0
September 23, 1992, Vol 268, No. 12 >
ARTICLE | September 23, 1992

Reconciling the Epidemiology, Physiology, and Molecular Biology of Colon Cancer FREE

John D. Potter, MD, PhD
[+] Author Affiliations

Based on a presentation originally given at the symposium in honor of Professor Saxon Graham, Buffalo, NY, June 11, 1991.

Reprint requests to Division of Epidemiology, School of Public Health, University of Minnesota, 1300 S Second St, Minneapolis, MN 55454-1015 (Dr Potter).


JAMA. 1992;268(12):1573-1577. doi:10.1001/jama.1992.03490120087033
Text Size: A A A
Published online
Article
References

A QUESTION relevant to the etiology of cancer that is seldom asked is: What gets cancer—the genes, the cell, the organ, the organism, or perhaps even the population? The potential answers are not necessarily exclusive, even given reductionist tendencies and the genuine and justified excitement over discoveries in the molecular biology of cancer. Rather, these are levels of explanation that may be more or less coherent within themselves but provide even more information when they exist in a framework provided by all of the explanatory modes. For the purpose of exemplifying this framework, consider that theories of the etiology of colon cancer have been presented at a number of levels—epidemiologic, physiological, and cellular/ molecular. It is proposed herein that it is worthwhile considering both the coherence and interdependence of these levels of explanation, not as a sterile exercise, but because of its heuristic value and its capacity to shape a

REFERENCES

1 +
Drasar BS, Irving D.  Environmental factors and cancer of the colon and breast. Br J Cancer . 1973;; 27:167-172.
2 +
Armstrong B, Doll R.  Environmental factors and cancer incidence and mortality in different countries with special reference to dietary practices. Int J Cancer . 1975;;15:617-631.
3 +
Heaton KW.  The colon and bile-acid metabolism.  In: Kasper H, Goebell H, eds. Colon and Nutrition . Lancaster, England: MTP Press Ltd; 1982;. Falk Symposium 32:117-125.
4 +
Haenszel W, Berg JW, Segi M, Kurihara M, Locke FB.  Large bowel cancer in Hawaiian Japanese. J Natl Cancer Inst . 1973;;51:1765-1799.
5 +
Bjelke E. Epidemiological Studies of Cancer of the Stomach, Colon and Rectum: vol 3, Case-Control Study of Gastrointestinal Cancer in Norway; vol 4, Case-Control Study of the Digestive Tract Cancers in Minnesota . Ann Arbor, Mich: Ann Arbor University Microfilms; 1973;.
6 +
Wynder EL, Shigematsu T.  Environmental factors of cancer of the colon and rectum. Cancer . 1967;;20:1529-1561.
7 +
Wynder EL, Kajitani T, Ishikana S, Dodo H, Tako A.  Environmental factors of cancer of the colon and rectum, II: Japanese epidemiologic data. Cancer . 1969;;23:1210-1220.
8 +
Potter JD.  Large bowel cancer: epidemiology and biology. Verh Bd . 1989;;24:137-140.
9 +
Hirayama TA.  A large-scale cohort study on the relationship between diet and selected cancers of the digestive organs.  In: Bruce WR, Correa P, Lipkin M, Tannenbaum FR, Wilkins TD, eds. Gastrointestinal Cancer: Endogenous Factors . Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 1981;:409-429. Banbury Report No. 7.
10 +
Phillips RL, Snowdon DA.  Dietary relationships with fatal colorectal cancer among Seventh-Day Adventists. J Natl Cancer Inst . 1985;;74:307-317.
11 +
Jain M, Cook GM, Davis FG, Grace MG, Howe GR, Miller AB.  A case-control study of diet and colo-rectal cancer. Int J Cancer . 1980;;26:757-768.
12 +
Potter JD, McMichael AJ.  Diet and cancer of the colon and rectum: a case-control study. J Natl Cancer Inst . 1986;;76:557-569.
13 +
Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE.  Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med . 1990;;323:1664-1672.
