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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
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
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
Potential Clinical Applications of Molecular Genetic Findings
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
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.
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