EDITORIAL
Etiology of Gastrointestinal Cancer Heredity vs Environment
In the current issue of the American Journal of Digestive Diseases, Bisordi and Lightdale have reported a very interesting case of a 22-year-old patient with a 16-year history of ulcerative colitis who developed colon cancer while his identical twin has been free from both ulcerative colitis and cancer (1). They postulated that the development of colon cancer superimposed on ulcerative colitis in the one case was more likely related to the inflammatory disease rather than to an independent genetic determinant. This situation raises the question of the relationship of genetic and environmental factors in the causation of gastrointestinal disease, particularly in the etiology of gastrointestinal cancer. Gastrointestinal diseases have been the subject of genetic inquiry when it is observed that there is an increased familial aggregation of a specific disease. However, in order to invoke a genetic etiology, it must be determined that environmental factors are not responsible for the increased incidence of the disease, since environmental influences may simulate the action of genes. Environmental influences may be unknown, undetected, or subject to long periods of latency before exerting clinical expression of disease. In many diseases, including cancer, some presently unknown environmental influence, such as a virus, may act early in life and result in disease later in life (2). Studies of twins have been one of the commonly applied techniques of genetic research. Studies of twins in combination with studies of other siblings may provide insight as to the importance of genetic factors. The comparative frequency of concordance and discordance in monozygotic or identical twins and dizygotic or fraternal twins may give a clue as to the importance of genetic factors in the causation
68
of a specific disease. If concordance for a disease is higher for monozygotic than for dizygotic twins, it could be regarded as evidence for a genetic influence in that condition (3). However, there are pitfalls in accepting this hypothesis completely, and as a result twin studies have fallen somewhat into disrepute. There is considerable bias in the collection of twin data. The collection of twin pairs must be systematic. Single interesting pairs as generally reported in the literature are not particularly helpful. There is a tendency to publish interesting cases. Cases of concordance of disease among monozygotic twins are more likely to be reported than concordance in dizygotic twins. There may also be errors in determining zygosity, although this becomes less likely now with HL-A typing and fingerprint analysis. Also it is likely that compared with dizygotic twins, monozygotic twins will be subjected to or choose a more exact type of environment because of their identical genetic composition and therefore be subject to these more identical environmental influences. Nevertheless, individual reports of single pairs of twins can be of value if there is discordance for the disease since, if monozygosity is unequivocal, this indicates that the condition is not completely genetic. It represents a challenge to elucidate the environmental factors concerned. This may mean that the twin with the disease is being exposed to environmental factors or the twin without the disease is being shielded by some protective environmental factor. The proof that a single gene is involved is the demonstration that predicted Mendelian ratios exist. However, most of the human diseases that appear to have some possible genetic predisposition resist analysis of specific gene difference. Manifest Digestive Diseases, Vol. 21, No. I (January 1976)
ETIOLOGY OF GASTROINTESTINAL CANCER
disease and genetic variability may be due to the combined action of a number of genes, the so-called polygenic or multifactorial inheritance. The presence or absence of clinically manifest disease may be all or none, but the underlying genetic basis may be characterized by a broad spectrum of variation in susceptibility which may reflect multifactorial inheritance. The resulting distribution of a disease in the population may therefore reflect both environmental and multifactorial genetic factors. In certain families the risk of developing cancer is much greater than in the general population. In familial polyposis and Gardner's syndrome genetic factors have been clearly demonstrated to be responsible for the increased frequency of neoplastic disease. These are precisely defined autosomal