The Genetics of Colorectal Carcinoma*

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1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 24, No. 4 Copyright 1994, Institute for Clinical Science, Inc. The Genetics of Colorectal Carcinoma* KENDALL KANE, M.D. Good Samaritan Hospital and Health Center, Dayton, OH ABSTRACT Colorectal neoplasms begin as monoclonal cell populations, presumably arising from a single mutation or from a series of mutations in a single epithelial cell. Identification of the earliest mutation has been elusive. The resulting neoplastic clone is genetically unstable, perhaps owing to reduced methyl content of the deoxyribonucleic acid (DNA) molecules. Loss of DNA repair mechanisms may also be a factor. There are multiple genetic pathways to colorectal carcinoma (CRC). The multiplicity of mutations which are often associated with carcinogenesis suggests that the cancer cell is specifically adapted to its parasitic role. This is especially apparent when cancer cells become capable of invasion and metastasis. Early therapeutic experiments in vitro suggest that the carcinogenic process may be disrupted by correction of any one of the multiple genetic defects. Background Carcinoma of the colon and rectum accounts for over 56,000 deaths annually in the United States.1 The disease is the third leading cause of cancer deaths among both men and women. It has long been recognized that there is a tendency for colorectal cancer to occur within families. An individual who has a close relative with CRC has approximately a threefold increased risk relative to the general population2 and should be screened for the disease at regular intervals. The disease is so common that population studies have not been able reliably to distinguish between true hereditary familial * Send reprint requests to: Kendall Kane, M.D., Department of Pathology, Good Samaritan Hospital and Health Center, 2222 Philadelphia Drive, Dayton, OH clusters and random clusters.3 Recent discoveries have begun to make this separation possible. Heredity and Environment Environment and heredity interact in the etiology of CRC and other cancers. One factor or the other may predominate in particular circumstances. Patients with familial adenomatous polyposis (FAP), which has long been known to follow strict Mendelian rules of heredity, inevitably develop carcinoma if the patient lives to age 50 or beyond.4 On the other hand, most cases of CRC appear to arise sporadically with no identifiable initiating cause. Environmental factors clearly play a role in sporadic carcinoma. The incidence of CRC correlates positively with total intake of fat and calories, show /94/ $01.20 Institute for Clinical Science, Inc.

2 288 KANE ing the effect of environment.2 Further, diets, high in fiber, which are derived from fruits and vegetables, have a protective role against the disease. The benefit of a diet high in cereal fiber is less well established. Research is rapidly expanding our knowledge of genetic influences on the origins of CRC. Further advances will lead to a better understanding of the interaction between heredity and environm ent. H ow ever, all cancers are thought to develop through the common mechanism of damage to the genome. According to this view ALL cancer is genetic in nature but NOT ALL cancer is hereditary. Carcinogenesis and Multiple Mutations Adenocarcinoma of the colon and rectum has long b een known to arise through the intermediate stage of adenomatous epithelium, usually in the form of adenomatous polyps or villous adenomas.5 This progression takes many years. For this reason Vogelstein et al chose this tumor to see if the progress of the neoplasm through adenoma to malignancy might correlate with mutations in the genom e.6 They studied 172 colorectal specimens including many polyps from patients with and without FAP, sporadic polyps w hich had undergone p a rtia l m a lig n a n t tra n sfo rm a tio n, and adenocarcinomas. Our previous understanding of hereditary malignancy was based on the concept that specific m alignancies are caused by mutations at one locus. This model serves to explain the hereditary patterns of retinoblastoma, of W ilm s tumor and of certain other malignancies, especially those which arise in childhood.7 In contrast, the Vogelstein group found that an accum ulation of many mutations, occurring at multiple loci, was required for the development of colorectal malignancy. The mutations tended to occur in a loosely ordered sequence. Four different loci were studied because of their previously known association with CRC. These will be discussed in their approximate order of appearance (figure 1). (1) Ras-gene mutations were usually the first to be found. Some but not all of these are found on the short arm of chromosome 12. These occur as point mutations and tend to be dominant. Ras-genes are proto-oncogenes, the products of which normally serve as important transmembrane messenger regulators. Alteration of the gene product by mutation F i g u r e 1. O c c u r rence of mutations with p ro g r e s s iv e d is e a s e. C lass I adenom as are from patients with FA P. Class II adenom as are from sporadic colorectal polyps. Class III adenomas are b enig n tissu e from adenom as w hich focally have developed carcinoma. Reprinted by perm ission o f the New E ngl J M ed 1988;319: Adenoma Adenoma Adenoma Type of Tumor

