Genetic changes and clonality relationship between primary colorectal cancers and their pulmonary metastases?An analysis by comparative genomic hybridization

Abstract

About 10% of colorectal carcinoma patients develop pulmonary metastases during their lifetime. We address whether and how the chromosomal abnormalities differ between the primary cancers and their metastatic counterparts, what the clonality relationship (CR) is between them, and whether certain genomic aberrations contribute to this disease progression. Comparative genomic hybridization (CGH) experiments were performed on 18 paired samples of primary and pulmonary metastases obtained from patients who had undergone two consecutive surgeries and from whom clinical data had been collected. The CGH profiles also were used as indexes for determining the CR between the cancers. The overall CGH abnormality profiles were similar for the primary colorectal carcinomas and their pulmonary metastases. Frequent gains were found on chromosome arms 20q, 8q, 13q, and 7q, whereas common losses were found on 18q, 8p, and 18p. The pulmonary metastases, however, contained more CGH abnormalities than did the primary carcinomas (total aberration events per tumor: 12.6 +/- 5.0 vs. 8.3 +/- 5.7, respectively, P = 0.024; gains: 7.6 +/- 3.1 vs. 5.1 +/- 3.5, respectively, P = 0.036; losses: 5.0 +/- 2.8 vs. 3.3 +/- 2.9, respectively, P = 0.076). Comparing CGH profiles between individual primary and metastasis pairs, we found that 10 of the 18 (56%) paired samples examined exhibited a high degree of CR, indicating that they were likely to have originated from the same clone and/or that not many additional chromosomal changes had occurred in the metastases, except for 4q loss, whose incidence was much higher in the metastases than in the primaries (60% vs. 10%; P = 0.030). Also, the primary tumors of the high-CR group carried more genomic aberrations, especially 8p loss, than did the primary tumors in the low-CR group. We found more chromosomal changes associated with the pulmonary metastases of colorectal cancer compared with the corresponding primary tumors. We concluded that primary cancers containing more genomic lesions, especially 8p losses, are more likely to metastasize to the lungs. Loss of 4q is potentially a supplementary factor contributing to the dissemination of this disease.

Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas

“…Possible candidate genes on chromosome 12 include Kirsten rat sarcoma viral oncogene homolog (KRAS2), cyclinD2, MDM2 and (wingless-type mmtv integration site family (WNT1). In addition, gains at 13q as observed here in sporadic duodenal carcinomas, were shown frequently in both colorectal 44,45,47,54 and gastric carcinomas. 48,49 Also a difference was observed in the hypermethylation status of the PAX6 gene between sporadic and FAP-related duodenal carcinomas.…”

“…Similar to what has been described for colorectal carcinomas; sporadic duodenal tumors showed frequent gains on chromosomes 8q, 12p, 13q and 20q. In contrast to sporadic colorectal cancer, only one loss at 18q was observed [44][45][46][47] in the duodenal carcinomas. In gastric carcinomas, again frequent gains involved 8q, 13q and 20q but only occasionally 12p.…”

Profiling Bladder Cancer Organ Site-Specific Metastasis Identifies LAMC2 as a Novel Biomarker of Hematogenous Dissemination

“…Although gain at 1q is rather common in metastasis across several tumor types, 28 gains at 3q, 7q, 12q, 17q, and 20q have all been observed in colorectal cancer lung metastases, although the 7q, 12q, and 20q lesions were particularly noted to arise during the transition between the primary tumor and lung met. 29 Another report actually compared CGH changes in patient liver and lung metastases from colorectal cancer, finding, just as we did in our in vivo selected bladder cell lines, a phenomenon of generally less total CGH changes in liver compared with lung metastases, although they did not identify in their lung metastases the 8q and 9q gains that we found in our lung selected cell lines. 30 For the 1q and 3q loci, these regions appeared to contain genes that were differentially expressed as a function of in vivo selection, including LAMC2 and two others of the eight core genes discovered to be overexpressed in both metastatic models.…”

Striking similarities in genetic aberrations between a rectal tumor and its lung recurrence

“…While we realize that aCGH analysis reveals the DNA copy number changes in tumor cells and not the exact origin of these cells, specific trends and patterns of genetic aberrations have been reported to be associated with specific tumor sites and types [10,13] . O'Connell et al [14] identified a recurrence risk score based on the expression of 12 genes (seven cancerrelated genes and five reference genes).…”