Cytogenetic Aberrations Detected by Flow Cytometry and Fluorescence in situ Hybridization in Colorectal Cancers: Two Cytogenetic Pathways in Colorectal Carcinogenesis

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Abstract

We measured DNA content by flow cytometry and determined the number of chromosomes 7, 17 and 18 by fluorescence in situ hybridization using DNA probes in 38 sporadic colorectal adenocarcinomas including 14 early cancers. Based on DNA ploidy and the copy number of chromosome 18, colorectal cancers were divided into two groups. In early cancers (mucosal and submucosal adenocarcinomas), monosomy 18 with DNA hypotriploidy was detected exclusively in 6 sessile tumors without adenoma portions. Seven of the remaining 8 tumors in which adenoma portions coexisted manifested disomy 18 and DNA diploidy or near diploidy. These tumors were considered to occur along the adenoma-carcinoma sequence. In contrast, monosomy 18 was accompanied by DNA diploidy or near diploidy in advanced cancers penetrating the muscularis propria. In advanced cancers, DNA hypertriploidy was linked with disomy 18 and chromosomes 7 and 17 were trisomic or tetrasomic. Observations indicate at least two different cytogenetic pathways in colorectal carcinogenesis. According to these findings, two thirds of advanced cancers were estimated to originate from adenoma, and the others were not.

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Mutations of mitotic checkpoint genes in human cancers.

D P Cahill, C Lengauer, J Yu … (1998)

Genetic instability was one of the first characteristics to be postulated to underlie neoplasia. Such genetic instability occurs in two different forms. In a small fraction of colorectal and some other cancers, defective repair of mismatched bases results in an increased mutation rate at the nucleotide level and consequent widespread microsatellite instability. In most colorectal cancers, and probably in many other cancer types, a chromosomal instability (CIN) leading to an abnormal chromosome number (aneuploidy) is observed. The physiological and molecular bases of this pervasive abnormality are unknown. Here we show that CIN is consistently associated with the loss of function of a mitotic checkpoint. Moreover, in some cancers displaying CIN the loss of this checkpoint was associated with the mutational inactivation of a human homologue of the yeast BUB1 gene; BUB1 controls mitotic checkpoints and chromosome segregation in yeast. The normal mitotic checkpoints of cells displaying microsatellite instability become defective upon transfer of mutant hBUB1 alleles from either of two CIN cancers.

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Common patterns of genetic evolution in human solid tumors.

S Shackney, T V Shankey (1997)

Human solid tumors develop multiple genetic evolutionary abnormalities as they evolve. Studies that have focused primarily on early colorectal cancer have suggested that genetic instability is a prominent feature of preinvasive disease. At least two separate mechanisms for the generation of genetic instability have been identified. The first, which involves widespread microsatellite instability in near-diploid cells, affects less than one-fifth of colon cancers. The second form of genetic instability is characterized by the development of p53 gene abnormalities that result in gross aneuploidy and multiple structural chromosomal changes. p53/aneuploidy affects most colon cancers, breast cancers, and many other solid tumors. This genetic evolutionary change commonly occurs at the interface between severe dysplasia and invasive disease. Specific post-aneuploid sequences of genetic changes that are relevant to tumor progression often involve the accumulation of multiple gain-of-function abnormalities in individual cells. The co-occurrence of Her-2/neu overexpression and EGF receptor overexpression in the same aneuploid cells defines an adeno/squamous genetic evolutionary sequence that is common to ductal breast cancers, non-small cell lung cancers, and other solid tumors. Later steps in this sequence include ras and c-myc overexpression. The neuroendocrine genetic evolutionary sequence is a separate branch of the p53/aneuploidy sequence with distinctive features that include loss of Rb and raf1 overexpression. Her-2/neu overexpression is not characteristic of this sequence; c-myc amplification/overexpression is common to both p53-associated sequences. The neuroendocrine sequence is found in small cell carcinoma of the lung and in minor proportions of other solid tumors, including breast cancer. Multiparameter cell-based methods are especially well suited for elucidation in human solid tumors of the genetic evolutionary sequences that could provide a rational scientific basis for determining prognosis and for optimizing therapy in individual cancer patients.

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Cytogenetics of colorectal adenocarcinomas.

Martine Muleris, Rémy-Jacques Salmon, Bernard Dutrillaux (1990)

The occurrence of nonrandom chromosomal anomalies in colorectal adenocarcinomas could be demonstrated from the cytogenetic study of 100 cases. The most frequent changes are a rearrangement of chromosome 17, leading to the loss of its short arm and a loss of one chromosome 18. Three types of tumors with abnormal karyotypes can be defined. First are the monosomic-type near-diploid tumors (MD), characterized by a monosomy of both 17p and chromosome 18 mostly associated with other recurrent monosomies. In two of three cases, one or several minor derived polyploid subclones are also observed. Second are the monosomic-type polyploid tumors (MP), which have a pattern of chromosome imbalance very similar to that of MD tumors. They derive from MD tumors by endoreduplication followed by complete disappearance of the original MD clone. Third are the trisomic-type tumors (TT), which lose either 17p or chromosome 18 or none, most of the anomalies being gains of entire chromosomes. These TT tumors never undergo endoreduplication. In addition, seven tumors with normal karyotypes were found and may constitute another category (NT). A nonrandom distribution of these tumor types in relation to tumor site was observed, since in the distal colon, TT and NT tumors are underrepresented and endoreduplications are significantly more frequent. The level of chromosomal mutagenesis is two- to threefold higher in MD and MP than in TT tumors. More than 95% of the rearrangements are unbalanced, and most of them result from breakpoints located in juxtacentromeric heterochromatin. A good correlation is found between our results and the available molecular data on allelic losses. The involvement of recessive tumor suppressor genes in colorectal tumorigenesis and the possible relationship between chromosomal imbalances and deviations in metabolic pathways is described.

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Journal

Journal ID (publisher-id): OCL

Journal ID (nlm-ta): Oncology

Journal ID (doi): 10.1159/issn.0030-2414

Title: Oncology

Publisher: S. Karger AG

ISSN (Print): 0030-2414

ISSN (Electronic): 1423-0232

Publication date Subscription-year: 1999

Publication date (Print): July 1999

Publication date (Electronic): 02 July 1999

Volume: 57

Issue: 1

Pages: 63-69

Affiliations

^aDepartment of Pathology, Yamaguchi University School of Medicine, Ube, ^bDepartment of Surgery, Yamagata Prefectural Central Hospital, Yamagata, and ^cDepartment of Surgery, University of Tsukuba, School of Medicine, Tsukuba, Japan

Article

Publisher ID: 12002 Other ID: Oncology 1999;57:63–69

DOI: 10.1159/000012002

PubMed ID: 10394127

SO-VID: b28ab6b2-585b-4c82-b0e6-3ac540fafb67

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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Cytogenetic Aberrations Detected by Flow Cytometry and Fluorescence in situ Hybridization in Colorectal Cancers: Two Cytogenetic Pathways in Colorectal Carcinogenesis

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Karger: Oncology

Most cited references 5

Mutations of mitotic checkpoint genes in human cancers.

Common patterns of genetic evolution in human solid tumors.

Cytogenetics of colorectal adenocarcinomas.

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