Impact of chromosomal instability on colorectal cancer progression and outcome

Abstract

BackgroundIt remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs).MethodsIn this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP).ResultsStage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p = 0.012, HR = 3; OS: p < 0.001, HR = 9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2–3 tumors showed strong association with early relapse (p < 0.001) and death (p < 0.007, p < 0.016). Both events showed frequent co-occurrence (p < 1x10-8) and could, therefore, mark for stage 2–3 CRC susceptible to negative outcome.ConclusionsOur data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2–3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors.

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

“…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. 69,88 Moreover, several genes in 18p showed copy number gains and overexpression. RALBP1 (18p11.3) has been reported to decrease cancer cell death and mediate resistance to anticancer compounds.…”

“…140 Codeletion of 16p13.3 (AXIN1) and 19q13.3 (BAX) strongly associates with poor prognosis in stage II and stage III CRCs. 88 Although the deletion of 16p13.2 also associates with adverse prognosis, the mechanisms remain to be illustrated. 141…”

Unexpected frequency of genomic alterations in histologically normal colonic tissue from colon cancer patients

“…For example, gains on chromosomes 7p, 13q, and 20p/q and loss on 18q were reported as early DNA alterations [5]. Gains at 8q, 13q, and 20p/q and losses at 8p, 15p, 17p, and 18q were shown to be significantly changed between adenomas and stage I carcinomas [6]. …”

Stage-specific frequency and prognostic significance of aneuploidy in patients with sporadic colorectal cancer—a meta-analysis and current overview

“…Alternatively, one may argue that the increasing frequency of aneuploidy is the result of selective pressure in CRC, which allows aneuploid cell clones to dominate progressively within the primary tumor, e.g., due to certain growth advantages [6]. Still, other groups could not find an increase in genomic instability represented by the number of breakpoints and the global genomic index upon array-CGHanalysis throughout the sequence of adenomas, UICC I-IV CRCs, and metastases [9].…”

“…Although the mere number of reported studies regarding aneuploidy in CRC has declined slightly throughout recent years, the issue remains highly relevant in the context of individualized medicine [8,9]. Aneuploidy is defined as an alteration of the normal nuclear DNA content of somatic cells, which is noted as 2c [10].…”