733
Editorials The Fabric Is Sound but the Edges Are Fraying IT WAS A BAD WEEK. Rumor had it that the Centers for Disease Control might recommend mandatory human immunodeficiency virus (HIV) antibody testing for health care workers with patient care responsibilities. Reports surfaced about companies establishing unwritten rules to relieve HIV antibody-positive workers of their duties. And I was asked by an Occupational Safety and Health Administration official to discuss a new blood-borne pathogen regulation that would list discarded "female sanitary napkins" as biohazardous medical waste material. Was anxiety getting an upper hand? Were feelings overwhelming facts? Observations and data are the bases of science. Science and compassion are the bases of medicine. Since 1980, 30,000-40,000 papers on HIV have appeared in English in medical journals. Since July 1990, this journal has published 17 papers, editorials, and letters on the subject. Topics ranged from basic science to diagnosis, treatment, ethics, and effects on public health, attitudes, and the profession. Yet another paper appears in this issue. I Data are certainly available. How can we use them to counter forces that lead to panic and chaos? * We must read. We need to read more than headlines, recalling that the purpose of headlines is to attract, to sell, not to educate. * We must remember the dictum we learned in pharmacology courses: One should not be the first, nor the last, to get on the bandwagon. Prescribing practices should not be swayed by the first paper about a drug, since additional information must be collected before safety and efficacy can be assured. On the other hand, one should learn about recent developments and modify the armamentarium when indicated. The same caveat holds true as we develop policies about HIV transmission and disease. One example out of millions of incidents is cause for interest and study but not for sweeping change. * We must provide a steady supply of data-based information to our patients and the media, for we know that "fear of AIDS [is] inversely correlated with knowledge."2 Physicians have been a source of strength during past plagues, wars, and other disasters. Our fair-mindedness, our well-informed actions, our integrity help society stay tightly knit. Our steadiness, our direction, and our guidance help bind families and communities. Physicians' willingness to stay the course, to learn, to speak about HIV is crucial as nightmarish situations and proposals threaten to tear society apart. It isn't easy to insist upon more research when we are pressed for immediate but intemperate action in response to fear. Indeed, it takes courage to rely upon facts rather than emotions. Bertolt Brecht's play, Galileo, follows the great scientist's life as it was affected by his heliocentric theory of the solar system. Galileo recanted his theory when he appeared before the Inquisition. In Brecht's recounting, Galileo regrets abandoning his position, regrets caving in to coercion: "The practice of science would seem to call for valor . . . . As a scientist I had an almost unique opportunity . . . . Had one man put up a fight, it could have had wide repercussions. I have come to believe that I was never in real danger . . . I have betrayed my profession."3 Just as observa-
tions, data, and compassion are necessary for good medicine, courage is also necessary as we work to reknit the ravelling sleeve HIV has presented to us. LINDA HAWES CLEVER, MD
REFERENCES 1. Kates DM, Sparling TG, Jetha N, Burdge DR: Alteration of the natural history of Pneumocystis carinii infection in patients with acquired immunodeficiency syndrome receiving aerosolized pentamidine. West J Med 1991; 154:721-723 2. Marshall PA, O'Keefe JP, Fisher SG, Caruso AJ, Surdukowski J: Patients' fear of contracting the acquired immunodeficiency syndrome from physicians. Arch Intern Med 1990; 150:1501-1506 3. Brecht B: Galileo. New York, Grove Weidenfeld, 1966, p 123-124
The Molecular Genetics of Colorectal Carcinoma-Knowledge for Knowledge's Sake? THE MOLECULAR GENETICS of colorectal carcinoma are among the best understood of any common human cancer. Progress in this area has been aided by the nature of the disease. Colorectal carcinoma is frequent in the United States population: It is the second most common cause of cancer deaths, resulting in about 60,000 deaths yearly. Approximately 110,000 new cases of colonic carcinoma and 45,000 new cases of rectal carcinoma occur each year.1 As a consequence, neoplasms for study are readily available. Second, the usual precursor lesion of colorectal carcinoma, the colorectal adenoma, is accessible at various stages in its development in specimens from surgical resection and colonoscopic polypectomy. This availability is in stark contrast to most human cancers in which the precursor cannot be obtained and studied easily. In addition, inheritance plays an important role in colorectal carcinoma. Two autosomal dominant syndromes are recognized. One, the adenomatous polyposis syndrome, predisposes to malignancy by producing hundreds to thousands of colorectal adenomas, with carcinoma occurring mainly in the left colon. The other syndrome, the hereditary nonpolyposis colorectal cancer syndrome, produces few adenomas (hence "nonpolyposis"), with carcinoma occurring mainly in the right and transverse colon. Knudson's hypothesis that the same genes are involved in the genesis of sporadic and inherited forms of a tumor2 suggests that these syndromes will provide important clues, and such has been the case. The APC [adenomatous polyposis coli] locus on the long arm of chromosome 53 and the MCC [mutated in colorectal carcinoma] gene in the same region4 are altered frequently in "sporadic" colorectal cancer. Less well-defined inheritance of colorectal carcinoma is also evident. Pedigree studies of large families have suggested that the ability to form colorectal adenomas is inherited as an autosomal dominant characteristic.' Furthermore, the occurrence of colorectal cancer in first-degree relatives (parents, siblings, and offspring) of patients with the disease is about three to four times that of the general population.6 Finally, environmental, particularly dietary, factors are well known to have a key role in the genesis of colorectal cancer, especially carcinomas of the left colon.' "Sporadic" carcinomas of the right and left colon have different molecular genetic alterations, with deletion of the p53 gene on the short arm of chromosome 17 a nearly universal finding in left colonic carcinomas but less common in right colonic carcinomas.8 Thus, the groundwork for understanding the interaction of