dominant diseases. There is some indication of a familial tendency in patients with colorectal cancer--a tendency that is probably multifactorial. The risk of cancer of the colon in relatives of patients with colorectal cancer is probably about three times that expected in the general population. There is suggestive evidence that patients under age 40 who develop carcinoma of the colon or rectum are more likely to have a family history of colonic cancer than those over 40 who develop the neoplasm. There are families that have been considered cancer families because of their striking incidence of malignancy at multiple anatomic sites (most frequently endometrium and colon), multiple primary malignant neoplasms, and early age of onset. A multifactorial basis may explain the occurrence of such families. However, carcinomas that appear to have a genetic basis resist analytic efforts to prove a single gene difference except for the familial polyposis syndromes (4-6). In regard to cancers that have both hereditary and nonhereditary forms, Knudson et al (7) offered the following hypothesis: The individual with the hereditary form already carries one mutation (germinal) that may lead to cancer but must get one more mutation (somatic) in order to develop the cancer. The patient with the nonhereditary form of cancer must acquire two or more new somatic mutations. As a result nonhereditary cases are of later onset than hereditary ones. Can individuals in families predisposed to develop gastrointestinal cancer be identified at an early stage of their disease, before evidence of malignancy appears? Can the phenotypic expressions of the genetic defect that increases an individual's risk of developing gastrointestinal cancer be studied and identified? Studies carried out by Lipkin and DeschDigestive Diseases, Vol. 21, No. 1 (January 1976)
ner and associates (8-10) have indicated that individuals in families predisposed to develop gastrointestinal cancer carry cells that have developed an increased ability to proliferate and to accumulate in affected regions before malignancy actually appears. Some of the changes that take place remain hidden on conventional examinations and can only be detected by special testing procedures that serve to identify them at an early stage of evolution. It was noted that abnormal proliferative activity could invariably be detected in the colonic cells of individuals in families predisposed to develop neoplasms of the colon, even before neoplastic lesions were noted. In patches of colonic mucosa epithelial cells were present that continued to synthesize and failed to repress the formation of new DNA during their lifespan as they migrated to the crypt surfaces. Patches of fiat mucosa containing these abnormal cells appeared to be foci for the formation of new excrescences that eventually developed in these patients. It was noted in other experiments utilizing a potent carcinogen, dimethylhydrazine (DMH), that the events leading to neoplastic transformation in the colon were quite similar to the events occurring in colonic epithelial cells in humans with a genetic predisposition to colon cancer (10). These findings have suggested that in both inherited and induced neoplastic disease of the colon a common defect in regulatory control of cell proliferation exists. Other observations indicate that the early manifestation of neoplastic transformation could be screened at various stages of development in individuals with familial predisposition to colon cancer. This could be demonstrated by biopsies of colon mucosa and by efficiently washing epithelial cells from the surface of the colon mucosa utilizing a dental irrigating machine (Water-Pik) and incubating the specimens with tritiated thymidine to detect the presence of abnormal proliferative changes (11-13). It would appear that the phenotypic expression of inherited disease leading to colon cancer may be identified as it becomes manifest by a failure of cells to repress DNA synthesis, progressing further in some cells to more advanced stages of adenomatosis and to cancer (8, 14, 15). Perhaps in other cells of individuals with a genetic defect leading to colon cancer, the proliferative apparatus may also not be normal and that transformation may be induced and detected by other methods (15). This would enable improved identification of individuals and families at high risk for the development of ma-
69
SHERLOCK
lignancy, entailing intensive continued surveillance and probably earlier diagnosis whicb is so crucial for increased cure rates (16). P A U L SHERLOCK, M D
