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Article ; Online: Noncoding Aberrations in Mismatch Repair Genes Underlie a Substantial Part of the Missing Heritability in Lynch Syndrome.

Te Paske, Iris B A W / Mensenkamp, Arjen R / Neveling, Kornelia / Hoogerbrugge, Nicoline / Ligtenberg, Marjolijn J L / De Voer, Richarda M

Gastroenterology

2022 Volume 163, Issue 6, Page(s) 1691–1694.e7

MeSH term(s)	Humans ; DNA Mismatch Repair/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
Language	English
Publishing date	2022-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2022.08.041
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Article ; Online: Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

Elze, Lisa / van der Post, Rachel S / Vos, Janet R / Mensenkamp, Arjen R / de Hullu, Mirjam S C / Nagtegaal, Iris D / Hoogerbrugge, Nicoline / de Voer, Richarda M / Ligtenberg, Marjolijn J L

Journal of the National Cancer Institute

2023 Volume 115, Issue 7, Page(s) 853–860

Abstract: Background: Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with ... ...

Abstract	Background: Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics. Methods: We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lynch syndrome and calculated the standardized incidence ratio for all tumor types. MSI status, somatic second hit alterations, and immunohistochemistry-based MMR status were analyzed in 236 noncolorectal and nonendometrial malignant tumors. Results: In individuals with Lynch syndrome MSI-H/dMMR occurred both in Lynch-spectrum and in non-Lynch-spectrum malignancies (85% vs 37%, P < .01). MSI-H/dMMR malignancies were found in nearly all non-Lynch-spectrum tumor types. Almost all breast carcinomas had medullary features, and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be associated with Lynch syndrome (standardized incidence ratio = 38.8, 95% confidence interval = 16.7 to 76.5). Conclusions: In individuals with Lynch syndrome, MSI-H/dMMR occurs in more than one-half of the malignancies other than colorectal and endometrial carcinomas, including tumor types without increased incidence. The Lynch-spectrum tumors should be expanded to breast carcinomas with medullary features. All malignancies in patients with Lynch syndrome, independent of subtype, should be tested for MSI-H/dMMR in case therapy with immune checkpoint inhibitors is considered. Moreover, Lynch syndrome should be considered an underlying cause of all MSI-H/dMMR malignancies other than colorectal and endometrial carcinomas.
MeSH term(s)	Humans ; Female ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Microsatellite Instability ; Immune Checkpoint Inhibitors ; DNA Mismatch Repair/genetics ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Breast Neoplasms ; Endometrial Neoplasms/epidemiology ; Endometrial Neoplasms/genetics
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2023-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djad063
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Article ; Online: Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review.

Hendricks, Linda A J / Schuurs-Hoeijmakers, Janneke / Spier, Isabel / Haadsma, Maaike L / Eijkelenboom, Astrid / Cremer, Kirsten / Mensenkamp, Arjen R / Aretz, Stefan / Vos, Janet R / Hoogerbrugge, Nicoline

European journal of medical genetics

2022 Volume 65, Issue 7, Page(s) 104533

Abstract: PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN ... ...

Abstract	PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy.
MeSH term(s)	Adolescent ; Adult ; Child ; Developmental Disabilities ; Female ; Hamartoma Syndrome, Multiple/diagnosis ; Hamartoma Syndrome, Multiple/genetics ; Hamartoma Syndrome, Multiple/pathology ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Megalencephaly ; Mosaicism ; PTEN Phosphohydrolase/genetics ; Young Adult
Chemical Substances	PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
Language	English
Publishing date	2022-05-28
Publishing country	Netherlands
Document type	Case Reports ; Journal Article ; Review
ZDB-ID	2184135-4
ISSN	1878-0849 ; 1769-7212
ISSN (online)	1878-0849
ISSN	1769-7212
DOI	10.1016/j.ejmg.2022.104533
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Article: Lessons learned from rapid exome sequencing for 575 critically ill patients across the broad spectrum of rare disease.

