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Proliferating cell nuclear antigen (PCNA) in relation to ras c-erbB-2 p53 clinico-pathological variables and prognosis in colorectal adenocarcinoma

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Znt. J. Cancer (Pred. Oncol.): 69,44-46 (1996)
0 1996 Wiley-Liss, Inc.
Publication of the International Union Agalnst Cancer
Publication de I'Union lnternatlonale Contre le Cancel
FAMILIAL RISK AND COLON CANCER
Randall W. BURT'
Division of Gastroenterology, University of Utah, Salt Lake City, UT. USA.
Familial occurrence in excess of that expected by chance is
common among cases of colon cancer. Only a small fraction of
these familial cases arise from well-described syndromes. There
are epidemiologic, colonoscopic, genealogic data base and large
prospective studies that characterize the familial occurrence
and risk for common colon cancer. Kindred studies suggest that
common familial occurrence arises from inherited susceptibility
of a mild to moderate magnitude. The responsiblegenes are yet
to be identified, though a number of candidate genes have been
suggested. Clinical features, especially age at diagnosis and
number of first-degree relatives with colon cancer, already
allow stratification of familial risk. Risk stratification is important for colon cancer screening, as some higher-risk persons
should probably have more intensive screening. Research is
needed to identify the genes or their polymorphisms that give
rise to common inherited susceptibility for colon cancer, to
examine how susceptibility genes interact with environmental
factors and nive rise to colonic neoplasms and to verify SUPgested screening approaches that incorporatefamilial risk.
-
determined the risk of colon cancer in first-degree relatives of
those with adenomatous polyps. It can reasonably be assumed
that the adenomas considered in these studies were large or
symptomatic, as colonoscopy was not mentioned and the
studies were done before colonoscopy was widely applied. The
risk of colon cancer was approximately 2-fold increased in
relatives of adenoma patients.
A number of colonoscopy studies have examined the risk of
adenomatous polyps in first-degree relatives of persons with
colon cancer. They have generally, but not always, found an
increased risk. Unfortunately, only 3 studies have included
control groups (Cannon-Albright let al., 1988;Guillem et al.,
1988;Rozen et al., 1987~).In each of these 3, an approximate
2-fold risk of adenomatous polyps has been found in relatives
compared with controls.
o 1996 Wiley-Lissh,c .
FAMILY STUDIES
A small fraction of colon cancer cases arise from welldescribed inherited syndromes, primarily familial adenomatous polyposis and hereditary non-polyposis colorectal cancer
(HNPCC). Together, these syndromes account for 5% or less
of cases. They are described in detail in the following sections.
The majority of colon cancer cases ( > 95%) are often considered sporadic (Burt et al., 1995). This section details these
common cases and recent observations which indicate that
familial risk is also important in this category.
The evidence for excess familial risk among the so-called
sporadic cases is presented first, followed by a review of studies
that suggest that this familial risk arises from inherited
susceptibility. Clinical observations that allow stratification of
common familial risk are then presented, as well as the
application of these observations to the clinical setting. Suggestions concerning future directions are also made.
We examined multiple, systematically selected kindreds for
adenomatous polyps and colon cancer to determine the basis
of common familial clustering (Cannon-Albright et al., 1988).
Kindred members and their spouses (as controls) were examined by endoscopy to determine the presence of colonic
neoplasms. Polyps were significantly more common in kindred
members compared with spouses, and segregation analysis
showed that familial occurrence patterns most likely represented autosomal dominant inheritance rather than recessive
inheritance or random clustering. Random clustering would be
expected if familial cases occurred by chance or on the basis of
shared environmental factors alone. The analysis also indicated that one-half of the neoplasms arose, at least in part,
from inherited susceptibility and that a susceptibility gene or
genes were present in up to one-third of the population
studied.
A subsequent family study from a large surgical practice in
EPIDEMIOLOGIC STUDIES
Australia also found autosomal dominant segregation patterns
Three large epidemiologic investigations first demonstrated to be the most likely cause of common familial clustering of
familial risk among common cases of colon cancer. The first, in colon cancer cases (Bishop et al.,, 1992). This investigation
the early 1950s, examined the risk of mortality from colon addressed cancer cases only.
