Genomic CGH-assessed structural DNA alterations in rectal carcinoma as related to local recurrence following primary operation for cure

Abstract

Abstract. Several factors determine overall outcome and possible local recurrence after curative surgery for rectal carcinoma. Surgical performance is usually believed to be the most pertinent factor, followed by adjuvant oncological treatment and tumor histopathology. However, chromosomal instability is common in colorectal cancer and tumor clones are assumed to differ in aggressiveness and potential of causing local recurrence. The aim of this study was, therefore, to evaluate if genetic alterations in primary rectal carcinoma are predictive of local recurrences. A large clinical database with linked bio-bank allowed for careful matching of two patient groups (R0) resected for rectal carcinoma. One group had developed early, isolated local recurrences and the other group seemed cured after 93 months follow-up. DNA from the primary tumors was analysed with array-CGH (comparative genomic hybridization) including 55,000 genomic probes. DNA from all primary tumors in both groups displayed previously reported and well-recognised DNA aberrations in colorectal carcinoma. Significant copy number gains were confirmed in the 4q31.1-31.22 region in DNA from tumors with subsequent local recurrence. Twenty-two affected genes in this region code for products with high relevance in tumor biology (p53 regulation, cell cycle activity, transcription). DNA from rectal carcinoma displayed well-known aberrations as described for colon carcinoma with no obvious prediction of local rectal recurrence. Gains in the 4q31.1-31.22 DNA region are highly potential for local recurrence despite R0 resection to be confirmed in larger patient materials. IntroductionColorectal cancer is the third most common malignancy in Europe and the USA (1,2). The treatment of patients with rectal cancer has improved significantly the past decades, where meticulous surgery with clear resection margins is important for cure. Besides improved surgery, preoperative radiotherapy and chemoradiotherapy add to improved treatment results. However, local recurrence after resection of rectal cancer is still a substantial clinical problem. Dedicated centers report local recurrence rates in selected series of less than 4% but population-based results are rather close to 10% (3-6). Such treatment failures lead to severe, often intractable symptoms and premature death in the majority of patients (7,8). Thus, it is important to gain further knowledge of factors that determine increased risks for local recurrence following primary operation of rectal carcinoma aimed at cure. The present study evaluates whole genomic array-CGH (comparative genomic hybridization) analysis comparing more than 55,000 DNA sites in primary rectal tumors from patients with tissue in a large bio-bank with linked clinical information. DNA from tumors that recurred locally and non-recurrent tumors were analyzed with the aim to link structural DNA-alterations to isolated local recurrence following R0-resections. Materials and methods Selection of patients.The Sahlgrenska University Hospital is a non-...

DNA alterations in Cd133+ and Cd133- tumour cells enriched from intra-operative human colon tumour biopsies

“…Well-known colon cancer alterations were also evaluated with Q-PCR; 1 region at chromosome 13 and 1 region at chromosome 20 as well as 1 region at chromosome 10 that is known to be unaffected in colorectal cancer (control) in DNA from tumour tissue biopsies. Primers were designed by TATAA Biocenter AB (Gothenburg, Sweden) with PrimerBlast (http://www.ncbi.nlm.nih.gov/tools/primer-blast/), primer sequences for chromosome 10, 13 and 20 are described elsewhere [10] and for chromosome 19 in Additional file 1: Table S1. The Q-PCR assays were validated on gBlocks to estimate the PCR efficiency of the assay.…”

Genomic changes in rectal adenocarcinoma associated with liver metastasis

“…Losses of both chromosome arms 8p and 18q had a statistically significant negative effect on disease-free survival [6]. Kodeda et al showed that gain of 4q31.1-q31.22 was associated with local recurrence after primary operation and 22 affected genes of this region had high relevance to tumor biology such as p53 regulation and cell cycle activity [7]. A study comparing the genomic profiling between tumor specimens and the corresponding pulmonary metastases showed that loss at chromosome arm 5q had difference in frequency in two groups [8].…”

Impact of chromosome 17q deletion in the primary lesion of colorectal cancer on liver metastasis

“…It was previously reported that abnormalities in Impact of chromosome 17q deletion in the primary lesion of colorectal cancer on liver metastasis gene and genomic copy numbers that contribute to lymph node metastases may be identified by comparative genomic hybridization (CGH) (13,14). It is expected that identification of specific gene and genomic variations may be used in the clinic as tumor markers and prognostic predictive factors for metastasis (12,15); these prognostic markers may serve as important tools for colorectal cancer treatment.…”

“…Recently, targeted cancer therapies have been developed and approved for use in treating various types of cancer, and in certain therapies, treatment efficacy may be predicted by analyzing the gene variation of the primary lesion (11,12 …”

“…Following NAC or CRT, excision of the primary lesion and distant metastasis is then performed (9). Early detection of the liver metastasis is important as long term survival related with size and a number of nodules of the liver metastasis (10).Recently, targeted cancer therapies have been developed and approved for use in treating various types of cancer, and in certain therapies, treatment efficacy may be predicted by analyzing the gene variation of the primary lesion (11,12 …”