734
environment and heredity is laid in colorectal carcinoma to a greater extent than in most other human cancers. In this issue of the journal, Dennis Ahnen, MD, reviews the current state of knowledge of the genetics of colorectal cancer. He points out the complexity of the situation, with involvement of both dominant-acting oncogenes (ras, myc, src9) and suppressor genes that undergo inactivation or loss (DCC,10 p53, APC/MCC, and probably loci on the short arm of chromosome 11 and the long arm of chromosome 2212). In addition, allelotyping of colorectal cancers reveals allelic deletions throughout the genome of some tumors,.3 raising the possibility of additional suppressor genes. As a further complicating feature, the phenotypic effects of altered suppressor genes can be produced by various mechanisms. In some suppressor genes, both alleles undergo inactivation, usually by mutation and deletion, eliminating all normal gene product. In other suppressor genes, however, mutation of one allele may exert an effect because the abnormal gene product eliminates the function of the remaining normal gene product (dominant negative effect). Alternatively, dosage effect may occur with the loss of one allele leaving insufficient normal gene product to maintain normal phenotype.14 The complex alterations in oncogenes and suppressor genes have been shown to accumulate in the adenoma-carcinoma sequence with evidence of a preferential order."5't6 Altered DNA methylation is an especially early event, evident even in small adenomas.17 18 Ahnen points out the potential benefits of this increasing knowledge in identifying high-risk populations for better prevention, screening, and intervention strategies to augment or replace current cytotoxic therapy. One of the frustrating aspects of the molecular genetics of colorectal carcinoma is the slow rate of the clinical application of knowledge to improved patient management. True, patients who have inherited the abnormal gene for the adenomatous polyposis syndrome can now be identified before the appearance of colorectal adenomas through the use of linkage analysis with molecular genetic probes near the APC gene. The same results can be obtained in most families, however, by careful indirect ophthalmoscopic examination of the retina for pigmented ocular fundic lesions manifested in affected persons at birth. 19,20 In addition, linkage analysis requires the availability of DNA from known affected family members. As a consequence, patients with a new mutation of the APC gene, as contrasted with familial cases, cannot be identified by linkage analysis. Even more frustrating, the adenomatous polyposis syndrome accounts for far less than 1% of all colorectal cancers, and the hereditary nonpolyposis form appears to account for about 5%. Thus, the successful application of molecular genetics in these syndromes will not make much of a dent in the overall morbidity and mortality from colorectal carcinoma in the US population. On the other hand, if the hypothesis of an inherited predisposition to apparently sporadic colorectal cancer is borne out and clarified, molecular genetics may lead to more accurate risk assessment for the general population. For screening and early detection of the disorder, the field of molecular genetics also has potential application. Perhaps detection in the feces of DNA with characteristic molecular genetic abnormalities from shed tumor cells may supplant the woefully inadequate fecal occult blood testing that is the current mainstay for screening. In the areas of surgical and medical therapy, molecular genetics may supplement staging
EDITORIALS
in assessing the prognosis of patients with colorectal cancer: Primary tumors with deletion of the DCC gene, deletion of the p53 gene, or high fractional allelic loss (a high proportion of evaluable nonacrocentric autosomal arms showing deletion) are associated with a poorer prognosis.8 The application of molecular genetics may eventually help in making decisions about the type of surgical resection-local excision versus abdominoperineal resection for rectal carcinomaand in selecting patients for adjuvant chemotherapy and radiotherapy.1 These possible applications require additional investigation. We can even dream of gene therapy to correct key molecular genetic abnormalities if the technology becomes available: Inserting in vitro wild-type p53 gene into a colonic carcinoma cell line lacking the p53 gene product dramatically suppressed colony formation and DNA synthesis in the subpopulation of tumor cells that expressed the inserted gene.21 Alternatively, pharmacologic agents to mimic normal gene function in tumor cells may be feasible to correct their neoplastic characteristics. The next several years should be exciting ones for research in the genetics of large bowel cancer. Let us hope that the results will benefit the large number of patients afflicted with the disease and not lead to only knowledge for knowledge's sake.