Gastroenterology Service Department of Medicine Memorial Sloan-Kettering Cancer Center Department of Medicine Cornell University Medical College New York, New York REFERENCES 1. Bisordi W, Lightdale C J: Identical twins discordant for ulcerative colitis with colon cancer. Am J Dig Dis 29:71-73, 1976 2. Sherlock P: Genetics and gastrointestinal disease. Gastroenterology 53:675-677, 1967 3. McConnell RB (ed): Genetics of gastrointestinal disorders. Clinics in Gastroenterology, Voi 2. London, WB Saunders Co Ltd, 1973 4. McKusick VA: Genetics and large bowel cancer. Am J Dig Dis 19:954-957, 1974 5. Lynch HT, Krush AJ: Heredity and adenocarcinoma of the colon. Gastroenterology 53:517-527, 1967 6. Sherlock P, Lipkin M, Winawer SJ: Predisposing factors in carcinoma of the colon. Adv Intern Med 20:121-150, 1975
70
7. Knudson AG, Jr, et al: Heredity and cancer in man. Progress in Medical Genetics. AG Steinberg, AG Bearn (eds). New York, Grune & Stratton, 1973 8. Lipkin M: Phase 1 and phase 2 proliferative lesions of colonic epithelial cells leading to colon cancer. Cancer 34:878888, 1974 9. Deschner EE, Lipkin M: Proliferative patterns in colonic mucosa in familial polyposis. Cancer 35:413--418, 1975 10. Thurnherr N, Deschner EL, Stonehill EH, Lipkin M: Induction of adenocarcinomas of the colon in mice by weekly injections of l i2-dimethylhydrazine. Cancer Res 33:940-945, 1973 11. Deschner EE, Lipkin M: Studies of human rectal epithelial cells in vitro 111. RNA, protein and DNA synthesis in polyps and adjacent mucosa. J Natl Cancer Inst 44:175-185, 1970 12. Deschner EE, Long FC, Katz S: The detection of aberrant DNA synthesis in a member of a high-risk canCer family. Am J Dig Dis 20:418-424, 1975 13. Deschner EE, Long FC, Katz S: Autoradiographic method for an expanded assessment of colonic cytology. Acta Cytol 17:435438, 1973 14. Lipkin M: Proliferation and differentiation ofgastrointestinal cells. Physiol Rev 53:891-915, 1973 15. Hadden JW (ed): Familial gastrointestinal cancer--Report from Sloan-Kettering Institute. Clin Bull 5:67-69, 1975 16. Sherlock P, Winawer S J: Modern approaches to early identification of large bowel cancer. Am J Dig Dis 19:95%964, 1974
Digestive Diseases, Vol. 21, No. 1 (January 1976)
Etiology of Gastrointestinal Cancer Heredity vs Environment
In the current issue of the American Journal of Digestive Diseases, Bisordi and Lightdale have reported a very interesting case of a 22-year-old patient with a 16-year history of ulcerative colitis who developed colon cancer while his identical twin has been free from both ulcerative colitis and cancer (1). They postulated that the development of colon cancer superimposed on ulcerative colitis in the one case was more likely related to the inflammatory disease rather than to an independent genetic determinant. This situation raises the question of the relationship of genetic and environmental factors in the causation of gastrointestinal disease, particularly in the etiology of gastrointestinal cancer. Gastrointestinal diseases have been the subject of genetic inquiry when it is observed that there is an increased familial aggregation of a specific disease. However, in order to invoke a genetic etiology, it must be determined that environmental factors are not responsible for the increased incidence of the disease, since environmental influences may simulate the action of genes. Environmental influences may be unknown, undetected, or subject to long periods of latency before exerting clinical expression of disease. In many diseases, including cancer, some presently unknown environmental influence, such as a virus, may act early in life and result in disease later in life (2). Studies of twins have been one of the commonly applied techniques of genetic research. Studies of twins in combination with studies of other siblings may provide insight as to the importance of genetic factors. The comparative frequency of concordance and discordance in monozygotic or identical twins and dizygotic or fraternal twins may give a clue as to the importance of genetic factors in the causation
68
