Identification of a characteristic copy number alteration profile by high‐resolution single nucleotide polymorphism arrays associated with metastatic sporadic colorectal cancer

Abstract

BACKGROUND: Metastatic dissemination is the most frequent cause of death in patients with sporadic colorectal cancer (sCRC). It is believed that the metastatic process is related at least in part to a specific background of genetic alterations accumulated in cells from primary tumors, and the ability to detect such alterations is critical for the identification of patients with sCRC who are at risk of developing metastases. METHODS: The authors used high-resolution, 500-K single nucleotide polymorphism arrays to identify copy number alteration profiles present at diagnosis in primary tumors from patients with metastatic (n 5 23) versus nonmetastatic (n 5 26) sCRC. RESULTS: The results revealed a characteristic pattern of copy number alterations in metastatic sCRC tumors that involved losses of 23 regions at chromosomes 1p, 17p, and 18q, together with gains of 35 regions at chromosomes 7 and 13q. CONCLUSIONS: In line with expectations, the copy number profile investigated involved multiple genes that were associated previously with sCRC (ie, SMAD2) and=or the metastatic process (ie, podocalyxin-like [PODXL]), and it also was associated with a poorer outcome. Cancer 2014;120:1948-59. V C 2014 American Cancer Society.KEYWORDS: liver metastases, colorectal carcinoma, copy number change, single nucleotide polymorphism array. INTRODUCTIONSporadic colorectal cancer (sCRC) is the second leading cause of death from cancer in the Western world. 1 Up to 50% of all patients with sCRC eventually will develop metastases, and their 5-year overall survival rate is approximately 50% to 60%. 2 Once metastases (ie, mostly liver metastasis) have occurred, a complete cure is unlikely, 2 and up to two-thirds of patients with sCRC who die have evidence of liver metastasis. 3 Accumulating evidence indicates that sCRC metastasis may emerge in the context of a specific genetic tumor background associated or not with other genetic alterations, further affecting cellular control of growth and proliferation. 4 The discovery of those specific genetic alterations that would contribute toward identifying patients who are at risk of harboring or developing metastases could contribute significantly to the development of new strategies for the diagnosis and management of the diseases.In recent years, multiple recurrent chromosomal abnormalities identified in primary tumors have been associated with metastatic CRC. 4,5 Among others, these include numerical gains of the long arm of chromosome 8 (8q), 13q, and 20q and losses of the short arm of chromosome 1 (1p), 8p, 17p, 18q, and 22q. In a recent study, we used interphase fluorescence in situ hybridization (iFISH) to further establish that 17p deletion (del[17p]) involving the 17p11.2 breakpoint region and del(22q) were highly prevalent cytogenetic alterations among patients with primary sCRC who had synchronous liver metastasis. 6 However, the identification of specific genes targeted by such chromosomal alterations has proven difficult, partially because of technical issues. In recent years, the ...

Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers

“…29 Yet another study identified more deletions of chr1p, 17p and 18q and gains of chr7 and 13q in metastatic CRC. 30 These associations deserve further validation in larger populations of more regions and species.…”

“…The CYP3A5 and CYP3A7 genes have been frequently found upregulated in primary CRCs. 30,106 Moreover, the PODXL gene (7q32) is associated with CRC metastasis 107 and poor survival 108 because of its function in cell adhesion and invasion. The RAPGEF5 (Rap guaninenucleotide exchange factor 5) gene located at 7p15.3 catalyzes the activation of RAS by promoting acquisition of guanosine triphosphate (GTP) to maintain the active GTP-bound state, and is the key link between cell surface receptors and RAS activation.…”

“…30 The deleted in colorectal carcinoma (DCC) gene has long been implicated in CRC. However, DCC-deficient mice displayed no increase in tumor predisposition, and thus its role as a tumor suppressor became suspectable.…”

“…83,84 In addition, the deletions of different subregions on 18q may associate with poor outcomes in CRC, 13 including 18q12-qter reported by Liu et al, 85 and 18q12.2 (harboring the BRUNOL4 gene) revealed by Poulogiannis et al 86 The 18q12.2 segment also includes MAPRE2 (microtubule-associated protein RP/EB family member 2), ZNF24 (zinc-finger protein 24) and PIK3C3 (phosphatidylinositol3-kinase catalytic subunit type 3) that are associated with CRC development or metastasis. 30 It was examined that loss of DNAM-1 (DNAX accessory molecule 1), SOCS6 (suppressor of cytokine signaling 6) and ACHR-7 (a-7 nictonic receptor) in 18q22 associate with poor outcome in CRC. 87 Other deletions of 18q including 18q11 (GATA6), 18q12, 18q21.2-21.3 (CCDC68, TCF4, RAX), 18q22 (BCL2) and 18q23 are associated with shorter overall survival in CRC.…”

TNFRSF10C copy number variation is associated with metastatic colorectal cancer

“…Copy number variations (CNVs) have been used to determine prognosis and subsequent treatment profile for a number of cancers, e.g., MYCN amplification for neuroblastoma (6). Comparisons between CNV of genes in primary CRC tumors and their matched metastatic disease sites are well documented, but less is known about how CNV of genes in CRC primary tumors differs between those associated with localized disease compared with those associated with distant metastatic disease (7)(8)(9)(10)(11)(12).…”