14 +
Stemmerman GN, Nomura AMY, Heilbrun LK.  Dietary fat and the risk of colorectal cancer. Cancer Res . 1984;;44:4633-4637.
15 +
Burkitt D.  Related disease—related cause? Lancet . 1969;;2:1229-1231.
16 +
Stubs P. Cited by Royal College of Physicians. Medical Aspects of Dietary Fibre . Bath, England: Pitman Medical; 1980;:3.
17 +
Steinmetz KA, Potter JD.  Vegetable, fruit, and cancer, I: epidemiology. Cancer Causes Control . 1991;;2:325-357.
18 +
Manousos 0, Day NE, Trichopoulos D, Gerovassilis F, Tzonou A, Polychronopoulou A.  Diet and colorectal cancer: a case-control study in Greece. Int J Cancer . 1983;;32:1-5.
19 +
Garabrant DH, Peters JM, Mack TM, Bernstein L.  Job activity and colon cancer risk. Am J Epidemiol . 1984;;119:1005-1014.
20 +
Vena JE, Graham S, Zielezny M, Swanson MK, Barnes RE, Nolan J.  Lifetime occupational exercise and colon cancer. Am J Epidemiol . 1985;;122: 357-365.
21 +
Gerhardsson M, Norell SE, Kiviranta H, Pederson NL, Ahlbom A.  Sedentary jobs and colon cancer. Am J Epidemiol . 1986;;123:775-780.
22 +
Slattery ML, Schumacher MC, Smith KR, West DW, Abd-Elghany N.  Physical activity, diet and risk of colon cancer in Utah. Am J Epidemiol . 1988;; 128:989-999.
23 +
McMichael AJ, Potter JD.  Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst . 1980;;65:1201-1207.
24 +
Weiss NS, Daling JR, Chow WH.  Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors. J Natl Cancer Inst . 1981;;67:57-60.
25 +
Potter JD, McMichael AJ.  Large bowel cancer in relation to reproductive and hormonal factors: a case-control study. J Natl Cancer Inst . 1983;;71: 703-709.
26 +
Howe GR, Craib KJP, Miller AB.  Age at first pregnancy and risk of colorectal cancer: a case-control study. J Natl Cancer Inst . 1985;;74:1155-1159.
27 +
Hill MJ, Aries VC.  Faecal steroid composition and its relationship to cancer of the large bowel. J Pathol . 1971;;104:129-139.
28 +
Stephen A, Cummings J.  Mechanism of action of dietary fibre in the human colon. Nature . 1980;; 284:283-284.
29 +
Cummings J.  Fermentation in the human large intestine: evidence and implications for health. Lancet . 1983;;1:1206-1209.
30 +
Sugimura T, Sato S.  Mutagens-carcinogens in foods. Cancer Res . 1983;;43( (suppl) ):2415s-2421s.
31 +
Corpet D, Stamp D, Medline A, Minkin S, Archer M, Bruce WR.  Promotion of colonic microadenoma growth in mice and rats fed cooked sugar or cooked casein and fat. Cancer Res . 1990;;50:6955-6958.
32 +
Steinmetz K, Potter J.  Vegetables, fruit, and cancer, II: mechanisms. Cancer Causes Control . 1991;;2:427-442.
33 +
Wattenberg LW.  Inhibition of chemical carcinogenesis. J Natl Cancer Inst . 1987;;60:11-18.
34 +
Wattenberg LW.  Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst . 1977;;58:195-198.
35 +
Newmark HL, Wargovich MJ, Bruce WR.  Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst . 1984;;72:1323-1325.
36 +
McMichael AJ, Potter JD.  Diet and colon cancer: integration of the descriptive, analytic, and metabolic epidemiology. Natl Cancer Inst Monog . 1985;;69:223-228.
37 +
Byers T, Graham S, Swanson M.  Parity and colorectal cancer risk in women. J Natl Cancer Inst . 1982;;69:1059-1062.
38 +
Papadimitriou C, Day N, Tzonou A, Gerovassilis F, Manousos O, Trichopoulos D.  Biosocial correlates of colorectal cancer in Greece. Int J Epidemiol . 1984;;13:155-159.
