Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer
Introduction
Identification of individuals and families with hereditary colorectal cancer syndromes provides a unique opportunity for reducing morbidity and mortality from the disease through inclusion of high-risk individuals in targeted surveillance programs. Diagnostics is challenging since different syndromes exist and correct recommendations for surveillance are complicated by unidentified genetic mechanisms and highly variable clinical presentations.1, 2 Up to one third of colorectal cancer is estimated to be caused by hereditary components, but disease-predisposing mutations account for <5% of the cases.3 The Amsterdam criteria were developed to identify families with high likelihood of Lynch syndrome, in which germline mismatch-repair (MMR) gene alterations lead to development of tumours characterised by microsatellite instability (MSI).4, 5 In approximately half of the families whose pedigrees fulfil the Amsterdam criteria, the tumours are MMR proficient and microsatellite stable (MSS) and affected individuals do not carry disease-predisposing germline MMR gene alterations. This subset of families is referred to as familial colorectal cancer type X, FCCTX.1 Whereas Lynch syndrome increases the risks also for extraintestinal tumours such as cancer of the endometrium, ovary, stomach, small intestine, and the upper urinary tract, FCCTX predominantly confers an increased risk of colorectal cancer.2, 6 Clinical presentation differs, which suggests different tumourigenic mechanisms with proximal colon cancer and early age at onset (median 45 years) characteristic of Lynch syndrome and distal colorectal cancer at higher age (median 60 years) typically seen in FCCTX.2
MMR status represents a major discriminator in the development of colorectal cancer. Differences apply to preferred tumour location, prognosis and chemotherapeutic response and are also reflected in the genomic profiles with widespread microsatellite instability (MSI) with few gross alterations in MMR defective tumours, and chromosomal instability (CIN) with multiple gains and losses in the MMR proficient subset.7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Distinct patterns of genetic instability are associated with the various hereditary colorectal cancer syndromes. Colorectal cancer associated with Lynch syndrome typically show diploid or near-diploid genomes, whereas tumours that develop as part of mutY homolog (MUTYH)-associated polyposis and familial adenomatous polyposis show frequent loss of heterozygocity as well as aneuploidy.16, 17, 18 Data on the genomic profile of colorectal cancer associated with FCCTX are scarce, but suggest genomic complexity with recurrent gains of 7p, 7q, 8q, 13q, 20p and 20q and losses of 17p, 18p and 18q.12, 14, 19, 20, 21, 22 With the aim to identify genomic regions of importance that discriminate between Lynch syndrome and FCCTX, we applied array-based comparative genomic hybridisation (aCGH) with comparison to sporadic colorectal cancers of the MSI and CIN subtypes.
Section snippets
Patients and tumours
Clinical and histopathological data are available in Table 1. All hereditary colorectal cancer cases were identified from the national Danish HNPCC register. Colorectal cancers of the FCCTX subtype were defined as families who fulfilled the Amsterdam criteria5 with tumours that showed retained MMR function (normal immunohistochemical MMR protein staining and normal MSI status, Table 1). The Lynch syndrome subset included tumours linked to disease-predisposing mutations in MLH1 (n = 10), MSH2 (n =
Results
The genome-wide copy number profiles in the four major subsets displayed striking differences as visualised in frequency plots (Fig. 1). MMR status was a major discriminator between simple and complex genomic profiles and MSI tumours, whether linked to Lynch syndrome or sporadic tumour development, showed simple genomic alterations. Lynch syndrome tumours had chromosomally stable profiles without any gains or losses in 7/23 samples. Gains on chromosomes 1p (26%), 17 (43%), 19 (48%) and 22q
Discussion
Genomic profiling studies in colorectal cancer have primarily focused on differences between sporadic MSI and CIN tumours and genetic alterations within the MSI subsets. We took advantage of families that fulfilled the Amsterdam criteria to study genomic characteristics of Lynch syndrome and FCCTX. The FCCTX associated tumours did, as a group, reveal genomic profiles similar to sporadic CIN tumours, albeit with a somewhat lower overall frequency of gains and losses. Recurrent chromosomal
Grant sponsor
The Danish Cancer Fund, the Lundbeck Foundation, and the Hvidovre University Hospital.
Role of the funding source
The study sponsors had no involvement in the study design, collection, analyses or interpretation of data.
Conflict of interest statement
None declared.
Acknowledgements
Technical help and assistance was provided by Anna Karlsson, Department of Oncology, Institute of Clinical Sciences, Lund University, Sweden. Statistical review was performed by Janne Petersen, Clinical Research Center, Hvidovre University Hospital.
References (40)
- et al.
New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC
Gastroenterology
(1999) - et al.
Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability
Eur J Cancer
(2002) - et al.
Identification of differentially expressed genes in microsatellite stable HNPCC and sporadic colon cancer
J Surg Res
(2008) - et al.
Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis
Am J Pathol
(2001) - et al.
Evidence for various 20q status using allelotyping, CGH arrays, and quantitative PCR in distal CIN colon cancers
Cancer Lett
(2009 Sep) - et al.
Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma
Mod Pathol
(2011) - et al.
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
(1998) - et al.
Allelic imbalance in colorectal cancer at the CRAC1 locus in early-onset colorectal cancer
Cancer Genet Cytogenet
(2003) - et al.
Lynch syndrome and related familial colorectal cancers
Crit Rev Oncog
(2008) - et al.
Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer
Int J Cancer
(2001)