Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Familial Cancer
Published in: Familial Cancer 4/2008

01-12-2008

Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas

Authors: Marjo van Puijenbroek, Anneke Middeldorp, Carli M. J. Tops, Ronald van Eijk, Heleen M. van der Klift, Hans F. A. Vasen, Juul Th. Wijnen, Frederik J. Hes, Jan Oosting, Tom van Wezel, Hans Morreau

Published in: Familial Cancer | Issue 4/2008

Login to get access

Abstract

Mismatch repair deficiency in tumors can result from germ line mutations in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2), or from sporadic promoter hypermethylation of MLH1. The role of unclassified variants (UVs) in MMR genes is subject to debate. To establish the extend of chromosomal instability and copy neutral loss of heterozygosity (cnLOH), we analyzed 41 archival microsatellite unstable carcinomas, mainly colon cancer, from 23 patients with pathogenic MMR mutations, from eight patients with UVs in one of the MMR genes and 10 cases with MLH1 promoter hypermethylation. We assessed genome wide copy number abnormalities and cnLOH using SNP arrays. SNP arrays overcome the problems of detecting LOH due to instability of polymorphic microsatellite markers. All carcinomas showed relatively few chromosomal aberrations. Also cnLOH was infrequent and in Lynch syndrome carcinomas usually confined to the locus harbouring pathogenic mutations in MLH1, MSH2 or PMS2 In the carcinomas from the MMR-UV carriers such cnLOH was less common and in the carcinomas with MLH1 promoter hypermethylation no cnLOH at MLH1 occurred. MSI-H carcinomas of most MMR-UV carriers present on average with more aberrations compared to the carcinomas from pathogenic MMR mutation carriers, suggesting that another possible pathogenic MMR mutation had not been missed. The approach we describe here shows to be an excellent way to study genome-wide cnLOH in archival mismatch repair deficient tumors.
Literature
1.
Parsons R, Li GM, Longley MJ et al (1993) Hypermutability and mismatch repair deficiency in Rer+ tumor-cells. Cell 75:1227–1236PubMedCrossRef
2.
Lynch HT, Smyrk T (1996) Hereditary nonpolyposis colorectal cancer (Lynch syndrome)—an updated review. Cancer 78:1149–1167PubMedCrossRef
3.
Yuen ST, Chan TL, Ho JWC et al (2002) Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 21:7585–7592PubMedCrossRef
4.
Ionov Y, Peinado MA, Malkhosyan S et al (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561PubMedCrossRef
5.
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819PubMedCrossRef
6.
Perucho M (1996) Cancer of the microsatellite mutator phenotype. Biol Chem 377:675–684PubMed
7.
Kouri M, Laasonen A, Mecklin JP et al (1990) Diploid predominance in hereditary nonpolyposis colorectal-carcinoma evaluated by flow-cytometry. Cancer 65:1825–1829PubMedCrossRef
8.
Kouri M (1993) Dna ploidy of colorectal-carcinoma by tumor site, gender and history of noncolorectal malignancies. Oncology 50:41–45PubMedCrossRef
9.
Trautmann K, Terdiman JP, French AJ et al (2006) Chromosomal instability in microsatellite-unstable and stable colon cancer. Clin Cancer Res 12:6379–6385PubMedCrossRef
10.
Kapiteijn E, Liefers GJ, Los LC et al (2001) Mechanisms of oncogenesis in colon versus rectal cancer. J Pathol 195:171–178PubMedCrossRef
11.
Frattini M, Balestra D, Suardi S et al (2004) Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res 10:4015–4021PubMedCrossRef
12.
Beart RW, Melton LJ, Maruta M et al (1983) Trends in right and left-sided colon cancer. Dis Colon Rectum26:393–398PubMedCrossRef
13.
Diep CB, Kleivi K, Ribeiro FR et al (2006) The order of genetic events associated with colorectal cancer progression inferred from meta-analysis of copy number changes. Genes Chromosomes Cancer 45:31–41PubMedCrossRef
14.
Nakao K, Mehta KR, Moore DH et al (2004) High-resolution analysis of DNA copy number alterations in colorectal cancer by array-based comparative genomic hybridization. Carcinogenesis 25:1345–1357PubMedCrossRef
15.
Lips EH, Dierssen JWF, van Eijk R et al (2005) Reliable high-throughput genotyping and loss-of-heterozygosity detection in formalin-fixed, paraffin-embedded tumors using single nucleotide polymorphism arrays. Cancer Res 65:10188–10191PubMedCrossRef
16.
Sugai T, Takahashi H, Habano W et al (2003) Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas. J Pathol 200:168–176PubMedCrossRef
17.
Young J, Simms LA, Biden KG et al (2001) Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 159:2107–2116PubMed
18.
Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130PubMedCrossRef
19.
de Jong AE, van Puijenbroek M, Hendriks Y et al (2004) Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10:972–980PubMedCrossRef
20.
Hendriks YM, Jagmohan-Changur S, van der Klift HM et al (2006) Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 130:312–322PubMedCrossRef
21.
Nygren AO, Ameziane N, Duarte HM et al (2005) Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res 33:e128PubMedCrossRef
22.
Oosting J, Lips EH, van Eijk R et al (2007) High-resolution copy number analysis of paraffin-embedded archival tissue using SNP BeadArrays. Genome Res 17:368–376PubMedCrossRef
23.