39 +
Wu AH, Paganini-Hill A, Ross RK, Henderson BE.  Alcohol, physical activity, and other risk factors for colorectal cancer: a prospective study. Br J Cancer . 1987;;55:687-694.
40 +
McMichael AJ, Potter JD.  Do intrinsic sex differences in lower alimentary tract physiology influence the sex-specific risks for bowel cancer and other biliary and intestinal diseases? Am J Epidemiol . 1983;;118:620-627.
41 +
Stephen AM, Wiggins HS, Englyst HN, Cole TJ, Wayman BJ, Cummings JH.  The effect of age, sex and level of intake of dietary fibre from wheat on large-bowel function in thirty healthy subjects. Br J Nutr . 1986;;56:349-361.
42 +
Lampe JW, Slavin JL, Potter JD.  Sex differences in colonic function: a randomized trial. Gut . In press.
43 +
Kaplan L, Spindel E, Isselbacher K, Chin W.  Tissue-specific expression of the rat galanin gene. Proc Natl Acad Sci U S A . 1988;;85:1065-1069.
44 +
McMichael AJ, Potter JD.  Dietary influences upon colon carcinogenesis.  In: Hayashi Y, Magao N, Sugimura T, et al, eds. Diet, Nutrition and Cancer . Tokyo, Japan: Japanese Scientific Society Press; 1986;:275-290.
45 +
Anzano MA, Riemann D, Pritchett W, Bowen-Pope DF, Grieg R.  Growth factor production by human colon carcinoma cell lines. Cancer Res . 1989;; 49:2898-2904.
46 +
Mukaida H, Hirabayashi N, Hirai T, Iwata T, Saeki S, Toge T.  Significance of freshly cultured fibroblasts from different tissue in promoting cancer cell growth. Int J Cancer . 1991;;48:423-427.
47 +
Thun MJ, Namboodiri MM, Heath CW.  Aspirin use and reduced risk of fatal colon cancer. N Engl J Med . 1991;;325:1593-1596.
48 +
Hill MJ, Morson BC, Bussey HJR.  Aetiology of adenoma—carcinoma sequence in large bowel. Lancet . 1978;;1:245-247.
49 +
Turesky RJ, Lang N, Butler MA, Teitel CH, Kadlubar FF.  Metabolic activation of carcinogenic heterocyclic aromatic amines by human liver and colon. Carcinogenesis . 1991;;12:1417-1422.
50 +
Kadlubar FF, Butler MA, Kaderlik KR, Chou HC, Lang NP.  Polymorphisms for aromatic amine metabolism in humans: relevance for human carcinogenesis. Environ Health Persp . In press.
51 +
Lipkin M.  Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res . 1988;;48:235-245.
52 +
Bird RP.  Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett . 1987;;37:147-151.
53 +
Baker S, Fearon E, Nigro J, et al.  Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science . 1989;;244:217-222.
54 +
Vogelstein B, Fearon E, Kern S, et al.  Allelotype of colorectal carcinomas. Science . 1989;;244: 207-212.
55 +
Kinzler K, Nilbert M, Vogelstein B, et al.  Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science . 1991;;251: 1366-1370.
56 +
Fearon E, Cho K, Nigro J, et al.  Identification of a chromosome 18q gene that is altered in colorectal cancers. Science . 1990;;247:49-56.
57 +
Fearon ER, Vogelstein B.  A genetic model for colorectal tumorigenesis. Cell . 1990;;61:759-767.
58 +
Nishisho I, Nakamura Y, Miyoshi Y, et al.  Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science . 1991;;253:665-669.
59 +
Groden J, Thliveris A, Samowitz W, et al.  Identification and characterization of the familial adenomatous polyposis coli gene. Cell . 1991;;66:589-600.
60 +
Kinzler K, Nilbert M, Su L-K, et al.  Identification of FAP locus genes from chromosome 5q21. Science . 1991;;253:661-665.
61 +
Joslyn G, Carlson M, Thliveris A, et al.  Identification of deletion mutations and three new genes at the familial polyposis locus. Cell . 1991;;66:601-613.