STANLEY R. HAMILTON, MD Department of Pathology and Oncology Center The Johns Hopkins University School of Medicine and Hospital
Baltimore, Maryland REFERENCES
1. Adjuvant therapy for patients with colon and rectal cancer (NIH Consensus Conference). JAMA 1990; 264:1444-1450 2. Knudson AG Jr: Hereditary cancers: Clues to mechanisms of carcinogenesis. Br J Cancer 1989; 59:661-666 3. Dunlop MG, Wyllie AH, Nakamura Y, et al: Genetic linkage map of six polymorphic DNA markers around the gene for familial adenomatous polyposis on chromosome 5. Am J Hum Genet 1990; 47:982-987 4. Kinzler KW, Nilbert MC, Vogelstein B, et al: Identification of a gene located at chromosome 5q2 that is mutated in colorectal cancers. Science 1991; 251:1366-1370 5. Cannon-Albright LA, Skolnick MH, Bishop T, Lee RG, Burt RW: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N EngI J Med 1988; 319:533-537 6. Hamilton SR: Genetic susceptibility to colorectal carcinoma, In Devita VT Jr, Hellman S, Rosenberg SA (Eds): Cancer Prevention. Philadelphia, Pa. JB Lippincott, 1990, pp I -I I, in press 7. Bufill JA: Colorectal cancer: Evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990; 113:779-788 8. Kern SE, Fearon ER, Tersmette KWF, et al: Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected titlel. JAMA 1989: 261:30993103; 262:1952 9. Cartwright CA, Camps MP, Meisler Al, Pipas JM, Eckhart W: pp60c-src activation in human colon carcinoma. J Clin Invest 1990; 83:2025-2033 10. Fearon ER, Cho KR, Nigro JM, et al: Identification of a chromosome 1 8q gene which is altered in colorectal cancers. Science 1990; 247:49-56 11. Leister 1, Weith A, Bruderlein S, et al: Human colorectal cancer: High frequency of deletions at chromosome I p35. Cancer Res 1990; 50:7232-7235 12. Miyaki M, Seki M, Okamoto M, et al: Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis. Cancer Res 1990; 50:7166-7173 13. Vogelstein B, Fearon ER. Kern SE, et al: Allelotype of colorectal carcinomas. Science 1989; 244:207-21 1 14. Baker SJ, Preisinger AC, Jessup JM, et al: p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 1990; 50:7717-7722 15. Vogelstein B, Fearon ER, Hamilton SR, et al: Genetic alterations during colorectal-tumor development. N EngI J Med 1988; 319:525-532 16. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990; 61:759-767 17. 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 USA 1991; 88:3470-3474 18. Silverman AL, Park JG, Hamilton SR, Gazdar AF, Luk GD, Baylin SB: Abnormal methylation of the calcitonin gene in human colonic neoplasms. Cancer Res 1989;
49:3468-3473 19. Traboulsi El, Maumenee IH, Krush AJ, et al: Congenital hypertrophy of the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome. Arch Ophthalmol 1990; 108:525-526 20. Traboulsi El, Murphy SF, de la Cruz ZC, Maumenee IH, Green WR: A -with extracolonic clinicopathologic study of the eyes in familial adenomatous polyposis manifestations (Gardner's syndrome). Am J Ophthalmol 1990; 110:550-561 21. Baker SJ, Markowitz S, Fearon ER, Willson JKV, Vogelstein B: Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990: 249:912-915
Editorials The Fabric Is Sound but the Edges Are Fraying IT WAS A BAD WEEK. Rumor had it that the Centers for Disease Control might recommend mandatory human immunodeficiency virus (HIV) antibody testing for health care workers with patient care responsibilities. Reports surfaced about companies establishing unwritten rules to relieve HIV antibody-positive workers of their duties. And I was asked by an Occupational Safety and Health Administration official to discuss a new blood-borne pathogen regulation that would list discarded "female sanitary napkins" as biohazardous medical waste material. Was anxiety getting an upper hand? Were feelings overwhelming facts? Observations and data are the bases of science. Science and compassion are the bases of medicine. Since 1980, 30,000-40,000 papers on HIV have appeared in English in medical journals. Since July 1990, this journal has published 17 papers, editorials, and letters on the subject. Topics ranged from basic science to diagnosis, treatment, ethics, and effects on public health, attitudes, and the profession. Yet another paper appears in this issue. I Data are certainly available. How can we use them to counter forces that lead to panic and chaos? * We must read. We need to read more than headlines, recalling that the purpose of headlines is to attract, to sell, not to educate. * We must remember the dictum we learned in pharmacology courses: One should not be the first, nor the last, to get on the bandwagon. Prescribing practices should not be swayed by the first paper about a drug, since additional information must be collected before safety and efficacy can be assured. On the other hand, one should learn about recent developments and modify the armamentarium when indicated. The same caveat holds true as we develop policies about HIV transmission