3 may lead to continuous and inappropriate stimulatory signals to the interior of the cell and to the nucleus. Ras-gene mutations were found in only 9 percent of adenomas less than 1 cm in size, but in 58 percent of larger adenomas, and in 47 percent of carcinomas. The remaining three loci which were studied are characterized by deletion of chromosomal information or by recombination defects. T hese chrom osom al abnorm alities suggest that the genes which are deleted or distorted would normally exhibit tumor suppressor activity. T he defects are u sually recessive. Because multiple loci are involved and because of the recessive character of tumor suppressor genes, one reviewer estimates that it requires eight to ten different mutations to cause sporadic CRC.8 (2) Deletions from the long arm of chromosome 5 are often the second genetic event in the evolution of CRC. This region is associated with the gene APC (Adenomatous Polyposis Coli) which causes FAP as well as sporadic CRC. Deletions or mitotic recombinations of chromosome band 5q were found in 29 percent of adenomas of sporadic origin (but not in adenomas from FAP patients, as will be discussed later). Thus, rasgene m utations and chrom osome 5q deletions tend to occur early in the neoplastic progression. (3) Deletions of the long arm of chromosome 18 occur in the region of the gene DCC (for D eleted in Colorectal Carcinoma). The DCC gene may code for a cell adhesion molecule,7 the lack of which would favor cellular dyshesion and m alignancy. This chrom osom al region was usually not altered in adenomatous tissue but was found to be defective in 73 percent of carcinomas. (4) Deletions from the short arm of chromosome 17 result in loss or abnormality of the tumor suppressor protein p53. Chromosome 17 abnormalities were not often seen in adenomas but were the most common defect in carcinomas, GENETICS OF COLORECTAL CARCINOMA 289 being present in 75 percent. D evelopment of the chromosome 17 defect was frequently associated with progression of individual tumors from adenoma to carcinoma. Further, loss or abnormalities of protein p53 have been found to occur in many other hum an cancers including breast, lung, b lad der and brain.9 Clearly, the normal p53 product is an important tumor suppressor agent, the absence of which strongly predisposes toward carcinogenesis. APC Gene Mutations as the Cause of FAP and of Sporadic Colorectal Carcinoma The long arm of chromosome 5 contains at least six genes w hich are expressed in normal colonic mucosa.10 The APC gene is located in chromosomal band 5q21. The normal allele of APC is expressed in normal colonic mucosa and in other adult and fetal tissues. However, mutations in the region of chromosomal band 5q21 are associated with the development of polyps in many FAP kindreds. Point gene mutations of APC are found in the germ line of patients with FAP and with Gardner s Syndrome (GS)11 (which is considered to be a variant of FAP). The gene causing FAP is dominantly inherited with 80 to 100 percent penetrance.4 The fact that the defect is transmitted through the germ line accounts for the Mendelian pattern of heredity for FAP. In contrast, deletion of somatic APC genes is found in sporadic colorectal adenomas and carcinoma as has been discussed previously. The germ line is normal. Loss of alleles within the 5q21 band is seen in adenomas as small as 5 mm. This may be the earliest genetic alteration in sporadic CRC.11 The gene MCC (for Mutated in Colorectal Carcinoma) is very closely linked to the APC gene on chromosome 5. Point mutations occur in both MCC and APC m uch m ore com m only than in the genome in general, possibly because the