62 +
Feinberg A, Vogelstein B.  Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun . 1983;;111:47-54.
63 +
El-Deiry WS, Nelkin BD, Celano P, et al.  High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci U S A . 1991;;88:3470-3474.
64 +
Hoffman RM.  Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. Biochim Biophys Acta . 1984;;738:49-87.
65 +
Morotomi M, Guillem J, LoGerfo P, Weinstein IB.  Production of diacylglycerol, an activator of protein kinase C, by human intestinal microflora. Cancer Res . 1990;;50:3595-3599.
66 +
Guillem JG, Weinstein IB.  The role of protein kinase C in colon neoplasia.  In: Herrera L, ed. Familial Adenomatous Polyposis . New York, NY: Alan R Liss Inc; 1990;:325-332.

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Drasar BS, Irving D.  Environmental factors and cancer of the colon and breast. Br J Cancer . 1973;; 27:167-172.
2 +
Armstrong B, Doll R.  Environmental factors and cancer incidence and mortality in different countries with special reference to dietary practices. Int J Cancer . 1975;;15:617-631.
3 +
Heaton KW.  The colon and bile-acid metabolism.  In: Kasper H, Goebell H, eds. Colon and Nutrition . Lancaster, England: MTP Press Ltd; 1982;. Falk Symposium 32:117-125.
4 +
Haenszel W, Berg JW, Segi M, Kurihara M, Locke FB.  Large bowel cancer in Hawaiian Japanese. J Natl Cancer Inst . 1973;;51:1765-1799.
5 +
Bjelke E. Epidemiological Studies of Cancer of the Stomach, Colon and Rectum: vol 3, Case-Control Study of Gastrointestinal Cancer in Norway; vol 4, Case-Control Study of the Digestive Tract Cancers in Minnesota . Ann Arbor, Mich: Ann Arbor University Microfilms; 1973;.
6 +
Wynder EL, Shigematsu T.  Environmental factors of cancer of the colon and rectum. Cancer . 1967;;20:1529-1561.
7 +
Wynder EL, Kajitani T, Ishikana S, Dodo H, Tako A.  Environmental factors of cancer of the colon and rectum, II: Japanese epidemiologic data. Cancer . 1969;;23:1210-1220.
8 +
Potter JD.  Large bowel cancer: epidemiology and biology. Verh Bd . 1989;;24:137-140.
9 +
Hirayama TA.  A large-scale cohort study on the relationship between diet and selected cancers of the digestive organs.  In: Bruce WR, Correa P, Lipkin M, Tannenbaum FR, Wilkins TD, eds. Gastrointestinal Cancer: Endogenous Factors . Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 1981;:409-429. Banbury Report No. 7.
10 +
Phillips RL, Snowdon DA.  Dietary relationships with fatal colorectal cancer among Seventh-Day Adventists. J Natl Cancer Inst . 1985;;74:307-317.
11 +
Jain M, Cook GM, Davis FG, Grace MG, Howe GR, Miller AB.  A case-control study of diet and colo-rectal cancer. Int J Cancer . 1980;;26:757-768.
12 +
Potter JD, McMichael AJ.  Diet and cancer of the colon and rectum: a case-control study. J Natl Cancer Inst . 1986;;76:557-569.
13 +
Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE.  Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med . 1990;;323:1664-1672.
14 +
Stemmerman GN, Nomura AMY, Heilbrun LK.  Dietary fat and the risk of colorectal cancer. Cancer Res . 1984;;44:4633-4637.
15 +
Burkitt D.  Related disease—related cause? Lancet . 1969;;2:1229-1231.
16 +
Stubs P. Cited by Royal College of Physicians. Medical Aspects of Dietary Fibre . Bath, England: Pitman Medical; 1980;:3.
17 +
Steinmetz KA, Potter JD.  Vegetable, fruit, and cancer, I: epidemiology. Cancer Causes Control . 1991;;2:325-357.
18 +
Manousos 0, Day NE, Trichopoulos D, Gerovassilis F, Tzonou A, Polychronopoulou A.  Diet and colorectal cancer: a case-control study in Greece. Int J Cancer . 1983;;32:1-5.
