1.4 Colon cancer pathogenesis - gene mutations

Increasing numbers of mutant genes accumulate in cells as they evolve from a more benign to a more malignant growth state.
We know so much about the genetic basis of tumor progression in the colon because the colonic epithelium is relatively accessible through colonoscopy
They examined the genomes of sizable groups of
small colonic adenomas, mid-sized adenomas, large adenomas, and carcinomas
It was plausible that as colonic tissues advanced progressively from normalcy to a high-grade malignancy
The epithelial cells in these various tissues would accumulate increasing numbers of mutations in various genes.

(NOTE: the identities of the tumor suppressor genes that participate in colon cancer pathogenesis were not known when they began their work, so they searched instead for chromosomal regions that suffered loss of heterozygosity (LOH) during tumor progression)

Landmark research: Colon Cancer
Early-stage adenomas often showed
loss of heterozygosity in the long arm of Chromosome 5

Almost half of slightly larger adenomas showed
in addition, a mutant K- ras oncogene.

Even larger adenomas tended to showed
high rates of LOH on the long arm of Chromosome 18
LOH on the short arm of Chromosome 17

These observations support the idea that
epithehial cells acquire increasingly neoplastic phenotypes during the course of tumor progression
Increasingly neoplastic phenotypes during the course of tumor progression

Tumor progression
Involves the activation of one proto-oncogene into an oncogene and the inactivation of at least three tumor suppressor genes

This was the first suggestion of a phenomenon that is now recognized to be quite common in human tumor cell genomes.
The most obvious way to rationalize the steps in colon cancer development involves
an ordered succession of genetic changes that strike the genomes of colonic epithelial cells as they evolve progressively toward malignancy

Colon cancer pathogenesis.
Most colon cancers will begin with a Chromosome 5 alteration, but then will take alternative genetic paths on the road toward full-fledged malignancy

The loss of heterozygosity on Chromosome 5q is almost always the first in the progression
the precise order of the subsequent changes may vary from tumor to tumor.
Some of these mutations appear to confer growth advantages at an early stage of tumor development
Other mutations promote the later stages, including invasion and metastasis, which are required for the malignant phenotype

Видео 1.4 Colon cancer pathogenesis - gene mutations канала Mark Temple