A likely hypothesis from these studies is that inherited
cancer among first-degree relatives of persons who had died of
colon cancer in Utah over a defined period (Woolf, 1958). The factors determine individual susceptibility to colonic neosecond study, in the 1960s,compared the mortality from colon plasms. Exposure to environmental factors, known to be
cancer in first-degree relatives of those with this malignancy to important to the pathogenesis of colorectal cancer, determines
that expected from state registry data in Ohio (Mackliu, 1960). which individuals develop small aldenomas, larger adenomas
The third study, in the 1970s,examined mortality from colon and finally colon cancer. A small fraction of colon cancer cases
cancer in first-degree relatives of patients referred to the St. are thus accounted for by the known inherited syndromes of
Mark's Hospital in London for colon cancer (Lovett, 1976).All familial adenomatous polyposis and HNPCC. Inherited pre3 investigations found an approximate 3.5-fold increased disposition dominates in these conditions, while environmenmortality from colon cancer among the first-degree relatives. tal factors are less important. In a much larger proportion of
Each of these studies used quite different methodologies and cases, possibly even the majority, inherited factors confer
susceptibility and interact with enviironmental factors to deterfound similar results.
Over the following 2 decades 7 studies were reported that mine expression of polyps and cancer. Finally, in some fraction
examined the incidence, as opposed to the mortality, of colon of cases, environmental exposures alone give rise to colonic
cancer in first-degree relatives of persons with colon cancer neoplasms.
(Bonelli et al., 1988;Duncan and Kyle, 1982; Guillem et al.,
1988;Maize et al., 1988;Ponz de Leon et al., 1987;Rozen et al.,
1987a,b;Stephenson et al., 1991). These investigations were
'Address correspondence and reprint requests to Randall W. Burt,
done in a number of different countries, but all showed an M.D., Professor of Medicine, Division of Gastroenterology, Room
increased risk of colorectal cancer in first-degree relatives. The 4R118, University of Utah Medical Center, Salt Lake City, UT 84132,
risk ranged from 1.8- to 8.0-fold. Four of these studies also USA.
FAMILIAL RISK AND COLON CANCER
STRATIFYING COMMON INHERITED SUSCEPTIBILITY
A number of clinical observations suggest that inherited
susceptibility is not only common but also heterogeneous.
Stratification of risk is important both for identifying susceptibility genes and for developing appropriate screening strategies. Two clinical factors appear to correlate with common
familial risk: (i) the number of first-degree relatives with colon
cancer and (ii) the age at cancer diagnosis.
Three studies have examined the risk for colonic neoplasm if
1 or 2 first-degree relatives were affected with colon cancer
(Lovett, 1976; Guillem et al., 1988; St. John et al., 1993). The
risks if 1 first-degree relative had this malignancy were 1.6-,
1.8- and 2.9-fold over control, respectively, for the 3 studies.
The corresponding increased risks for 2 affected first-degree
relatives were 3.0-, 5.7- and 8.3-fold. The first 2 studies used
colonoscopy to find adenomatous polyps in relatives, while the
third quantified the risk of colon cancer.
The second of these studies also related age at diagnosis to
risk. The risk for colon cancer in first-degree relatives was
approximately double that of controls if cancer was diagnosed
in the index case at an age of 55 years or more. The risk was
approximately triple if the diagnosis was between the ages of
4.5 and 54 years and quadruple if the diagnosis was made at an
age below 45 years.
The first prospective study of colon cancer risk in firstdegree relatives of persons with colon cancer was reported by
Fuchs et al. (1994). This study combined the Nurses Health
Study and the Health Professionals Follow-up Study. There
were 87,031 women and 32,085 men, followed an average of 8
and 6 years, respectively. Ten percent of participants had a
first-degree relative with colon cancer. The relative risk of
colon cancer in those with an affected first-degree relative was
1.72 (95% CI = 1.34-2.19) and was near equivalent for women
and men. Relative risk increased with younger age of the
participant. The highest risk was 5.37 for those 30-44 years of
age, and the lowest was 1.00 for those 2 7 0 years of age. The
risk in persons with a family history in the 3540-year age
group was equivalent to the risk in persons without a family
history in the 50-year age group.
The relative risk for persons with 2 or more affected
first-degree relatives was 2.75 compared to 1.65 for those with
only 1. Rectal cancer was not associated with increased
familial risk, whereas proximal and distal colon, excluding
rectum, was. Detailed environmental exposures were quantified and did not differ between individuals with and without a
family history of colon cancer, suggesting that the observed
increased risk was likely from inherited susceptibility.
An investigation from Utah combined Utah genealogies
with the Utah cancer and death registries (Utah Population
Database) to examine colon cancer risk in relatives of persons
with this malignancy (Slattery and Kerber, 1994). This resource has the advantage of complete ascertainment and
allows risk assessment in relatives more distant than firstdegree. There were 1,244 men and 1,299 women with colon
cancer in the data base. Odds ratios (ORs) for colon cancer in
persons with an affected first-degree relative were 2.2 for men
and 2.6 for women. This did not significantly differ if the
relative was a parent or sibling. If 2 or more first-degree
relatives were affected, the ORs for colon cancer were 9.2 for
men and 5.0 for women. ORs with an affected second-degree
relative were 1.5 for men and 1.3 for women. ORs ratios were
the same with an affected third-degree relative but were not
increased for affected fourth- or fifth-degree relatives. This
study showed significantly increased risk whether the relative
was diagnosed at an age older or younger than 50 years. Risks
were also equivalently increased in both men and women for
cancers of the proximal colon, distal colon and rectum.