19 +
Garabrant DH, Peters JM, Mack TM, Bernstein L.  Job activity and colon cancer risk. Am J Epidemiol . 1984;;119:1005-1014.
20 +
Vena JE, Graham S, Zielezny M, Swanson MK, Barnes RE, Nolan J.  Lifetime occupational exercise and colon cancer. Am J Epidemiol . 1985;;122: 357-365.
21 +
Gerhardsson M, Norell SE, Kiviranta H, Pederson NL, Ahlbom A.  Sedentary jobs and colon cancer. Am J Epidemiol . 1986;;123:775-780.
22 +
Slattery ML, Schumacher MC, Smith KR, West DW, Abd-Elghany N.  Physical activity, diet and risk of colon cancer in Utah. Am J Epidemiol . 1988;; 128:989-999.
23 +
McMichael AJ, Potter JD.  Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst . 1980;;65:1201-1207.
24 +
Weiss NS, Daling JR, Chow WH.  Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors. J Natl Cancer Inst . 1981;;67:57-60.
25 +
Potter JD, McMichael AJ.  Large bowel cancer in relation to reproductive and hormonal factors: a case-control study. J Natl Cancer Inst . 1983;;71: 703-709.
26 +
Howe GR, Craib KJP, Miller AB.  Age at first pregnancy and risk of colorectal cancer: a case-control study. J Natl Cancer Inst . 1985;;74:1155-1159.
27 +
Hill MJ, Aries VC.  Faecal steroid composition and its relationship to cancer of the large bowel. J Pathol . 1971;;104:129-139.
28 +
Stephen A, Cummings J.  Mechanism of action of dietary fibre in the human colon. Nature . 1980;; 284:283-284.
29 +
Cummings J.  Fermentation in the human large intestine: evidence and implications for health. Lancet . 1983;;1:1206-1209.
30 +
Sugimura T, Sato S.  Mutagens-carcinogens in foods. Cancer Res . 1983;;43( (suppl) ):2415s-2421s.
31 +
Corpet D, Stamp D, Medline A, Minkin S, Archer M, Bruce WR.  Promotion of colonic microadenoma growth in mice and rats fed cooked sugar or cooked casein and fat. Cancer Res . 1990;;50:6955-6958.
32 +
Steinmetz K, Potter J.  Vegetables, fruit, and cancer, II: mechanisms. Cancer Causes Control . 1991;;2:427-442.
33 +
Wattenberg LW.  Inhibition of chemical carcinogenesis. J Natl Cancer Inst . 1987;;60:11-18.
34 +
Wattenberg LW.  Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst . 1977;;58:195-198.
35 +
Newmark HL, Wargovich MJ, Bruce WR.  Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst . 1984;;72:1323-1325.
36 +
McMichael AJ, Potter JD.  Diet and colon cancer: integration of the descriptive, analytic, and metabolic epidemiology. Natl Cancer Inst Monog . 1985;;69:223-228.
37 +
Byers T, Graham S, Swanson M.  Parity and colorectal cancer risk in women. J Natl Cancer Inst . 1982;;69:1059-1062.
38 +
Papadimitriou C, Day N, Tzonou A, Gerovassilis F, Manousos O, Trichopoulos D.  Biosocial correlates of colorectal cancer in Greece. Int J Epidemiol . 1984;;13:155-159.
39 +
Wu AH, Paganini-Hill A, Ross RK, Henderson BE.  Alcohol, physical activity, and other risk factors for colorectal cancer: a prospective study. Br J Cancer . 1987;;55:687-694.
40 +
McMichael AJ, Potter JD.  Do intrinsic sex differences in lower alimentary tract physiology influence the sex-specific risks for bowel cancer and other biliary and intestinal diseases? Am J Epidemiol . 1983;;118:620-627.
41 +
Stephen AM, Wiggins HS, Englyst HN, Cole TJ, Wayman BJ, Cummings JH.  The effect of age, sex and level of intake of dietary fibre from wheat on large-bowel function in thirty healthy subjects. Br J Nutr . 1986;;56:349-361.
