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Please note: This article is part of the Cancer Center's News Archive and is here for historical purposes. The information and links may no longer be up-to-date.

Michigan Oncology Journal Spring 2000

A Primer on the Genetics and Molecular Biology of Colorectal Cancer

Eric R. Fearon, M.D., Ph.D.,
Associate Professor of Internal Medicine, Human Genetics and Pathology
Associate Director, Basic Science Research
U-M Comprehensive Cancer Center

Roughly 140,000 new cases of colon and rectal cancer were diagnosed in the United States in 1999, and more than 45% of these patients will likely die from their disease. These statistics reflect the grim reality that, as for most common epithelial cancers, limited progress has been made in treating advanced colorectal cancer with chemotherapy and radiation therapy. Moreover, relatively little is known about specific dietary or pharmacological strategies that will effectively prevent or delay colorectal cancer development. Nevertheless, despite present uncertainties and obstacles in preventing and treating colorectal cancer, colorectal tumors have offered many insights into the nature, role and origins of mutations in a common human cancer, in large part because of their natural history (i.e., the adenoma-carcinoma sequence) and the success in elucidating the genetic basis of several syndromes that strongly predispose to cancer. The insights gained have not only shed light on the pathogenesis of colorectal and other cancer types, but will hopefully provide the foundation for important advances in our ability to prevent, detect and treat the disease. The goals of this article are three-fold: i) to review terminology and concepts in the cancer genetics and molecular oncology fields; ii) to discuss the genetic defects that underlie familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC); and iii) to outline some possible clinical applications of advances in our understanding of the genetics and molecular biology of colorectal cancer.

Genetic Changes and Clonal Selection
Cancers arise, at least in part, through two distinct but linked processes. The first is mutation of cellular genes. The second process, termed clonal selection, promotes outgrowth of those variant progeny with the most robust proliferative and/or survival properties. Two classes of genes - proto-oncogenes and tumor suppressor genes - are affected by mutations in cancer cells. Oncogenes are distinguished from their normal cellular counterparts, the proto-oncogenes, by the fact that they harbor "gain-of-function" mutations endowing them with increased or novel function. In contrast, tumor suppressor genes are affected by "loss-of-function" mutations in cancer. A third class of mutated genes, with a rather more indirect role in cancer initiation and progression, is the DNA repair pathway genes. Because DNA repair genes are affected by "loss-of-function" mutations in cancer, they are usually considered to represent a subset of the tumor suppressor gene class.

The Adenoma-Carcinoma Sequence
The adenomatous polyp or adenoma is believed to be a precursor lesion in the majority of colorectal cancers, and there is considerable clinical and histopathological evidence to support this view. By some estimates, the lifetime risk of one or more adenomas in an individual in the U.S. may be nearly 50%. Only a fraction of adenomas progress to cancer, as the incidence of colorectal cancer in the U.S. is roughly 5%.

Genetics of Hereditary Colorectal Cancer
Hereditary syndromes predisposing to colorectal cancer include familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). Several other much rarer syndromes are also associated with an increased, but less clearly defined, risk of colorectal cancer, including Peutz-Jeghers syndrome, Cowden's disease and juvenile polyposis syndrome. The genes responsible for these inherited syndromes have been identified (Table 1). In all cases, inactivating mutations in both alleles are present in the cancers that arise in affected individuals. With the exception of the DPC4 gene and the genes that underlie FAP and HNPCC, defects in these other familial cancer genes do not appear to contribute to sporadic cases of colorectal cancer.

Familial Adenomatous Polyposis and the APC Gene
FAP is an autosomal dominant syndrome, affecting about 1 in 8,000 in the U.S. and accounting for about 0.5% of all colorectal cancer cases. The defective gene in those with FAP is known as the adenomatous polyposis coli (APC) gene. Variant polyposis syndromes attributable to APC gene defects and in which extracolonic tumors are seen include Gardner syndrome (jaw osteomas and desmoids) and Turcot's (brain tumors, particularly medulloblastomas). In addition, a number of families with an attenuated form of polyposis have been seen (termed AAPC), and other families with multiple desmoid tumors and few, if any, colorectal adenomas or carcinomas have also been described. There appears to be a genotype-phenotype correlation for some disease features. However, because quite variable disease features can be seen even in affected members of a single family, all of whom harbor the same germline APC mutation, modifying genes elsewhere in the genome and possibly dietary and environmental factors appear to have a significant role in determining the severity and nature of colonic and extracolonic disease in APC mutation carriers.

