This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Giaretti, W. Articles by Geido, E. Search for Related Content PubMed PubMed Citation Articles by Giaretti, W. Articles by Geido, E.

American Journal of Pathology, Vol 149, 237-245, Copyright © 1996 by American Society for Investigative Pathology

REGULAR ARTICLES

Intratumor heterogeneity of K-ras2 mutations in colorectal adenocarcinomas: association with degree of DNA aneuploidy

W Giaretti, R Monaco, N Pujic, A Rapallo, S Nigro and E Geido
Laboratory of Biophysics and Cytometry, National Institute for Cancer Research (IST), Genoa, Italy.

Detailed information about intratumor K-ras2 mutations in colorectal adenocarcinomas and a possible association with DNA content heterogeneity is still lacking. DNA diploid and aneuploid subclones, detected among multiple histologically selected primary sectors (57 superficial and 40 deep) and 9 lymph node metastases, were flow cytometrically sorted and separately submitted to codons 12-13 K-ras2 mutation spectrum analysis. DNA aneuploidy was absent among 20 near and 20 distant mucosa sites and present in 7/9 lymph node metastases and in 17/19 primary tumors (90%). Primary intratumor DNA multiclonality was approximately 50%. Degree of DNA aneuploidy (DNA Index) distribution was nonrandom and showed peaks at approximate mean DNA Index values 1.2, 1.5, and 1.8. K-ras2 mutations were detected in 0/20 mucosa cases, in 2/9 lymph node metastases, and in 9/19 adenocarcinomas (47%). No more than one mutation type per tumor was detected. Intratumor distribution of K-ras2 mutations was homogeneous in 6 and heterogeneous in 3 cases. Homogeneous distribution was associated with DNA near- diploid aneuploidy. K-ras2 mutations were strongly associated with DNA Index in the near-diploid region (83%) and almost absent (5%) among DNA near-triploid subclones (P = 0.0001). K-ras2 mutation intratumor heterogeneity indicates that sampling of the tumor may be a critical step and suggests that K-ras2 activation may be a late event in a subgroup of tumors. Our data also suggest the existence of an early process of the colorectal carcinogenesis that favors both K-ras2 mutations and DNA near-diploid aneuploidy. Onset of DNA near-triploid subclones appears, instead, to be independent from K-ras2 activation.

This article has been cited by other articles:

				L. Losi, B. Baisse, H. Bouzourene, and J. Benhattar Evolution of intratumoral genetic heterogeneity during colorectal cancer progression Carcinogenesis, May 1, 2005; 26(5): 916 - 922. [Abstract] [Full Text] [PDF]

				S. Tortola, R. Steinert, M. Hantschick, M. A. Peinado, I. Gastinger, P. Stosiek, H. Lippert, W. Schlegel, and M. A. Reymond Discordance Between K-ras Mutations in Bone Marrow Micrometastases and the Primary Tumor in Colorectal Cancer J. Clin. Oncol., June 1, 2001; 19(11): 2837 - 2843. [Abstract] [Full Text] [PDF]

				W. Giaretti, A. Rapallo, E. Geido, A. Sciutto, F. Merlo, M. Risio, and F. P. Rossini Specific K-ras2 Mutations in Human Sporadic Colorectal Adenomas Are Associated with DNA Near-Diploid Aneuploidy and Inhibition of Proliferation Am. J. Pathol., October 1, 1998; 153(4): 1201 - 1209. [Abstract] [Full Text] [PDF]

				R. Li, A. Sonik, R. Stindl, D. Rasnick, and P. Duesberg Aneuploidy vs. gene mutation hypothesis of cancer: Recent study claims mutation but is found to support aneuploidy PNAS, March 28, 2000; 97(7): 3236 - 3241. [Abstract] [Full Text] [PDF]