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Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2010

Open Access 01-12-2010 | Research

A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

Authors: Els van Riel, Margreet GEM Ausems, Frans BL Hogervorst, Irma Kluijt, Marielle E van Gijn, Jeanne van Echtelt, Karen Scheidel-Jacobse, Eric FAM Hennekam, Rein P Stulp, Yvonne J Vos, G Johan A Offerhaus, Fred H Menko, Johan JP Gille

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2010

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Abstract

Background

An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.

Methods

We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.

Results

The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.

Conclusions

We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.
Appendix
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Literature
1.
Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR: Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009, 76: 1–18. 10.1111/j.1399-0004.2009.01230.xCrossRefPubMedPubMedCentral
2.
Vasen HF, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, et al.: Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007, 44: 353–362. 10.1136/jmg.2007.048991CrossRefPubMedPubMedCentral
3.
Woods MO, Williams P, Careen A, Edwards L, Bartlett S, McLaughlin JR, Younghusband HB: A new variant database for mismatch repair genes associated with Lynch syndrome. Hum Mutat 2007, 28: 669–673. 10.1002/humu.20502CrossRefPubMed
4.
Peltomäki P, Vasen H: Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 2004, 20: 269–276.CrossRefPubMedPubMedCentral
5.
Ou J, Niessen RC, Lutzen A, Sijmons RH, Kleibeuker JH, de Wind N, Rasmussen LJ, Hofstra RM: Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Hum Mutat 2007, 28: 1047–1054. 10.1002/humu.20580CrossRefPubMed
6.
Lucci-Cordisco E, Boccuto L, Neri G, Genuardi M: The use of microsatellite instability, immunohistochemistry and other variables in determining the clinical significance of MLH1 and MSH2 unclassified variants in Lynch syndrome. Cancer Biomark 2006, 2: 11–27.PubMed
7.
van Puijenbroek M, Middeldorp A, Tops CM, van Eijk R, van der Klift HM, Vasen HF, Wijnen JT, Hes FJ, Oosting J, van Wezel T, Morreau H: Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas. Fam Cancer 2008, 7: 319–330. 10.1007/s10689-008-9194-8CrossRefPubMed
8.
Gille JJ, Hogervorst FB, Pals G, Wijnen JT, van Schooten RJ, Dommering CJ, Meijer GA, Craanen ME, Nederlof PM, de Jong D, et al.: Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. Br J Cancer 2002, 87: 892–897. 10.1038/sj.bjc.6600565CrossRefPubMedPubMedCentral
9.
Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, et al.: Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat 2008, 29: 852–860. 10.1002/humu.20735CrossRefPubMed
10.
Drost M, Zonneveld JB, van Dijk L, Morreau H, Tops CM, Vasen HF, Wijnen JT, de Wind N: A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1. Hum Mutat 2010, 31: 247–253. 10.1002/humu.21180CrossRefPubMed
11.
Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, et al.: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004, 96: 261–268. 10.1093/jnci/djh034CrossRefPubMedPubMedCentral
12.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998, 58: 5248–5257.PubMed
13.
Wagner A, Hendriks Y, Meijers-Heijboer EJ, de Leeuw WJ, Morreau H, Hofstra R, Tops C, Bik E, Brocker-Vriends AH, van Der Meer C, et al.: Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. J Med Genet 2001, 38: 318–322. 10.1136/jmg.38.5.318CrossRefPubMedPubMedCentral
14.
Eisen DB, Michael DJ: Sebaceous lesions and their associated syndromes: part II. J Am Acad Dermatol 2009, 61: 563–578. quiz 579–580 10.1016/j.jaad.2009.04.059CrossRefPubMed
15.
Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C: Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res 2007, 67: 4595–4604. 10.1158/0008-5472.CAN-06-3509CrossRefPubMed
16.
Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X, Xicola RM, Rodriguez-Moranta F, Paya A, Jover R, Bessa X: Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 2005, 293: 1986–1994. 10.1001/jama.293.16.1986CrossRefPubMed
17.
Southey MC, Jenkins MA, Mead L, Whitty J, Trivett M, Tesoriero AA, Smith LD, Jennings K, Grubb G, Royce SG, et al.: Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 2005, 23: 6524–6532. 10.1200/JCO.2005.04.671CrossRefPubMed
18.
Hofstra RM, Spurdle AB, Eccles D, Foulkes WD, de Wind N, Hoogerbrugge N, Hogervorst FB: Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance. Hum Mutat 2008, 29: 1292–1303. 10.1002/humu.20894CrossRefPubMedPubMedCentral
19.
Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lonnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, et al.: Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology 2005, 129: 537–549.PubMed
20.
Goel A, Nguyen TP, Leung HC, Nagasaka T, Rhees J, Hotchkiss E, Arnold M, Banerji P, Koi M, Kwok CT, et al.: De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer 2010, in press.
21.
Niessen RC, Berends MJ, Wu Y, Sijmons RH, Hollema H, Ligtenberg MJ, de Walle HE, de Vries EG, Karrenbeld A, Buys CH, et al.: Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer. Gut 2006, 55: 1781–1788. 10.1136/gut.2005.090159CrossRefPubMedPubMedCentral
22.
Lagerstedt Robinson K, Liu T, Vandrovcova J, Halvarsson B, Clendenning M, Frebourg T, Papadopoulos N, Kinzler KW, Vogelstein B, Peltomaki P, et al.: Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst 2007, 99: 291–299. 10.1093/jnci/djk051CrossRefPubMed
23.
Ou J, Niessen RC, Vonk J, Westers H, Hofstra RM, Sijmons RH: A database to support the interpretation of human mismatch repair gene variants. Hum Mutat 2008, 29: 1337–1341. 10.1002/humu.20907CrossRefPubMed
24.
Fokkema IF, den Dunnen JT, Taschner PE: LOVD: easy creation of a locus-specific sequence variation database using an "LSDB-in-a-box" approach. Hum Mutat 2005, 26: 63–68. 10.1002/humu.20201CrossRefPubMed
25.
Hirata K, Kanemitsu S, Nakayama Y, Nagata N, Itoh H, Ohnishi H, Ishikawa H, Furukawa Y: A novel germline mutation of MSH2 in a hereditary nonpolyposis colorectal cancer patient with liposarcoma. Am J Gastroenterol 2006, 101: 193–196. 10.1111/j.1572-0241.2005.00308.xCrossRefPubMed
26.
Lynch HT, Deters CA, Hogg D, Lynch JF, Kinarsky Y, Gatalica Z: Familial sarcoma: challenging pedigrees. Cancer 2003, 98: 1947–1957. 10.1002/cncr.11743CrossRefPubMed
27.
Sijmons R, Hofstra R, Hollema H, Mensink R, van der Hout A, Hoekstra H, Kleibeuker J, Molenaar W, Wijnen J, Fodde R, et al.: Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer. Genes Chromosomes Cancer 2000, 29: 353–355. 10.1002/1098-2264(2000)9999:9999<::AID-GCC1042>3.0.CO;2-TCrossRefPubMed
28.
South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A: The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst 2008, 100: 277–281. 10.1093/jnci/djm291CrossRefPubMed
29.
Lachiewicz AM, Wilkinson TM, Groben P, Ollila DW, Thomas NE: Muir-Torre syndrome. Am J Clin Dermatol 2007, 8: 315–319. 10.2165/00128071-200708050-00008CrossRefPubMed
Metadata
Title
A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome
Authors
Els van Riel
Margreet GEM Ausems
Frans BL Hogervorst
Irma Kluijt
Marielle E van Gijn
Jeanne van Echtelt
Karen Scheidel-Jacobse
Eric FAM Hennekam
Rein P Stulp
Yvonne J Vos
G Johan A Offerhaus
Fred H Menko
Johan JP Gille
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2010
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/1897-4287-8-7

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