of a specific disease. If concordance for a disease is higher for monozygotic than for dizygotic twins, it could be regarded as evidence for a genetic influence in that condition (3). However, there are pitfalls in accepting this hypothesis completely, and as a result twin studies have fallen somewhat into disrepute. There is considerable bias in the collection of twin data. The collection of twin pairs must be systematic. Single interesting pairs as generally reported in the literature are not particularly helpful. There is a tendency to publish interesting cases. Cases of concordance of disease among monozygotic twins are more likely to be reported than concordance in dizygotic twins. There may also be errors in determining zygosity, although this becomes less likely now with HL-A typing and fingerprint analysis. Also it is likely that compared with dizygotic twins, monozygotic twins will be subjected to or choose a more exact type of environment because of their identical genetic composition and therefore be subject to these more identical environmental influences. Nevertheless, individual reports of single pairs of twins can be of value if there is discordance for the disease since, if monozygosity is unequivocal, this indicates that the condition is not completely genetic. It represents a challenge to elucidate the environmental factors concerned. This may mean that the twin with the disease is being exposed to environmental factors or the twin without the disease is being shielded by some protective environmental factor. The proof that a single gene is involved is the demonstration that predicted Mendelian ratios exist. However, most of the human diseases that appear to have some possible genetic predisposition resist analysis of specific gene difference. Manifest Digestive Diseases, Vol. 21, No. I (January 1976)
ETIOLOGY OF GASTROINTESTINAL CANCER
disease and genetic variability may be due to the combined action of a number of genes, the so-called polygenic or multifactorial inheritance. The presence or absence of clinically manifest disease may be all or none, but the underlying genetic basis may be characterized by a broad spectrum of variation in susceptibility which may reflect multifactorial inheritance. The resulting distribution of a disease in the population may therefore reflect both environmental and multifactorial genetic factors. In certain families the risk of developing cancer is much greater than in the general population. In familial polyposis and Gardner's syndrome genetic factors have been clearly demonstrated to be responsible for the increased frequency of neoplastic disease. These are precisely defined autosomal dominant diseases. There is some indication of a familial tendency in patients with colorectal cancer--a tendency that is probably multifactorial. The risk of cancer of the colon in relatives of patients with colorectal cancer is probably about three times that expected in the general population. There is suggestive evidence that patients under age 40 who develop carcinoma of the colon or rectum are more likely to have a family history of colonic cancer than those over 40 who develop the neoplasm. There are families that have been considered cancer families because of their striking incidence of malignancy at multiple anatomic sites (most frequently endometrium and colon), multiple primary malignant neoplasms, and early age of onset. A multifactorial basis may explain the occurrence of such families. However, carcinomas that appear to have a genetic basis resist analytic efforts to prove a single gene difference except for the familial polyposis syndromes (4-6). In regard to cancers that have both hereditary and nonhereditary forms, Knudson et al (7) offered the following hypothesis: The individual with the hereditary form already carries one mutation (germinal) that may lead to cancer but must get one more mutation (somatic) in order to develop the cancer. The patient with the nonhereditary form of cancer must acquire two or more new somatic mutations. As a result nonhereditary cases are of later onset than hereditary ones. Can individuals in families predisposed to develop gastrointestinal cancer be identified at an early stage of their disease, before evidence of malignancy appears? Can the phenotypic expressions of the genetic defect that increases an individual's risk of developing gastrointestinal cancer be studied and identified? Studies carried out by Lipkin and DeschDigestive Diseases, Vol. 21, No. 1 (January 1976)