4 2 9 0 KANE cells containing either mutation have a selective growth advantage. The MCC and APC genes appear to reside at independent but closely linked loci, either of which, in the mutated state, may lead to sporadic CRC. It is estimated that at least 15 percent of CRC contain gross structural alterations or point mutations of MCC. Mutations of MCC are found only in sporadic CRC and do not correlate with FAP. Familial Colon Carcinoma The previous discussion has been concerned almost exclusively with CRC which arises sporadically. The only exception has been the hereditary carcinoma which inevitably arises in patients with FAP, accounting for approximately 1 percent of CRC.3 A second clinical picture of hereditary CRC is designated H ereditary N onpolyposis Colorectal Cancer (HNPCC) which is estimated to include 13 percent of all CRC. It is defined by the presence of three or more members of a family with CRC in two or more successive generations with at least one member diagnosed before age T h e H N P C C p a tie n ts are also at increased risk for cancer of the stomach, biliopancreatic system, and urinary tract.3 A new mutation on chromosome 2 has recently been described which correlates with the clinical pattern of HNPCC.3,12 The defective gene is called FCC (for Familial Colon Carcinoma).13 The nature of the genetic defect is unique in that it is characterized by marked variation in the number of DNA sequences called microsatellites. Microsatellites are short, noncoding DNA repeat sequences which are a normal component of the genetic structure. Microsatellites normally replicate and are inherited in an orderly and stable fashion. However, when the FCC gene is defective, the number of microsatellite repeats is usually erratically increased at various loci. At other loci, the repeat sequences may be decreased. Further, marked variation in microsatellite repeat number is not limited to chromosome 2 (which contains the defective allele) but is noted on other chromosomes throughout the genome. The original mutation apparently causes extensive replication errors, i.e., multiple secondary mutations, during DNA replication. Carcinomas which are associated with the FCC gene defect have a high frequency of other genetic defects including ras-gene and p53 abnormalities,12 paralleling the findings by Vogelstein et al in sporadic colorectal cancers. The FCC gene has not yet been isolated. T hus, its DNA seq u en ce is unknown. The mutation does not appear to be an allelic loss, suggesting that this is not a tumor suppressor gene. Rather, the wild-type allele seems to be required for normal DNA replication involving microsatellite loops. The FCC gene accounts for approximately 13 percent of all colorectal cancers.12 It is estimated that one person in 200 carries the gene.13 Prior to the discovery of FCC, these cancers had been considered to be sporadic but vaguely familial. Fortunately, the FCC gene is very closely lin k ed to the m arker sequence D2S123. It is now possible to reclassify such cases as hereditary if they show linkage to a D2S123 allele which is associated with carcinoma within the kindred. Persons who carry the FCC gene should be closely observed for colonic polyps and for carcinomas as well as for the other tumors in the FCC complex including carcinoma of the stomach, biliopancreatic system, and urinary tract. Carcinomas of the endom etrium and ovary may also be associated with the FCC gene.13 Colon carcinoma which is associated with the FCC gene has a characteristic clinical profile. The cancers occur in the

5 right colon and have a relatively favorable prognosis.12 It is not yet clear w hether or not these carcinomas pass through an intermediate stage of adenomatous polyps. However, the FCC mutation does not cause the spectacular polyposis which is seen in FAP. Genetics of Invasion and Metastasis Accelerated growth, increased cell longevity, and increased cell mass are common characteristics of adenomas and carcinomas. Invasion and destruction of adjacent normal tissue are characteristic of carcinoma. Malignant cells must be able to exert proteolysis directed toward the invaded tissue, followed by movement into that tissue. Metastasis requires invasion plus the ability for malignant cells to enter and to survive in a new environment, (e.g., blood, lymphatics, or serous spaces). Malignant tumor emboli must then be able to invade tissue at a distant site and to colonize there. The complexity of these processes leads us to consider that cancer cells, especially those which metastasize, are not merely randomly destructive, but rather resemble carefully adapted parasites. It is believed that many cancers, as a result of genetic instability, develop multiple malignant clones within the primary tumor. An individual clone may acquire selective growth and survival advantage by developing the capacity to m etastasize. This concept has led to a search for a m etastatic phenotype which probably involves many individual genes.14 It has been possible to bestow metastatic ability onto previously non-metastatic tumorigenic cells by transfection, implanting specific DNA sequences into recipient cells by means of viruses. Transfer of single oncogenes has achieved this effect, converting nonmetastasizing cells into cells capable of metastasis. GENETICS OF COLORECTAL CARCINOMA 291 Therapeutic Implications The view that cancer cells are highly adapted through m ultiple m utations offers new insight into future treatment possibilities. The complexity of the cancer adaptation makes it vulnerable to intervention at any of several stages. Early in vitro results utilizing this concept have been impressive. One study performed viral transfection experiments on human colorectal cancer cell lines which were mutant for the p53 gene.15 When the cancer cells were successfully transfected with a wild-type p53 gene carried by a cytomegalovirus, the growth of the malignant cell line was effectively suppressed. Growth of colorectal cancer cells has also been disrupted by implantation of single normal chromosomes into the malignant cell line.16 The malignant cells contained mutations of gene APC on chromosome 5 (5q21), gene p53 on chromosome 17 (17pl3) and possibly gene DCC on chromosome 18 (18q21). Indiv id u al hum an chrom osom es w ere implanted by means of microcell fusion. When chromosome 17 was implanted, providing wild-type p53, then no viable cell colonies could be obtained. In contrast, implantation of the irrelevant chromosome 15 as a control left the malignant cells unchanged in m orphology and growth dynamics. Implantation of chromosome 5 resulted in cells which were morphologically different from the parent malignant cells and were markedly impaired in tumorigenicity. It was concluded that correction of any one of several mutations was sufficient to disrupt the malignant process. The practical task of correcting a genetic defect in a living organism is formidable. It has been possible to implant a h ealth y cystic fibrosis gene into afflicted mice using plasmids as gene carriers applied directly to the airway.17 Viruses may serve as transfecting agents

