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Carcinogenesis Advance Access published online on February 24, 2005
Carcinogenesis, doi:10.1093/carcin/bgi044
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received September 23, 2004
Revised February 2, 2005
Accepted February 6, 2005

CANCER BIOLOGY

Evolution of intratumoral genetic heterogeneity during colorectal cancer progression

Lorena Losi 1, Bénédicte Baisse 2, Hanifa Bouzourene 2, and Jean Benhattar 2*

1 Department of Pathology, University of Modena and Reggio Emilia, 4110 Modena, Italy
2 Institute of Pathology, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland

* To whom correspondence should be addressed.
Jean Benhattar, E-mail: Jean.Benhattar{at}chuv.hospvd.ch


  Abstract

Evolution of intratumoral genetic heterogeneity during colorectal tumor progression has not been investigated so far. Multiple sample areas in colorectal adenocarcinoma at early and advanced stages and in metastases were studied for the well known genetic alterations: K-ras and p53 point mutations and loss of heterozygosity (LOH) on chromosomes 5q and 18q. In primary colorectal cancers, intratumoral genetic heterogeneity was more often observed in early than in advanced stages, 90 and 67% respectively. All but one of the advanced colorectal cancers were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of early cancers. At the early stage, the last events produced, p53 mutation and LOH of 18q, were also the most heterogeneous. At the advanced stage, the LOH of 5q and 18q were the most frequent heterogeneous events (67% and 58%, respectively). The intratumoral heterogeneity for mutations was significantly reduced, from the early to advanced stages (from 60 to 20% for K-ras and from 70% to 20% for p53. On the other hand, a quasi absence of intratumoral genetic heterogeneity was observed for K-ras and p53 in distant metastasis. In conclusion, colorectal adenocarcinomas are characterized by marked intratumoral genetic heterogeneity. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during colorectal cancer progression, clonal selection and chromosome instability continue, while an increase cannot be proven.

Keywords: colorectal cancer; intratumoral heterogeneity; K-ras mutation; p53 mutation; loss of heterozygosity.
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