Lips EH, van Eijk R, de Graaf E et al (2008) Progression and tumor heterogeneity analysis in early rectal cancer. Clin Cancer Res 14:772–781PubMedCrossRef
24.
de Leeuw WJ, van PM, Merx R et al (2001) Bias in detection of instability of the (C)8 mononucleotide repeat of MSH6 in tumours from HNPCC patients. Oncogene 20:6241–6244
25.
Larramendy ML, El-Rifai W, Kokkola A et al (1998) Comparative genomic hybridization reveals differences in DNA copy number changes between sporadic gastric carcinomas and gastric carcinomas from patients with hereditary nonpolyposis colorectal cancer. Cancer Genet Cytogenet 106:62–65PubMedCrossRef
26.
Gaasenbeek M, Howarth K, Rowan AJ et al (2006) Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex changes and multiple forms of chromosomal instability in colorectal cancers. Cancer Res 66:3471–3479PubMedCrossRef
27.
Hemminki A, Peltomaki P, Mecklin JP et al (1994) Loss of the wild-type Mlh1 gene is a feature of hereditary nonpolyposis colorectal-cancer. Nat Genet 8:405–410PubMedCrossRef
28.
Lu SL, Akiyama Y, Nagasaki H et al (1996) Loss or somatic mutations of hMSH2 occur in hereditary nonpolyposis colorectal cancers with hMSH2 germline mutations. Jpn J Cancer Res 87:279–287PubMed
29.
Tannergard P, Liu T, Weger A et al (1997) Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer. Hum Genet 101:51–55PubMedCrossRef
30.
Kuismanen SA, Holmberg MT, Salovaara R et al (2000) Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 156:1773–1779PubMed
31.
Potocnik U, Glavac D, Golouh R et al (2001) Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening. Cancer Genet Cytogenet 126:85–96PubMedCrossRef
32.
de Abajo AS, de la Hoya M, van Puijenbroek M et al (2006) Dual role of LOH at MMR loci in hereditary non-polyposis colorectal cancer? Oncogene 25:2124–2130CrossRef
33.
Tuupanen S, Karhu A, Jarvinen H et al (2007) No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer. Oncogene 26:2513–2517PubMedCrossRef
34.
Ollikainen M, Hannelius U, Lindgren CM et al (2007) Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach. Oncogene 26:4541–4549PubMedCrossRef
35.
Konishi M, KikuchiYanoshita R, Tanaka K et al (1996) Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 111:307–317PubMedCrossRef
36.
Horii A, Han HJ, Sasaki S et al (1994) Cloning, characterization and chromosomal assignment of the human genes homologous to yeast Pms1, a member of mismatch repair genes. Biochem Biophys Res Commun 204:1257–1264PubMedCrossRef
37.
Nicolaides NC, Carter KC, Shell BK et al (1995) Genomic organization of the human Pms2 gene family. Genomics 30:195–206PubMedCrossRef
38.
De Vos M, Hayward BE, Picton S et al (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964PubMedCrossRef
39.
Hayward BE, De Vos M, Valleley EMA et al (2007) Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat 28:424–430PubMedCrossRef
40.
Li LS, Kim NG, Kim SH et al (2003) Chromosomal imbalances in the colorectal carcinomas with microsatellite instability. Am J Pathol 163:1429–1436PubMed
41.
Camps J, Armengol G, del Rey J et al (2006) Genome-wide differences between microsatellite stable and unstable colorectal tumors. Carcinogenesis 27:419–428PubMedCrossRef
42.
Douglas EJ, Fiegler H, Rowan A et al (2004) Array comparative genomic hybridization analysis of colorectal cancer cell lines and primary carcinomas. Cancer Res 64:4817–4825PubMedCrossRef
43.
Haiman CA, Le ML, Yamamato J et al (2007) A common genetic risk factor for colorectal and prostate cancer. Nat Genet 39:954–956PubMedCrossRef
44.
Poynter JN, Figueiredo JC, Conti DV et al (2007) Variants on 9p24 and 8q24 are associated with risk of colorectal cancer: results from the colon cancer family registry. Cancer Res 67:11128–11132PubMedCrossRef
45.
Tomlinson I, Webb E, Carvajal-Carmona L et al (2007) A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39:984–988PubMedCrossRef
46.
Zanke BW, Greenwood CM, Rangrej J et al (2007) Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39:989–994PubMedCrossRef
Metadata
Title
Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas
Authors
Marjo van Puijenbroek
Anneke Middeldorp
Carli M. J. Tops
Ronald van Eijk
Heleen M. van der Klift
Hans F. A. Vasen
Juul Th. Wijnen
Frederik J. Hes
Jan Oosting
Tom van Wezel
Hans Morreau
Publication date
01-12-2008
Publisher
Springer Netherlands
Published in
Familial Cancer / Issue 4/2008
Print ISSN: 1389-9600
Electronic ISSN: 1573-7292
DOI
https://doi.org/10.1007/s10689-008-9194-8

Other articles of this Issue 4/2008

Familial Cancer 4/2008 Go to the issue

OriginalPaper

Screen positive rates among six family history screening protocols for breast/ovarian cancer in four cohorts of women

OriginalPaper

Predicting breast cancer risk: implications of a “weak” family history

Letter

The three nucleotide deletion within the 3′untranslated region of MLH1 resulting in gene expression reduction is not a causal alteration in Lynch syndrome

OriginalPaper

Family history and colorectal cancer survival in women

Erratum

Delivering cancer genetics services-new ways of working

ReviewPaper

Predictors of choosing life-long screening or prophylactic surgery in women at high and moderate risk for breast and ovarian cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits