A genetic model for colorectal tumorigenesis

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.

Genetic alterations during colorectal-tumor development.

Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.

The fundamental role of epigenetic events in cancer

Lessons from Hereditary Colorectal Cancer

The remarkable family study of renal carcinoma reported in this issue of the Journal provides us with the first example of a dominantly inherited chromosomal aberration that imposes a high risk of a specific cancer. In this pedigree a translocation between chromosomes 3 and 8 is associated with an extraordinary risk of renal carcinoma. As in other familial cancers the median age of onset is considerably younger than for the general population and the tumor is often multifocal, with a probability that primary tumors will arise bilaterally that steadily increases with age. Each carrier of the genetic abnormality in the . . .

Persons at high risk of cancer.

Neuroblastoma is the classic tumor that illustrates the phenomenon of spontaneous regression. The most dramatic cases of regression occur in those infants who have disseminated disease involving li...

Sounding board. Regression of neuroblastoma IV-S: a genetic hypothesis.

Boveri's idea that somatic mutations are at the root of cancer found its first specific support with the investigation of leukemia and Burkitt's lymphoma, and the discovery of the mechanism of oncogene activation by balanced translocation. The study of retinoblastoma later led to the cloning of the first antioncogene, or tumor suppressor gene, and to understanding the mechanisms by which the wild-type genes lose activity. Only a small subset of cancer involves simple mechanisms. A category of hereditary disorders called the phakomatoses provide a perspective on the chain of oncogenic events in such cancers because of two-hit precursor lesions that have a low probability of malignant transformation. The common carcinomas are much more complex and are typically genetically unstable, owing either to mutational instability or chromosomal instability.

Chasing the Cancer Demon

Treatment of a child affected by type II mucopolysaccharidosis (Hunter's syndrome) with leukocyte transfusions produced dramatic biochemical and clinical changes. The biochemical changes, consisting of greatly increased urinary excretion of glycosaminoglycans and their products of degradation, were transient. The clinical changes, on the other hand, were protracted, which suggests that the mobilization and degradation of stored glycosaminoglycans was not followed by their reaccumulation to initial levels. The effects obtained with this treatment are superior to those produced by plasma infusion, and have implications for therapeutic attempts in the treatment of other hereditary diseases.

Alfred G. Knudson

Papers

Persons at high risk of cancer.

Sounding board. Regression of neuroblastoma IV-S: a genetic hypothesis.

Chasing the Cancer Demon

Effect of leukocyte transfusion in a child with type II mucopolysaccharidosis.

All in the (cancer) family.