVMs. Mutations in two genes cause HHT; ENG (HHT1) and ACVRL1 (HHT2). Although the hallmark for clinical diagnosis is the presence of telangiectases, there are few publications reporting the relative distribution and frequency of these features between HHT1 and HHT2. Here, the results of such analysis of telangiectases in 268 patients with HHT1 and 130 patients with HHT2 are described. Localization of the telangiectases is reported, and patients were clustered by age to estimate the site prevalence for different age categories. We show that telangiectases of the nasal mucosa are present at a higher prevalence and start to appear earlier in life than those of the oral mucosa or dermal sites in patients with either HHT1 or HHT2. Oral and nasal mucosal telangiectases are present earlier in life in patients with HHT1 compared to patients with HHT2, whereas dermal lesions are more frequent and appear earlier in life in patients with HHT2. In patients with either HHT1 or HHT2, the number of sites affected increases with age. In patients with HHT1, more women than men had skin telangiectases, particularly on the face. These results confirm that the frequency of AVMs differ between patients with HHT1 and HHT2, and that these differences can be detected on physical examination.
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http://dx.doi.org/10.1002/ajmg.a.32243DOI Listing
November 2008

Assessment of intestinal vascular malformations in patients with hereditary hemorrhagic teleangiectasia and anemia.

Eur J Gastroenterol Hepatol 2007 Feb;19(2):153-8

Department of Gastroenterology, St Antonius Hospital, Nieuwegein, The Netherlands.

Introduction: Hereditary hemorrhagic teleangiectasia (HHT) is an autosomal dominant disorder with mucocutaneous teleangiectasia and visceral arteriovenous malformations. Mutations of endoglin and Activin A receptor like kinase-1 have different phenotypes, HHT1 and HHT2, respectively. The gastrointestinal tract is frequently affected, but limited information is available on the relationship with genotype.

Aim: To determine whether different genotypes have different phenotypes with respect to intestinal teleangiectasia.

Methods: HHT patients, referred for anemia, underwent videocapsule endoscopy. Chart review was performed for information on genotype and HHT manifestations.

Results: Twenty-five patients were analyzed (men/women 13/9, mean age 49+/-15 years.), 14 HHT1, eight HHT2 and three without known mutation. Epistaxis occurred in 96% of patients. Gastroduodenoscopy revealed teleangiectasia in 7/12 (58%) HHT1 and 3/8 (38%) HHT2 patients. Videocapsule endoscopy found teleangiectasia in all HHT1 and 5/8 (63%) HHT2 patients. In 9/14 HHT1 patients, teleangiectasia were large. Teleangiectasia in the colon was restricted to 6/11 (55%) HHT1 patients. Hepatic arteriovenous malformations were present in 1/7 HHT1 and 5/6 HHT2 patients.

Conclusion: Large teleangiectasia in small intestine and colon appear to occur predominantly in HHT1. Hepatic arteriovenous malformations are mainly found in HHT2. In HHT patients with unexplained anemia, videocapsule endoscopy should be considered to determine the size and extent of teleangiectasia and exclude other abnormalities.
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http://dx.doi.org/10.1097/01.meg.0000252633.88419.04DOI Listing
February 2007

A pulmonary right-to-left shunt in patients with hereditary hemorrhagic telangiectasia is associated with an increased prevalence of migraine.

Chest 2005 Oct;128(4):2485-9

Department of Cardiology, St. Antonius Hospital., 3435 CM Nieuwegein, Netherlands.

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant vascular dysplasia with a high prevalence of pulmonary arteriovenous malformation (PAVM). Recent studies report an increased prevalence of migraine in patients with a cardiac right-to-left shunt. The aim of our study was to evaluate whether there is also an increased prevalence of migraine in patients with a pulmonary right-to-left shunt (PAVM).

Methods: All patients with HHT referred to our hospital till April 2004 with or without PAVM and with or without migraine were included in the study.

Results: In total, 538 HHT patients (41.6% men; mean age +/- SD, 39.3 +/- 18.6 years) could be included. PAVM was present in 208 patients (38.7%; mean age, 39.3 +/- 17.6 years). Significantly more women were present in the PAVM subgroup compared to the non-PAVM subgroup, 65.4% vs 53.9% (p = 0.009). Migraine occurred in 88 patients with HHT, a prevalence of 16.4%. The prevalence of migraine in women with HHT was significantly higher compared to men, 19.4% vs 12.1%, respectively (p = 0.03) The prevalence of migraine in patients with PAVM was 21.2%, which was significantly higher then in patients without PAVM, 13.3% (p = 0.02). The occurrence of PAVM in the patients with migraine is significantly higher than in those without migraine, 50.0% vs 36.4%, respectively (p = 0.02).

Conclusion: This study showed a higher prevalence of PAVM in patients with migraine and HHT. The right-to-left shunt due to the PAVM might play a causal role in the pathogenesis of migraine in patients with HHT. This needs to be determined in further studies.
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http://dx.doi.org/10.1378/chest.128.4.2485DOI Listing
October 2005