Despite the relative rarity of germline APC mutations in colorectal cancer, somatic (i.e., arising during tumor development) APC mutations are present in more than 75% of all colorectal adenomas and carcinomas. The APC tumor suppressor gene encodes a large protein of approximately 300 kDa. Recent studies indicate a critical function of the APC protein in colonic epithelial cells is the regulation of the ability of b-catenin protein to activate transcription of genes regulated by a transcription factor known as Tcf-4 (for T cell factor 4). The precise identities and functions of these Tcf-4-regulated target genes are not yet well understood, though they appear to include some powerful stimulators of cell growth and proliferation (e.g., the c-MYC and cyclin D1 proto-oncogenes) and some extracellular proteases (e.g., matrix metalloprotease 7) that may facilitate invasion and metastasis. Loss of APC function thus leads to over-expression of genes that actively promote tumor development.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Several clinical criteria have been useful in identifying the families most likely to be affected by the HNPCC syndromes: (i) three relatives with histologically documented colorectal cancer, at least two of which must be first-degree relatives; (ii) two or more successive generations affected; and (iii) at least one of the affected individuals must have developed colorectal cancer prior to age 50. While other tumors are often seen in families with HNPCC, including endometrial, ovarian, stomach, brain, biliary and urinary tract cancers, these cancers are not usually included in the diagnostic criteria for HNPCC. On clinical grounds, HNPCC cases are estimated to account for about 2 to 4% of all colorectal cancer cases. Despite the fact that genetic heterogeneity and variability in disease presentation have been well-documented in those affected by HNPCC, germline mutation of one allele of a DNA mismatch repair gene (hMSH2, hMLH1, PMS1, PMS2, GTBP/MSH6) forms the common basis for tumor predisposition in nearly all individuals affected by the HNPCC syndromes (Table 2). The prevalence of germline mutations in the DNA mismatch repair genes in those colorectal cancer patients that do not meet the strict clinical criteria for HNPCC is not yet fully understood. However, some studies suggest that roughly 30 to 50% of patients younger than 35 years of age and without any family history of colorectal cancer may have a germline mutation in one of the known HNPCC genes. However, in patients older than 40 years of age and whose family history does not fulfill the clinical criteria for HNPCC outlined above, germline mutations are likely to be present in less than 5% of cases.

In the cancers arising in those with HNPCC, a somatic mutation inactivates the remaining wild-type allele of the particular mismatch repair gene mutated in the patient's germline. Following inactivation of both alleles of a critical DNA damage recognition and repair gene, the cell has a decreased ability to detect and repair DNA mismatches that arise in a dividing cell (Figure 1). Hence, the tumor cells have a mutator or replication error (so-called "RER+") phenotype. While germline mutations in the known mismatch repair genes have only been detected in 2 to 4% of colorectal cancer patients, upwards of 15% of all colorectal cancers show the RER+ phenotype. This observation indicates that germline and/or somatic defects in mismatch repair pathway genes may be present in a substantial fraction of all colorectal cancers, regardless of the family history. In the majority of the roughly 15% of all sporadic colon cancers that have the RER+ phenotype, inactivation of mismatch repair gene function, particularly the MLH1 gene, appears to occur via DNA methylation silencing of gene regulatory sequences rather than through somatic mutation in mismatch repair genes. Finally, while many of the mutations that arise in cells with the RER+ phenotype may be detrimental to cell growth, a subset may activate oncogenes or inactivate tumor suppressor genes and lead to clonal outgrowth. An example of a gene that is nearly universally inactivated in colorectal cancers with the RER+ phenotype is the TGF-bIIR gene, which encodes a receptor for the TGF-b growth factors, a family of molecules that exert strong growth suppressive effects on normal colon epithelial cells.

