Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer

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Abstract

Lynch syndrome and familial colorectal cancer type X, FCCTX, represent the two predominant colorectal cancer syndromes. Whereas Lynch syndrome is clinically and genetically well defined, the genetic cause of FCCTX is unknown and genomic differences between Lynch syndrome and FCCTX tumours are largely unknown. We applied array-based comparative genomic hybridisation to 23 colorectal cancers from FCCTX with comparison to 23 Lynch syndrome tumours and to 45 sporadic colorectal cancers. FCCTX tumours showed genomic complexity with frequent gains on chromosomes 20q, 19 and 17 and losses of 18, 8p and 15. Gain of genetic material in two separate regions encompassing, 20q12-13.12 and 20q13.2-13.32, was identified in 65% of the FCCTX tumours. Gain of material on chromosome 20q and loss on chromosome 18 significantly discriminated colorectal cancers associated with FCCTX from Lynch syndrome, which likely signifies different preferred tumourigenic pathways.

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.

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