Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Abstract

Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here, we aimed to identify and characterize recurrent copy-number alterations (CNAs) associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Colorectal neoplasia specimens and paired germline samples from 144 patients (40 adenomas and 104 carcinomas) as well as 40 CRC cell lines were investigated. This large dataset revealed frequent loss, including homozygous loss, at chr16p13.2 (from 5.9 to 7.42Mb). The loss was observed in 30% of adenomas and even more frequently in carcinomas, 56%, indicating that the loss define a subset of adenomas with a propensity for invasion. Consistent with this, the loss occurred twice as frequent in villous (40%) as in tubular adenomas (20%). The loss occurred independently of microsatellite stability and could be validated by qPCR in an independent sample cohort (n 5 71). In Stage II/III, microsatellite stable (MSS) CRC it was associated with poor recurrence free survival (hazard ratio 2.4; p 5 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1, located in the region showed no mutations. Correlation with other CNAs was established for chr3p22 in carcinomas and chr20p (inverse) in adenomas. FISH documented the chr16p13.2 region to be involved in complex structural rearrangements that included translocation to chr3p22 in some cases. The findings indicate that structural rearrangements involving chr16p13.2 are very frequent in colorectal neoplasia, often lead to homozygous deletion, and are associated with poor clinical outcome.Despite major efforts over the recent years toward improving the survival outcome of patients with colorectal cancer (CRC), the disease remains a major health burden with over one million cases worldwide and a disease-specific mortality of $33% in the developed world. 1 Currently, the gold standard for prognostication is clinicopathological staging, based on the Tumor, Node, Metastasis (TNM) classifcation. However. Although CRC is often diagnosed at a stage where complete resection of the primary cancer (Stages I-III) is possible, 40-50% of patients who undergo potentially curative surgery alone relapse and die of metastatic disease. 2 Although most patients with Stage III (lymph-node positive) cancer receive adjuvant treatment, it is offered to only a subset of Stage II (localized disease) patients presenting with specific high-risk clinical features, including tumor perforation or invasion of adjacent organs. 3 This approach is clearly suboptimal, resulting in undertreatment of $20% of Stage II patients who will recur. Similarly, current adjuvant treatment is clearly ineffective in many Stage III patients, with a recurrence rate of $40% 4,5 highlighting the need for treatment with more aggressive or newly emerging targeted therapies, e.g., inhibitors of epidermal growth factor recepto...

Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells

“…1A) as previously reported (7)(8)(9)35). The homozygous deletions of 9p21 were detected in all MM samples, and the allele losses of 22q were frequently found in all histological types of cells.…”

Single nucleotide polymorphism array analysis of microsatellite-stable, diploid/near-diploid colorectal carcinomas without the CpG island methylator phenotype

“…Alternatively, the recurrent loss of genetic material may arise as a consequence of recurrent translocation events that, as has been appreciated recently, are not as rare in solid tumours as previously thought (17). Notably, Andersen et al's study of interphase and metaphase-FISH for 16p13.2 using four commercial colorectal carcinoma cell lines for SW620 revealed a balanced translocation (t [3;16]) with the breakpoint centering on 16p13; for the other three cell lines, however, the deletions were interstitial deletions (14). Furthermore, rearrangements of the MACROD2, A2BP1 and FHIT genes in colorectal carcinoma were observed in a study by Bass et al (18), putatively due to structural fragility.…”

“…While the majority were distributed over the genome in no apparent order, recurrence was observed at three gene loci, viz., FHIT, MACROD2 and A2BP1, introducing the possibility of a potential functional role. In previous SNP array studies of colorectal carcinoma, deletions at 16p13.2 centering on A2BP1 have been described in a single study by Andersen et al (14). These authors also sequenced the gene in cases with deletions, failing to find mutations, and the deletions did not appear to correlate with differences of gene expression.…”

Methylation status in patients with early stage colon cancer: A new prognostic marker?

“…3 We would like to contribute on the subject of CRC prognostic biomarkers by briefly reporting on our studies, in which we assessed the possibility of predicting recurrence for the most critical group of CRC patients, i.e., Stage II, by investigating the prognostic implications of promoter CpG island hypermethylation status, a common epigenetic alteration in sporadic CRC. 4 The subset of sporadic cancers with widespread promoter methylation constitutes a distinct phenotype, often referred to as the CpG island methylator phenotype (CIMP or CIMP high), 4 which has been associated with proximal colon location, microsatellite instability (MSI) and high frequency of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations.…”

“…2 For this reason, we have read with utmost interest the article by Andersen et al 3 The authors investigated the association between genomic alterations (in terms of copy-number variations) and risk of recurrence in patients with Stages II and III CRC and identified a copy-number loss on chromosome 16 (16p13.2) that was predictive of metastatic recurrence in microsatellite-stable (MSS) Stages II and III CRCs. 3 We would like to contribute on the subject of CRC prognostic biomarkers by briefly reporting on our studies, in which we assessed the possibility of predicting recurrence for the most critical group of CRC patients, i.e., Stage II, by investigating the prognostic implications of promoter CpG island hypermethylation status, a common epigenetic alteration in sporadic CRC. 4 The subset of sporadic cancers with widespread promoter methylation constitutes a distinct phenotype, often referred to as the CpG island methylator phenotype (CIMP or CIMP high), 4 which has been associated with proximal colon location, microsatellite instability (MSI) and high frequency of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations.…”