Marouane, Abderrahim / Neveling, Kornelia / Deden, A Chantal / van den Heuvel, Simone / Zafeiropoulou, Dimitra / Castelein, Steven / van de Veerdonk, Frank / Koolen, David A / Simons, Annet / Rodenburg, Richard / Westra, Dineke / Mensenkamp, Arjen R / de Leeuw, Nicole / Ligtenberg, Marjolijn / Matthijsse, Rene / Pfundt, Rolph / Kamsteeg, Erik Jan / Brunner, Han G / Gilissen, Christian /

Feenstra, Ilse / de Boode, Willem P / Yntema, Helger G / van Zelst-Stams, Wendy A G / Nelen, Marcel / Vissers, Lisenka E L M

Frontiers in genetics

2024 Volume 14, Page(s) 1304520

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2024-01-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2023.1304520
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Article ; Online: Somatic Nonepigenetic Mismatch Repair Gene Aberrations Underly Most Mismatch Repair-Deficient Lynch-Like Tumors.

Elze, Lisa / Mensenkamp, Arjen R / Nagtegaal, Iris D / van Zelst-Stams, Wendy A G / de Voer, Richarda M / Ligtenberg, Marjolijn J L

Gastroenterology

2020 Volume 160, Issue 4, Page(s) 1414–1416.e3

MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cohort Studies ; Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; DNA Mismatch Repair ; DNA Mutational Analysis ; Female ; Humans ; Male ; Microsatellite Instability ; Middle Aged ; Molecular Epidemiology ; Mutation ; Netherlands/epidemiology ; Prevalence ; Young Adult
Language	English
Publishing date	2020-11-28
Publishing country	United States
Document type	Journal Article ; Observational Study
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2020.11.042
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Article: Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS).

Hendricks, Linda A J / Verbeek, Katja C J / Schuurs-Hoeijmakers, Janneke H M / Mensenkamp, Arjen R / Brems, Hilde / de Putter, Robin / Anastasiadou, Violetta C / Villy, Marie-Charlotte / Jahn, Arne / Steinke-Lange, Verena / Baldassarri, Margherita / Irmejs, Arvids / de Jong, Mirjam M / Links, Thera P / Leter, Edward M / Bosch, Daniëlle G M / Høberg-Vetti, Hildegunn / Tveit Haavind, Marianne / Jørgensen, Kjersti /

Mæhle, Lovise / Blatnik, Ana / Brunet, Joan / Darder, Esther / Tham, Emma / Hoogerbrugge, Nicoline / Vos, Janet R

Cancers

2024 Volume 16, Issue 5

Abstract: Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020- ... ...

Abstract	Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0-1 times/week physical activity than ≥2 times (OR
Language	English
Publishing date	2024-02-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16050953
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Article ; Online: The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.

Hinić, Snežana / Cybulski, Cezary / Van der Post, Rachel S / Vos, Janet R / Schuurs-Hoeijmakers, Janneke / Brugnoletti, Fulvia / Koene, Saskia / Vreede, Lilian / van Zelst-Stams, Wendy A G / Kets, C Marleen / Haadsma, Maaike / Spruijt, Liesbeth / Wevers, Marijke R / Evans, D Gareth / Wimmer, Katharina / Schnaiter, Simon / Volk, Alexander E / Möllring, Anna / de Putter, Robin /

Soikkonen, Leila / Kahre, Tiina / Tooming, Mikk / de Jong, Mirjam M / Vaz, Fátima / Mensenkamp, Arjen R / Genuardi, Maurizio / Lubinski, Jan / Ligtenberg, Marjolijn / Hoogerbrugge, Nicoline / de Voer, Richarda M

Genetics in medicine : official journal of the American College of Medical Genetics

2024 Volume 26, Issue 5, Page(s) 101101

Abstract: Purpose: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.: ...

Abstract	Purpose: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. Methods: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291). Results: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. Conclusion: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.
Language	English
Publishing date	2024-02-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1016/j.gim.2024.101101
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Article ; Online: Megalobastic anemia, infantile leukemia, and immunodeficiency caused by a novel homozygous mutation in the DHFR gene.