and disease. One example out of millions of incidents is cause for interest and study but not for sweeping change. * We must provide a steady supply of data-based information to our patients and the media, for we know that "fear of AIDS [is] inversely correlated with knowledge."2 Physicians have been a source of strength during past plagues, wars, and other disasters. Our fair-mindedness, our well-informed actions, our integrity help society stay tightly knit. Our steadiness, our direction, and our guidance help bind families and communities. Physicians' willingness to stay the course, to learn, to speak about HIV is crucial as nightmarish situations and proposals threaten to tear society apart. It isn't easy to insist upon more research when we are pressed for immediate but intemperate action in response to fear. Indeed, it takes courage to rely upon facts rather than emotions. Bertolt Brecht's play, Galileo, follows the great scientist's life as it was affected by his heliocentric theory of the solar system. Galileo recanted his theory when he appeared before the Inquisition. In Brecht's recounting, Galileo regrets abandoning his position, regrets caving in to coercion: "The practice of science would seem to call for valor . . . . As a scientist I had an almost unique opportunity . . . . Had one man put up a fight, it could have had wide repercussions. I have come to believe that I was never in real danger . . . I have betrayed my profession."3 Just as observa-
tions, data, and compassion are necessary for good medicine, courage is also necessary as we work to reknit the ravelling sleeve HIV has presented to us. LINDA HAWES CLEVER, MD
REFERENCES 1. Kates DM, Sparling TG, Jetha N, Burdge DR: Alteration of the natural history of Pneumocystis carinii infection in patients with acquired immunodeficiency syndrome receiving aerosolized pentamidine. West J Med 1991; 154:721-723 2. Marshall PA, O'Keefe JP, Fisher SG, Caruso AJ, Surdukowski J: Patients' fear of contracting the acquired immunodeficiency syndrome from physicians. Arch Intern Med 1990; 150:1501-1506 3. Brecht B: Galileo. New York, Grove Weidenfeld, 1966, p 123-124
The Molecular Genetics of Colorectal Carcinoma-Knowledge for Knowledge's Sake? THE MOLECULAR GENETICS of colorectal carcinoma are among the best understood of any common human cancer. Progress in this area has been aided by the nature of the disease. Colorectal carcinoma is frequent in the United States population: It is the second most common cause of cancer deaths, resulting in about 60,000 deaths yearly. Approximately 110,000 new cases of colonic carcinoma and 45,000 new cases of rectal carcinoma occur each year.1 As a consequence, neoplasms for study are readily available. Second, the usual precursor lesion of colorectal carcinoma, the colorectal adenoma, is accessible at various stages in its development in specimens from surgical resection and colonoscopic polypectomy. This availability is in stark contrast to most human cancers in which the precursor cannot be obtained and studied easily. In addition, inheritance plays an important role in colorectal carcinoma. Two autosomal dominant syndromes are recognized. One, the adenomatous polyposis syndrome, predisposes to malignancy by producing hundreds to thousands of colorectal adenomas, with carcinoma occurring mainly in the left colon. The other syndrome, the hereditary nonpolyposis colorectal cancer syndrome, produces few adenomas (hence "nonpolyposis"), with carcinoma occurring mainly in the right and transverse colon. Knudson's hypothesis that the same genes are involved in the genesis of sporadic and inherited forms of a tumor2 suggests that these syndromes will provide important clues, and such has been the case. The APC [adenomatous polyposis coli] locus on the long arm of chromosome 53 and the MCC [mutated in colorectal carcinoma] gene in the same region4 are altered frequently in "sporadic" colorectal cancer. Less well-defined inheritance of colorectal carcinoma is also evident. Pedigree studies of large families have suggested that the ability to form colorectal adenomas is inherited as an autosomal dominant characteristic.' Furthermore, the occurrence of colorectal cancer in first-degree relatives (parents, siblings, and offspring) of patients with the disease is about three to four times that of the general population.6 Finally, environmental, particularly dietary, factors are well known to have a key role in the genesis of colorectal cancer, especially carcinomas of the left colon.' "Sporadic" carcinomas of the right and left colon have different molecular genetic alterations, with deletion of the p53 gene on the short arm of chromosome 17 a nearly universal finding in left colonic carcinomas but less common in right colonic carcinomas.8 Thus, the groundwork for understanding the interaction of
734