42 +
Lampe JW, Slavin JL, Potter JD.  Sex differences in colonic function: a randomized trial. Gut . In press.
43 +
Kaplan L, Spindel E, Isselbacher K, Chin W.  Tissue-specific expression of the rat galanin gene. Proc Natl Acad Sci U S A . 1988;;85:1065-1069.
44 +
McMichael AJ, Potter JD.  Dietary influences upon colon carcinogenesis.  In: Hayashi Y, Magao N, Sugimura T, et al, eds. Diet, Nutrition and Cancer . Tokyo, Japan: Japanese Scientific Society Press; 1986;:275-290.
45 +
Anzano MA, Riemann D, Pritchett W, Bowen-Pope DF, Grieg R.  Growth factor production by human colon carcinoma cell lines. Cancer Res . 1989;; 49:2898-2904.
46 +
Mukaida H, Hirabayashi N, Hirai T, Iwata T, Saeki S, Toge T.  Significance of freshly cultured fibroblasts from different tissue in promoting cancer cell growth. Int J Cancer . 1991;;48:423-427.
47 +
Thun MJ, Namboodiri MM, Heath CW.  Aspirin use and reduced risk of fatal colon cancer. N Engl J Med . 1991;;325:1593-1596.
48 +
Hill MJ, Morson BC, Bussey HJR.  Aetiology of adenoma—carcinoma sequence in large bowel. Lancet . 1978;;1:245-247.
49 +
Turesky RJ, Lang N, Butler MA, Teitel CH, Kadlubar FF.  Metabolic activation of carcinogenic heterocyclic aromatic amines by human liver and colon. Carcinogenesis . 1991;;12:1417-1422.
50 +
Kadlubar FF, Butler MA, Kaderlik KR, Chou HC, Lang NP.  Polymorphisms for aromatic amine metabolism in humans: relevance for human carcinogenesis. Environ Health Persp . In press.
51 +
Lipkin M.  Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res . 1988;;48:235-245.
52 +
Bird RP.  Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett . 1987;;37:147-151.
53 +
Baker S, Fearon E, Nigro J, et al.  Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science . 1989;;244:217-222.
54 +
Vogelstein B, Fearon E, Kern S, et al.  Allelotype of colorectal carcinomas. Science . 1989;;244: 207-212.
55 +
Kinzler K, Nilbert M, Vogelstein B, et al.  Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science . 1991;;251: 1366-1370.
56 +
Fearon E, Cho K, Nigro J, et al.  Identification of a chromosome 18q gene that is altered in colorectal cancers. Science . 1990;;247:49-56.
57 +
Fearon ER, Vogelstein B.  A genetic model for colorectal tumorigenesis. Cell . 1990;;61:759-767.
58 +
Nishisho I, Nakamura Y, Miyoshi Y, et al.  Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science . 1991;;253:665-669.
59 +
Groden J, Thliveris A, Samowitz W, et al.  Identification and characterization of the familial adenomatous polyposis coli gene. Cell . 1991;;66:589-600.
60 +
Kinzler K, Nilbert M, Su L-K, et al.  Identification of FAP locus genes from chromosome 5q21. Science . 1991;;253:661-665.
61 +
Joslyn G, Carlson M, Thliveris A, et al.  Identification of deletion mutations and three new genes at the familial polyposis locus. Cell . 1991;;66:601-613.
62 +
Feinberg A, Vogelstein B.  Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun . 1983;;111:47-54.
63 +
El-Deiry WS, Nelkin BD, Celano P, et al.  High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci U S A . 1991;;88:3470-3474.
64 +
Hoffman RM.  Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. Biochim Biophys Acta . 1984;;738:49-87.
65 +
Morotomi M, Guillem J, LoGerfo P, Weinstein IB.  Production of diacylglycerol, an activator of protein kinase C, by human intestinal microflora. Cancer Res . 1990;;50:3595-3599.
66 +
Guillem JG, Weinstein IB.  The role of protein kinase C in colon neoplasia.  In: Herrera L, ed. Familial Adenomatous Polyposis . New York, NY: Alan R Liss Inc; 1990;:325-332.

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