Gain of Chromosome 20q Is an Indicator of Poor Prognosis in Colorectal Cancer

Colorectal cancer is the second leading cause of cancer death in the Western world, and its incidence is still rising. Improved surgery and preoperative radiotherapy have resulted in reduced local recurrences for rectal cancer, but no dramatic improvements in clinical outcome of colorectal cancer overall have been achieved. Still approximately fifty percent ultimately develop metastatic disease, which generally is fatal despite systemic chemotherapy. Adjuvant chemotherapy for CRC patients with unfavourable characteristics, i.e. presence of lymph node metastasis (stage III cancer) has proven to be beneficial. Adjuvant chemotherapy for stage II colorectal cancer is not standard, although this category harbours a subgroup of patients that do develop metastatic disease and could benefit from adjuvant chemotherapy. In addition to heterogeneity in clinical behaviour, colorectal cancer is also a heterogeneous disease at the level of underlying genetic changes with chromosomal instability as one of the key features occurring in eighty five percent of colorectal cancers [3,4,6,9]. Within the large category of chromosomal instable colorectal cancer, different combinations of aberrations occur. In a series of colorectal adenomas and carcinomas, analysed by comparative genomic hybridisation (CGH), we showed that seven chromosomal aberrations (loss at 8p21-pter, 15q11-q21, 17p1213 and 18q12-21, and gain at 8q23-qter, 13q14-31 and 20q13) were specifically associated with adenoma to carcinoma progression [7]. Hierarchic cluster analysis demonstrated the presence of three distinct subgroups of adenomas, marked by characteristic combinations of genetic aberrations in the adenomas; one cluster was marked by 17p12-13 loss and K-ras mutation, one by 8q23-qter and 13q14-31 gain, and one by 18q12-21 loss and 20q13 gain. Clustering of all carcinomas yielded two subgroups. One group showed among other abnormalities, a high frequency of 17p1213 losses and a low frequency of 18q12-21 loss and 20q13 gain, while the other group showed a reverse pattern. So these chromosomal abnormalities occurred in specific combinations of a few abnormalities rather than as a mere accumulation of events, indicating the existence of multiple independent chromosomal instability pathways of colorectal cancer progression [7]. Some of these abnormalities, like 18q loss and 20q gain, have been associated with a more aggressive clinical behaviour [2,5]. We investigated which chromosomal aberrations in colorectal cancer are related with patient’s survival in a series of 18 colorectal cancer patients previously studied by CGH. Patients with TNM stage I tumors and patients that died within three months after surgery were excluded. Mean follow up was 60.7 months (range 9–119). Eight patients were male and 10 were female, with a mean age of 67.9 years (range 45–85). Ten carcinomas were TNM stage II, 6 were stage III and 2 were stage IV. Nine tumors were located at the proximal colon and 9 at the distal colon. Two carcinomas were well, 14 moderately and 2 poor differentiated. DNA was isolated from formaldehyde fixed and paraffin embedded tumor samples and CGH was performed as described before [7]. Mean numbers of losses and gains were 6.0 (range 0–16) and 3.8 (range 0–9), respectively. Most frequent losses (i.e. >40%) concerned 8p (44%), 17p (56%) and 18q (61%), and most frequent gains 8q (50%), 13q (67%) and 20q (50%). Gain of 20q was associated with a significantly worse patient survival (P = 0.002) (Fig. 1), in fact all six patients that died of disease had tumors with 20q gain, out of a total of nine with 20q gain. Fewer patients with TNM stage II disease (40%) had 20q gain in their tumor than patients with stage III or IV disease (63%), but this was not significant in the present series. Also no correlations were found between presence of 20q gain and other clinico-pathological parameters (Table 1). In the present small series, there was a trend (P = 0.09) for stage being associated with death of disease (DOD). Outcome of patients with colon cancer has improved by adjuvant chemotherapy, especially in those with TNM stage III. Although stage II carcinomas are not