6 2 9 2 KANE F i g u r e 2. C um ulative number of mutations o b se rv e d at d iffe re n t s ta g e s o f n e o p la s ia. Progression of neoplasia is a sso c ia te d w ith an in c re a s e d n u m b e r o f mutations in each tumor. However some carcinom as d id n o t c o n ta in d e te c ta b le m u ta tio n s. Reprinted by permission of the New Engl J Med ;3 1 9 : Class I Class II Class III Type of Tumor by w h ic h h e a lth y g en e s m ay be implanted into deep-seated tumors. In the event that actual im plantation of healthy genes should prove impractical, an alternative approach might be to provide the product of the wild-type gene without correcting the mutation directly. Discussion Normal colonic mucosa arises from many different stem cells and is polyclonal. Tumors, in contrast, are basically monoclonal.9 This is true of the smallest adenomas studied. The clear implication is that tumors arise as a single mutation within a single cell. No one trigger mutation for this has been identified; there may be more than one possible initiator. While loss of 5q21 and the APC gene have been proposed as the earliest mutation to occur in sporadic CRC,11 one is reminded that some tumors progress to invasive carcinoma while showing no mutations at the loci which were tested (figure 2). Clearly, there is much more to be learned. Neoplastic cells display mounting genetic instability. 7 Thus, the initially monoclonal tum or population often degenerates into m ultiple monoclonal lines with varying degrees of aggressiveness. Growth and survival mechanics will favor the more aggressive clones, including those with the ability to invade and metastasize. One cause of the genetic Instability may be a significant reduction in methyl groups w ithin DNA which occurs early in colorectal tumorigenesis.9 The lack of methyl groups leads to inhibition of chromosome condensation and may lead to frequent DNA replication errors. The newly discovered FCC gene, associated with the special group of familial CRC designated HNPCC, is characterized by widespread errors in replication of m icrosatellite repeats. Since the gene has not been sequenced th e m e c h a n ic s of th e d e fe c t are still unknown. Acknowledgment The author wishes to express his appreciation to Juliana Szakacs, M.D. who review ed the manuscript prior to publication. References 1. Boring CC, Squires TS, Tong T, Montgomery S. Cancer statistics, CA-A Cancer J for Phys 1994;44:7-26.

7 GENETICS OF COLORECTAL CARCINOMA W illett W. The search for the causes of breast and colon cancer. Nature 1989;338: Peltomaki P, Aaltonen LA, Sistonen P, Pylkkanen L, Mecklin J-P, Jarvinen H, et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 1993;260: Haggitt RC, Reid BJ. Hereditary gastrointestinal polyposis syndromes. Am J Surg Path 1986; 10: Muto T, Bussey HJR, Morson BC. The evolution of cancer of the colon and rectum. Cancer 1975;36: Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alteration during colorectal-tum or development. New Engl J Med 1988;319: Bishop JM. Molecular themes in oncogenesis. Cell 1991;64: Marx G. Research news: many gene changes found in cancer. Science 1989;246: Fearon EC, Vogelstein B. A genetic model for colorectal carcinogenesis. Cell 1990;61: Kinzler KW, Nilbert MC, Su L-K, Vogelstein B, Bryan TM, Levy DB, et al. Identification of FAP locus gene from chromosome 5q21. Science 1991;253: Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253: Aaltonen LA, Paivi P, Leach FS, Sistonen P, Pylkkanen L, Hemilton SR, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993;260: Marx G. Research news: new colon cancer gene discovered. Science 1993;260: Fidler IJ, Radinsky R. Editorials. Genetic control of cancer metastasis. J Natl Cancer Inst 1990;82: Baker SJ, Markowitz S, Fearon ER, Willson JKV, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990;249: Goyette MC, Cho K, Fasching CL, Levy DB, Kinzler KW, Paraskeva C, et al. Progression of colorectal cancer is associated with m ultiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect by chromosome transfer. Mol Cell Biol 1992;12: Hyde SC, Gill DR, Higgins CF, Trezise AEO, MacVinish LJ, Cuthbert AW, et al. Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy. Nature 1993; 362:250-5.

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