environment and heredity is laid in colorectal carcinoma to a greater extent than in most other human cancers. In this issue of the journal, Dennis Ahnen, MD, reviews the current state of knowledge of the genetics of colorectal cancer. He points out the complexity of the situation, with involvement of both dominant-acting oncogenes (ras, myc, src9) and suppressor genes that undergo inactivation or loss (DCC,10 p53, APC/MCC, and probably loci on the short arm of chromosome 11 and the long arm of chromosome 2212). In addition, allelotyping of colorectal cancers reveals allelic deletions throughout the genome of some tumors,.3 raising the possibility of additional suppressor genes. As a further complicating feature, the phenotypic effects of altered suppressor genes can be produced by various mechanisms. In some suppressor genes, both alleles undergo inactivation, usually by mutation and deletion, eliminating all normal gene product. In other suppressor genes, however, mutation of one allele may exert an effect because the abnormal gene product eliminates the function of the remaining normal gene product (dominant negative effect). Alternatively, dosage effect may occur with the loss of one allele leaving insufficient normal gene product to maintain normal phenotype.14 The complex alterations in oncogenes and suppressor genes have been shown to accumulate in the adenoma-carcinoma sequence with evidence of a preferential order."5't6 Altered DNA methylation is an especially early event, evident even in small adenomas.17 18 Ahnen points out the potential benefits of this increasing knowledge in identifying high-risk populations for better prevention, screening, and intervention strategies to augment or replace current cytotoxic therapy. One of the frustrating aspects of the molecular genetics of colorectal carcinoma is the slow rate of the clinical application of knowledge to improved patient management. True, patients who have inherited the abnormal gene for the adenomatous polyposis syndrome can now be identified before the appearance of colorectal adenomas through the use of linkage analysis with molecular genetic probes near the APC gene. The same results can be obtained in most families, however, by careful indirect ophthalmoscopic examination of the retina for pigmented ocular fundic lesions manifested in affected persons at birth. 19,20 In addition, linkage analysis requires the availability of DNA from known affected family members. As a consequence, patients with a new mutation of the APC gene, as contrasted with familial cases, cannot be identified by linkage analysis. Even more frustrating, the adenomatous polyposis syndrome accounts for far less than 1% of all colorectal cancers, and the hereditary nonpolyposis form appears to account for about 5%. Thus, the successful application of molecular genetics in these syndromes will not make much of a dent in the overall morbidity and mortality from colorectal carcinoma in the US population. On the other hand, if the hypothesis of an inherited predisposition to apparently sporadic colorectal cancer is borne out and clarified, molecular genetics may lead to more accurate risk assessment for the general population. For screening and early detection of the disorder, the field of molecular genetics also has potential application. Perhaps detection in the feces of DNA with characteristic molecular genetic abnormalities from shed tumor cells may supplant the woefully inadequate fecal occult blood testing that is the current mainstay for screening. In the areas of surgical and medical therapy, molecular genetics may supplement staging
EDITORIALS
in assessing the prognosis of patients with colorectal cancer: Primary tumors with deletion of the DCC gene, deletion of the p53 gene, or high fractional allelic loss (a high proportion of evaluable nonacrocentric autosomal arms showing deletion) are associated with a poorer prognosis.8 The application of molecular genetics may eventually help in making decisions about the type of surgical resection-local excision versus abdominoperineal resection for rectal carcinomaand in selecting patients for adjuvant chemotherapy and radiotherapy.1 These possible applications require additional investigation. We can even dream of gene therapy to correct key molecular genetic abnormalities if the technology becomes available: Inserting in vitro wild-type p53 gene into a colonic carcinoma cell line lacking the p53 gene product dramatically suppressed colony formation and DNA synthesis in the subpopulation of tumor cells that expressed the inserted gene.21 Alternatively, pharmacologic agents to mimic normal gene function in tumor cells may be feasible to correct their neoplastic characteristics. The next several years should be exciting ones for research in the genetics of large bowel cancer. Let us hope that the results will benefit the large number of patients afflicted with the disease and not lead to only knowledge for knowledge's sake.
