PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 1668893

A population perspective on multistage carcinogenesis.

S H Moolgavkar
View original source ↗Export metadata ↓

Abstract

The concept of multistage carcinogenesis is one of the central dogmas of cancer research today. Recent laboratory work suggests that many specific genetic changes are associated with carcinogenesis. At the same time, there is increasing evidence that cell proliferation kinetics are important in carcinogenesis. In 1971, Knudson proposed his now celebrated two-mutation model for embryonal tumors. In fact, a two-mutation model that explicitly considers cell kinetics is the most parsimonious model consistent with the incidence of both childhood and adult cancer in human populations. This model has been known to be consistent, as well, with other epidemiologic and experimental data. But can such a model be reconciled with the laboratory evidence suggesting that many genetic alterations are required for malignant transformation? In this paper, I examine multistage carcinogenesis from the population perspective. Can cancer incidence data in populations provide some insight into the number and nature of stages involved in malignant transformation? I focus attention on carcinoma of the colon because of the considerable amount of information that is now available on the genetics of these tumors. Also, as is the case with retinoblastoma, colon cancer occurs in sporadic and dominantly inherited forms. A comparison of the incidence of these two forms of colon cancer suggests that mutation at the familial adenomatous polyposis (FAP) locus is not necessary for colon cancer, and that inheritance of the gene for FAP is not equivalent to inheriting one of the essential steps on the pathway to colon cancer. Thus, colon cancer does not follow the retinoblastoma paradigm. The incidence of colon cancer in the general population and among polyposis subjects is consistent with two or three mutations on the pathway to malignancy. A three-mutation model is more consistent with the genetic alterations observed in colon carcinogenesis. I present and discuss a working model for colon cancer.

Explore related subjects

Adenomatous Polyposis ColiColonic NeoplasmsFemaleGenes, Tumor SuppressorHumansMaleModels, BiologicalMutationOncogenesJournal ArticleReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

S H Moolgavkar. 1991. A population perspective on multistage carcinogenesis.. https://pubmed.ncbi.nlm.nih.gov/1668893/

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2007

Familial adenomatous polyposis patients have high levels of arachidonic acid and docosahexaenoic acid and low levels of linoleic acid and alpha-linolenic acid in serum phospholipids.

Familial adenomatous polyposis (FAP) provides a model of APC inactivation as an early genetic event for the approximately 85% of colorectal cancers that develop from polyps. Abnormal fatty acid composition of tissues and serum phospholipids has been linked to cancer risk. Our aim was to describe the composition of fatty acids in serum phospholipids in 38 colectomized FAP patients as compared to 160 healthy subjects. Mean fatty acid intakes were similar between the groups. Colectomy was done on average 16 years prior to inclusion, and 18% were diagnosed with colorectal cancer at colectomy. The levels (weight %) of linoleic and alpha-linolenic acid were higher among the reference subjects (difference: 3.96, 95% confidence interval (CI) = 2.87, 5.04, and difference: 0.06, 95% CI = 0.04, 0.08, respectively), and the levels of arachidonic and docosahexaenoic acid were lower (difference: -3.70, 95% CI = -4.35, -3.06, and difference: -5.26, 95% CI = -6.25, -4.28, respectively) as compared to the FAP patients (all p < or = 0.0001). The abnormal fatty acid composition was not related to time since colectomy, intestinal reconstruction or history of colorectal cancer for any of the fatty acids assessed. Compositional differences in the fatty acid profile of serum phospholipids have not been described before in FAP patients. Further studies are needed to confirm these findings and assess clinical significances of a possible distorted fatty acid metabolism, including a potentially different dietary need of essential fatty acids. The relevance of these findings for APC induced cancers remains unclear.

Adenomatous Polyposis Coli↗
PubMed2007

Balance between endoscopic and genetic information in the choice of ileorectal anastomosis for familial adenomatous polyposis.

BACKGROUND AND OBJECTIVES: The number of rectal polyps and the site of mutations in the APC (Adenomatous polyposis coli) gene have been used to guide the surgical management in patients with familial adenomatous polyposis (FAP). The aim of this study is to assess the utility of the APC mutation screening compared to the degree of the rectal polyposis in surgical decision making. METHODS: The post-surgical courses of 25 patients submitted to subtotal colectomy with ileorectal anastomosis (IRA) were reviewed. Preservation of the rectum was prospectively decided on the basis of well-defined endoscopic criteria. The number of rectal polyps was assessed preoperatively and every 6-12 months. APC gene was screened for mutations by heteroduplex analysis, single strand conformation polymorphism, in vitro synthesized protein (IVSP), and DNA sequencing. Patients negative for APC mutations were tested for MYH mutations. RESULTS: On the basis of preoperative polyp rectal count we categorized patients as follows: Group I, 5 or fewer adenomas; Group II, 6-9 adenomas; Group III, 10 or more adenomas. After a follow-up ranging from 12 to 225 months we have observed a significant difference of recurrent rectal adenomas between Groups I-II versus III. No difference was detected among patients of Group I and II. The mean number of adenomas/year/patient was 0.67, 1.62, and 9.29 for Group I, II, and III, respectively. Carpeting polyposis of the rectal stump developed in three patients with APC mutation at codon 1309 and two of them needed later proctectomy. Diffuse rectal polyposis was observed in one patient with mutation at exon 9 who had 10 small polyps at time of surgery. Mutation at the 5'-end of APC (codons 144-232), mutation of MYH and unknown APC or MYH mutation were correlated with a low number of polyps both at presentation and follow-up. No IRA patients developed rectal cancer. CONCLUSIONS: In our experience fewer than 10 rectal polyps at presentation can predict a favorable outcome after IRA. Identification of specific germ-line APC or MYH mutation can address the choice of surgical treatment.

Adenomatous Polyposis Coli↗