Kuijpers, Taco W / de Vries, Andrica C H / van Leeuwen, Ester M / Ermens, A Ton A M / de Pont, Saskia / Smith, Desirée E C / Wamelink, Mirjam M C / Mensenkamp, Arjen R / Nelen, Marcel R / Lango Allen, Hana / Pals, Steven T / Beverloo, Berna H B / Huidekoper, Hidde H / Wagner, Anja

Blood advances

2022 Volume 6, Issue 22, Page(s) 5829–5834

MeSH term(s)	Humans ; Homozygote ; Leukemia ; Mutation ; Anemia
Language	English
Publishing date	2022-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022007233
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Article ; Online: PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.

van de Beek, Irma / Glykofridis, Iris E / Oosterwijk, Jan C / van den Akker, Peter C / Diercks, Gilles F H / Bolling, Maria C / Waisfisz, Quinten / Mensenkamp, Arjen R / Balk, Jesper A / Zwart, Rob / Postma, Alex V / Meijers-Heijboer, Hanne E J / van Moorselaar, R Jeroen A / Wolthuis, Rob M F / Houweling, Arjan C

Human molecular genetics

2022 Volume 32, Issue 7, Page(s) 1223–1235

Abstract: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, ... ...

Abstract	Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. By whole exome sequencing we identified a heterozygous missense variant (p.(Cys677Tyr)) in a zinc-finger encoding domain of the PRDM10 gene which co-segregated with the phenotype in the family. We show that PRDM10Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN. We propose that PRDM10 controls an extensive gene program and acts as a critical regulator of FLCN gene transcription in human cells. The germline variant PRDM10Cys677Tyr curtails cellular folliculin expression and underlies a distinguishable syndrome characterized by extensive lipomatosis, fibrofolliculomas and renal cell carcinomas.
MeSH term(s)	Humans ; Birt-Hogg-Dube Syndrome/genetics ; Birt-Hogg-Dube Syndrome/pathology ; Carcinoma, Renal Cell/genetics ; Genes, Tumor Suppressor ; Skin Neoplasms/genetics ; Lipomatosis/genetics ; Kidney Neoplasms/genetics ; DNA-Binding Proteins/genetics ; Transcription Factors/genetics ; Proto-Oncogene Proteins/genetics ; Tumor Suppressor Proteins/genetics
Chemical Substances	PRDM10 protein, human ; DNA-Binding Proteins ; Transcription Factors ; FLCN protein, human ; Proto-Oncogene Proteins ; Tumor Suppressor Proteins
Language	English
Publishing date	2022-11-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddac288
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Article ; Online: Optimising clinical care through

Luo, Xi / Maciaszek, Jamie L / Thompson, Bryony A / Leong, Huei San / Dixon, Katherine / Sousa, Sónia / Anderson, Michael / Roberts, Maegan E / Lee, Kristy / Spurdle, Amanda B / Mensenkamp, Arjen R / Brannan, Terra / Pardo, Carolina / Zhang, Liying / Pesaran, Tina / Wei, Sainan / Fasaye, Grace-Ann / Kesserwan, Chimene / Shirts, Brian H /

Davis, Jeremy L / Oliveira, Carla / Plon, Sharon E / Schrader, Kasmintan A / Karam, Rachid

Journal of medical genetics

2022 Volume 60, Issue 6, Page(s) 568–575

Abstract: Background: Germline pathogenic variants in : Methods: CDH1: Results: Updated : Conclusions: The development and evolution ... ...

Abstract	Background: Germline pathogenic variants in Methods: CDH1 Results: Updated Conclusions: The development and evolution of
MeSH term(s)	Humans ; Genetic Variation ; Genetic Testing ; Germ-Line Mutation/genetics ; Stomach Neoplasms/genetics ; Germ Cells ; Antigens, CD/genetics ; Cadherins/genetics
Chemical Substances	CDH1 protein, human ; Antigens, CD ; Cadherins
Language	English
Publishing date	2022-12-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmg-2022-108807
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