STANLEY R. HAMILTON, MD Department of Pathology and Oncology Center The Johns Hopkins University School of Medicine and Hospital
Baltimore, Maryland REFERENCES
1. Adjuvant therapy for patients with colon and rectal cancer (NIH Consensus Conference). JAMA 1990; 264:1444-1450 2. Knudson AG Jr: Hereditary cancers: Clues to mechanisms of carcinogenesis. Br J Cancer 1989; 59:661-666 3. Dunlop MG, Wyllie AH, Nakamura Y, et al: Genetic linkage map of six polymorphic DNA markers around the gene for familial adenomatous polyposis on chromosome 5. Am J Hum Genet 1990; 47:982-987 4. Kinzler KW, Nilbert MC, Vogelstein B, et al: Identification of a gene located at chromosome 5q2 that is mutated in colorectal cancers. Science 1991; 251:1366-1370 5. Cannon-Albright LA, Skolnick MH, Bishop T, Lee RG, Burt RW: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N EngI J Med 1988; 319:533-537 6. Hamilton SR: Genetic susceptibility to colorectal carcinoma, In Devita VT Jr, Hellman S, Rosenberg SA (Eds): Cancer Prevention. Philadelphia, Pa. JB Lippincott, 1990, pp I -I I, in press 7. Bufill JA: Colorectal cancer: Evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990; 113:779-788 8. Kern SE, Fearon ER, Tersmette KWF, et al: Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected titlel. JAMA 1989: 261:30993103; 262:1952 9. Cartwright CA, Camps MP, Meisler Al, Pipas JM, Eckhart W: pp60c-src activation in human colon carcinoma. J Clin Invest 1990; 83:2025-2033 10. Fearon ER, Cho KR, Nigro JM, et al: Identification of a chromosome 1 8q gene which is altered in colorectal cancers. Science 1990; 247:49-56 11. Leister 1, Weith A, Bruderlein S, et al: Human colorectal cancer: High frequency of deletions at chromosome I p35. Cancer Res 1990; 50:7232-7235 12. Miyaki M, Seki M, Okamoto M, et al: Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis. Cancer Res 1990; 50:7166-7173 13. Vogelstein B, Fearon ER. Kern SE, et al: Allelotype of colorectal carcinomas. Science 1989; 244:207-21 1 14. Baker SJ, Preisinger AC, Jessup JM, et al: p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 1990; 50:7717-7722 15. Vogelstein B, Fearon ER, Hamilton SR, et al: Genetic alterations during colorectal-tumor development. N EngI J Med 1988; 319:525-532 16. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990; 61:759-767 17. 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 USA 1991; 88:3470-3474 18. Silverman AL, Park JG, Hamilton SR, Gazdar AF, Luk GD, Baylin SB: Abnormal methylation of the calcitonin gene in human colonic neoplasms. Cancer Res 1989;
49:3468-3473 19. Traboulsi El, Maumenee IH, Krush AJ, et al: Congenital hypertrophy of the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome. Arch Ophthalmol 1990; 108:525-526 20. Traboulsi El, Murphy SF, de la Cruz ZC, Maumenee IH, Green WR: A -with extracolonic clinicopathologic study of the eyes in familial adenomatous polyposis manifestations (Gardner's syndrome). Am J Ophthalmol 1990; 110:550-561 21. Baker SJ, Markowitz S, Fearon ER, Willson JKV, Vogelstein B: Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990: 249:912-915