45
There are several notable points concerning this investigation. The presence of risk conferred by distant relatives favors
an inherited etiology for common familial clustering. The
finding of familial risk for rectal cancer is also notable. It is
possible that negative referral bias could affect other studies as
rectal cancer is generally believed not to be familial. Finally,
this investigation also assessed the risk of colon cancer if
first-degree relatives had cancer of other sites. Breast, uterine,
ovarian and prostate cancer in relatives conferred some risk
for both men and women in all cases. ORs varied from 1.2 to
2.0. Thus, risk was less than that from colon cancer in relatives
but nonetheless significant.
The findings for common familial risk are summarized as
follows. Persons with a first-degree relative with colon cancer
have an approximate 2- to 3-fold increased risk for this
malignancy. If 2 first-degree relatives are affected, the risk is
again doubled. If a first-degree relative is diagnosed at an age
less than 50 years, the risk is also approximately doubled.
These findings apply to both proximal and distal colonic
tumors and possibly to rectal malignancies. Adenomatous
polyps in first-degree relatives also confer some risk, as do
cancers of the breast, uterus, ovaries or prostate. It appears
that only a small fraction of those with young age at onset or
with 2 first-degree relatives with colon cancer will actually have
HNPCC. Common familial risk is thus quite heterogeneous
and may represent a number of different genes and etiologies.
POSSIBLE CAUSES OF COMMON FAMILIAL CLUSTERING OF
CASES
It is not known what genes are involved with common
familial risk. Possibilities include mild mutations of the genes
known to exhibit severe germ-line mutations in familial adenomatous polyposis (FAP) and HNPCC. A n attenuated form of
FAP, in fact, has been described. Mutations at the extreme
proximal end of theAPC gene give rise to a phenotype of fewer
adenomas (about 30) and a later age at onset for adenomas
and cancer (Spirio et al., 1993). Polymorphisms of genes
involved in the acetylation of amines and glutathione transferase are other possibilities (Lang et al., 1986; Tsuchida and
Sato, 1992). Several studies have found a 2-fold increased risk
for colon cancer associated with “rapid acetylator” status. Bile
acid, a known promoter, has been found to be increased in the
stool of persons with colon cancer. Certain inherited defects of
bile acid physiology could thus confer risk for colorectal
cancer. There are many other similar possibilities. Shared
environmental exposures could also account for some of the
familial clustering. Until genetic markers are available to
accurately identify common inherited susceptibility, the frequency of inherited susceptibility and how it interacts with
environmental factors will remain somewhat speculative.
CLINlCAL APPLICATION AND FUTURE DIRECTION
The increased risks for colon cancer described above indicate that at least “standard” colon cancer screening be
recommended for all individuals who have relatives with colon
cancer. This would include annual fecal occult blood testing
and sigmoidoscopy every 3-5 years. Screening should probably
begin by age 3 5 4 0 years. If a first-degree relative has colon
cancer diagnosed at an age (50 years or if 2 first-degree
relatives are affected, the degree of risk would indicate full
colon examination as the appropriate screening. This screening should begin 5 years earlier than the youngest diagnosis of
colon cancer in the family and should probably be repeated
every 3-5 years. Standard screening should also be recommended if first-degree relatives have adenomatous polyps or
cancer of the breast, ovary, uterus or prostate.
46
BURT
Present findings indicate a number of important research
directions: (i) It is first important to identify the genetic
polymorphisms and/or enzyme systems involved in common
familial pre-disposition. Such information would allow more
accurate stratification of risks for screening and would also
suggest preventive and intetventional strategies. (ii) Prospective screening studies need to be performed in the familial risk
groups to examine and verify the empiric, risk-based recommendations. (iii) Studies of environmental exposures and life-styles
need to be performed in common genetic risk groups. Simi-
larly, genetic risk could be assessed in epidemiologic investigations where the environmental factors have already been
quantified. These studies would help to clarify the specifics of
genetic-environmental interaction in the pathogenesis of common colorectal adenomatous polyps and cancer and would
likewise suggest screening and preventive methods.
ACKNOWLEDGEMENT
This work was supported by NIH grant CA #40641.
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ras, pcna, pathologic, relations, colorectal, p53, antigen, adenocarcinoma, prognosis, cells, nuclear, clinics, variables, erbb, proliferation
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