ner and associates (8-10) have indicated that individuals in families predisposed to develop gastrointestinal cancer carry cells that have developed an increased ability to proliferate and to accumulate in affected regions before malignancy actually appears. Some of the changes that take place remain hidden on conventional examinations and can only be detected by special testing procedures that serve to identify them at an early stage of evolution. It was noted that abnormal proliferative activity could invariably be detected in the colonic cells of individuals in families predisposed to develop neoplasms of the colon, even before neoplastic lesions were noted. In patches of colonic mucosa epithelial cells were present that continued to synthesize and failed to repress the formation of new DNA during their lifespan as they migrated to the crypt surfaces. Patches of fiat mucosa containing these abnormal cells appeared to be foci for the formation of new excrescences that eventually developed in these patients. It was noted in other experiments utilizing a potent carcinogen, dimethylhydrazine (DMH), that the events leading to neoplastic transformation in the colon were quite similar to the events occurring in colonic epithelial cells in humans with a genetic predisposition to colon cancer (10). These findings have suggested that in both inherited and induced neoplastic disease of the colon a common defect in regulatory control of cell proliferation exists. Other observations indicate that the early manifestation of neoplastic transformation could be screened at various stages of development in individuals with familial predisposition to colon cancer. This could be demonstrated by biopsies of colon mucosa and by efficiently washing epithelial cells from the surface of the colon mucosa utilizing a dental irrigating machine (Water-Pik) and incubating the specimens with tritiated thymidine to detect the presence of abnormal proliferative changes (11-13). It would appear that the phenotypic expression of inherited disease leading to colon cancer may be identified as it becomes manifest by a failure of cells to repress DNA synthesis, progressing further in some cells to more advanced stages of adenomatosis and to cancer (8, 14, 15). Perhaps in other cells of individuals with a genetic defect leading to colon cancer, the proliferative apparatus may also not be normal and that transformation may be induced and detected by other methods (15). This would enable improved identification of individuals and families at high risk for the development of ma-
69
SHERLOCK
lignancy, entailing intensive continued surveillance and probably earlier diagnosis whicb is so crucial for increased cure rates (16). P A U L SHERLOCK, M D
Gastroenterology Service Department of Medicine Memorial Sloan-Kettering Cancer Center Department of Medicine Cornell University Medical College New York, New York REFERENCES 1. Bisordi W, Lightdale C J: Identical twins discordant for ulcerative colitis with colon cancer. Am J Dig Dis 29:71-73, 1976 2. Sherlock P: Genetics and gastrointestinal disease. Gastroenterology 53:675-677, 1967 3. McConnell RB (ed): Genetics of gastrointestinal disorders. Clinics in Gastroenterology, Voi 2. London, WB Saunders Co Ltd, 1973 4. McKusick VA: Genetics and large bowel cancer. Am J Dig Dis 19:954-957, 1974 5. Lynch HT, Krush AJ: Heredity and adenocarcinoma of the colon. Gastroenterology 53:517-527, 1967 6. Sherlock P, Lipkin M, Winawer SJ: Predisposing factors in carcinoma of the colon. Adv Intern Med 20:121-150, 1975
70
7. Knudson AG, Jr, et al: Heredity and cancer in man. Progress in Medical Genetics. AG Steinberg, AG Bearn (eds). New York, Grune & Stratton, 1973 8. Lipkin M: Phase 1 and phase 2 proliferative lesions of colonic epithelial cells leading to colon cancer. Cancer 34:878888, 1974 9. Deschner EE, Lipkin M: Proliferative patterns in colonic mucosa in familial polyposis. Cancer 35:413--418, 1975 10. Thurnherr N, Deschner EL, Stonehill EH, Lipkin M: Induction of adenocarcinomas of the colon in mice by weekly injections of l i2-dimethylhydrazine. Cancer Res 33:940-945, 1973 11. Deschner EE, Lipkin M: Studies of human rectal epithelial cells in vitro 111. RNA, protein and DNA synthesis in polyps and adjacent mucosa. J Natl Cancer Inst 44:175-185, 1970 12. Deschner EE, Long FC, Katz S: The detection of aberrant DNA synthesis in a member of a high-risk canCer family. Am J Dig Dis 20:418-424, 1975 13. Deschner EE, Long FC, Katz S: Autoradiographic method for an expanded assessment of colonic cytology. Acta Cytol 17:435438, 1973 14. Lipkin M: Proliferation and differentiation ofgastrointestinal cells. Physiol Rev 53:891-915, 1973 15. Hadden JW (ed): Familial gastrointestinal cancer--Report from Sloan-Kettering Institute. Clin Bull 5:67-69, 1975 16. Sherlock P, Winawer S J: Modern approaches to early identification of large bowel cancer. Am J Dig Dis 19:95%964, 1974
Digestive Diseases, Vol. 21, No. 1 (January 1976)