Variant APC Alleles and Familial Aggregations of Colorectal Cancer
In some individuals, a diagnosis of FAP or HNPCC can be made quite readily on clinical grounds and/or family history. However, in many families with two or more cases of colorectal cancer, evidence that a single gene defect has a primary role in cancer predisposition is far from conclusive. There has been, therefore, considerable interest stimulated by a recent study offering new insights into familial forms of colorectal cancer that are not highly penetrant. The study was initiated because eight colorectal adenomas were found in a 39-year-old patient with a modest family history of colorectal cancer. A diagnosis of HNPCC was excluded by molecular analyses. While the diagnosis of FAP was unlikely based on clinical findings, detailed studies of the patient's APC gene sequences were carried out. A germline mutation at codon 1307 of the APC gene was found, resulting in a substitution of lysine (K) for isoleucine (I). Hence, the altered version of the APC gene was referred to as the APC I1307K allele. The single amino acid change appears not to alter the function of the APC protein. However, at the DNA sequence level, the variant APC allele has an extended mononucleotide tract in the coding region [i.e., (A)8 instead of (AAATAAAA)]. Epidemiological studies have revealed the I1307K allele is present only in individuals of Ashkenazi Jewish origin, and those who carry the I1307K allele have a roughly two-fold increase in their lifetime risk of colorectal cancer. Moreover, the localized somatic APC mutations pre-sent in colorectal cancers of those carrying the I1307K allele have been found to be nearly always small insertions or deletions present in or immediately adjacent to the (A)8 mononucleotide repeat tract. The somatic mutations create frameshifts that inactivate APC function. Therefore, the I1307K allele appears to be a novel cancer predisposition allele that exerts its effects not by directly altering APC protein function, as do APC mutations of the type found in patients with classic forms of polyposis. Rather, the I1307K allele contains a DNA sequence tract that is a much more frequent target for somatic mutation in colonic epithelial cells than the normal APC sequence. Further work may establish that subtle or unconventional mutations in other cancer-causing genes also contribute to cancer predisposition via similar mechanisms.

Potential Clinical Applications of Molecular Genetic Findings
Risk Assessment
The identification and characterization of inherited genetic alterations that predispose to the development of colorectal tumors has already proven useful for genetic counseling of individuals and families with a few well-defined forms of inherited colorectal cancer. Though genetic counseling and presymptomatic diagnosis for FAP and HNPCC are presently being carried out in a number of institutions, a number of ethical, legal and technical problems still must be addressed before widespread testing for presymptomatic diagnosis of at-risk individuals becomes a reality. Among the hurdles are the labor-intensive technologies currently available for mutation detection; the heterogeneity of germline mutations in the APC gene in those with FAP and in multiple different mismatch repair genes in those with HNPCC; and the uncertainties in predicting the precise clinical course in those who carry pathogenic mutations.

Early Detection
In addition to identifying those at increased risk of colorectal cancer as a result of inherited mutations, it may someday be possible to apply molecular genetic approaches to early detection of colorectal tumors in the general population. For example, though some theoretical and technical problems exist at present, the detection of somatic mutations in oncogenes or tumor suppressor genes in stool specimens may ultimately prove useful in early detection of clinically significant adenomas and early carcinomas.

Prognosis, Patient Stratification and Therapy
Other possible clinical applications include improved/increased prognostic information about the likelihood of tumor recurrence and subsequent distant metastasis, and perhaps improved stratification of patients for adjuvant chemotherapeutic intervention. For example, inactivation of one or more tumor suppressor genes on chromosome 18q appears to predict poor outcome in Stage II patients and probably Stage III patients as well, though further work is needed to determine whether the chromosome 18q genetic marker is useful for stratifying patients for chemotherapy or for predicting response. Finally, an implied promise of the present molecular genetic studies to elucidate the pathogenesis of cancer is that such studies will identify novel drug targets, as well as novel therapeutic approaches.

Selected References

  1. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998; 338:1481-1487.
  2. Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science 1997; 278:1043-1050.
  3. Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995; 332:839-847.
  4. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998; 391:184-187.
  5. Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 1998; 280:1086.
  6. Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994; 331:213-221.
  7. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87:159.
  8. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 1997; 17:79-83.
  9. Markowitz AJ, Winawer SJ. Screening and surveillance for colorectal cancer. Semin Oncol 1999; 26:485-498.
  10. Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 1995; 87:1114.
  11. Wijnen JT, Vasen HF, Khan PM, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339:511-518.


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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.
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