close

Вход

Забыли?

вход по аккаунту

?

380

код для вставкиСкачать
Znt. J. Cancer (Pred. Oncol.): 69,35-37 (1996)
0 1996 Wiley-Liss, Inc. *This article is a US Government work
and, as such, is in the public domain in the United States of America.
Puoltcalo? of t i e mle.nattonal Un'on Aga.is! Cancer
.-2 A
EARLY DETECTION RESEARCH PROGRAM AT THE NCI
Sudhir SRIVASTAVA'
and Susan C. ROSSI
Early Detection and Community Oncology Program, Division of Cancer Prevention and Control, National Cancer Institute,
Bethesda, MD 20892, USA.
The Early Detection Branch, Division of Cancer Prevention
and Control, National Cancer Institute, has created a program
called The Early Detection Research Network (EDRN). EDRN's
mission is to support translational research leading to early
detection of cancer. The objectives are to ( i ) establish a
network of institutions with the facilities, resources, personnel
and interest to undertake biomarker research in early cancer
detection; (ii) advance the understandingof the molecular basis
of tumorigenesis in relation to screening, early detection and
risk assessment; (iii) identify potential biomarkers that can be
used as outcome measures or as intermediate end-points for
cancer screening studies and (iv) respond to late-breaking
developments in the field of biomarkers in a timely fashion. This
program has the singular purpose of studying biologic, molecular and genetic markers relevant to the early detection of
prostate, colorectal, lung, head and neck, bladder and breast
cancers.
o 1996 Wiley-Liss,Inc. *
One of the critical requirements in studying molecular
progression is the availability of a well-defined set of tissues
representing normal, pre-neoplastic, in situ and metastatic
stages of disease. Each cancer is likely to have its own natural
history of progression. Colorectal cancer has provided a model
system for studying the underlying molecular mechanisms of
carcinogenesis and cancer progression in general. The National Cancer Institute's (NCI) Early Detection Research
Network (EDRN) has established a network of investigators
charged with developing and maintaining a biorepository in
conjunction with a historical data base of epidemiological and
clinical information. The EDRN institutions set up a biorepository of well-characterized prospectively and serially biopsied
pre-malignant, malignant and normal tissues as well as blood
samples using standardized protocols for processing, storage
and shipping. Medical histories, tumor stage/grade, patient
therapies and clinical outcomes are indexed with collected
tissues. The EDRN thus provides a reliable and comprehensive source of tissues for doing well-designed molecular progression studies. It is hoped that with the results of such studies
one could distinguish a collection of useful markers for
susceptibility, early detection and prognosis. The EDRN is
designed to enable investigators to focus on critical research
issues rather than the time-consuming task of setting up a
high-quality biorepository. Colorectal cancer has provided a
useful model for cancer research, but much remains to be done
with respect to identification of markers which will be useful
for genetic screening of high-risk families and the general
population.
EARLY DETECTION OF COLORECTAL CANCER
Colorectal cancer is the second most common cause of
cancer death in the United States (Miller et al., 1993). Most
colorectal cancer cases are detected at advanced stages when
surgical treatment, which continues to have disappointing
results, appears to be the only option. Early detection appears
to be the only viable option that could play a significant role in
the secondary prevention of colon cancer. Current methods of
screening include examination of stool for occult blood,
air-contrast barium enema examination and endoscopy includ-
ing rigid and flexible sigmoidoscopy and colonoscopy (Smart et
al., 1991).
Several studies have concluded that there is an increased
incidence of colorectal cancer in persons with polyps, which
varies with the relative position of the polyps (i.e., proximal to
the sigmoid colon; Prager et al., 1974; Lotfi et al., 1986; Simons
et al., 1992), pointing to the importance of monitoring early
events in colon tumor development. This tumor type has been
shown to progress from normal tissue to adenoma and carcinoma through accumulation of genetic alterations (Vogelstein
et al., 1988). To date, we know of mutations which affect
oncogenes such as K-ras (Bos et al., 1987) and several tumor
suppressor genes, including p53 (Hollstein et al., 1991),MCC
(mutated in colorectal cancer; Kinzler et al., 1991), APC
(adenomatous polyposis coli; Groden et al., 1991) and DCC
(deleted in colon cancer; Fearon et al., 1990). Some of these
genetic alterations are presently being tested for their potential to serve as clinical biomarkers of colon tumor development. For example, restriction fragment length polymorphism
(RFLP) of chromosome 5q21-22 (for loss of theAPC gene) has
been shown to be useful for pre-morbid diagnosis and counseling in familial adenomatous polyposis (FAP; Peterson et al.,
1991). Although FAP is a rare disorder, occurring in only 1 in
500 persons, and accounts for less than 1%of colonic carcinomas, mutations of the APC gene occur in 60% of patients with
colorectal carcinoma and are thought to be the earliest genetic
abnormalities in the progression of colorectal carcinoma.
The focus of molecular research has moved to a new class of
genes that predisposes individuals to colon cancer. Hereditary
non-polyposis colorectal cancer (HNPCC), also known as
Lynch syndrome (Lynch et al., 1985, 1988), is found in as many
as 1in 200 individuals in the Western world (Lynch et al., 1993)
and has been the subject of intense study. Tumors manifesting
this mutator phenotype have been termed replication errorpositive (RER+). A gene responsible for HNPCC has been
identified on chromosome 2p16 (Leach et al., 1993), and
because of its homology to the bacterial mutS and yeast MSH2
mismatch repair genes, it has been named hMSH2 (Leach et
al., 1993).Avariety of other genes have now been implicated in
HNPCC: hMLHl, hPMSl and hPMS2 (Papadopoulos et al.,
1994;Bronner et al., 1994;Nicolaides et al., 1994).Mutations in
any of these genes produce instability of micro-satellite sequences and have far-reaching implications that could affect
large numbers of individuals, making them susceptible to
various types of common epithelial malignancy. Thus, the
potential for genetic screening and early intervention for those
at high risk is enormous. With the discovery of 2 types of
genetic marker, micro-satellite instability and the genetic
susceptibility genes hMSH2, hMLHl, WMSl and hPMS2, it is
now possible to define colon cancer risk for families and
individuals. However, these markers must be validated in
population-based studies prior to their application for mass
screening.
'To whom correspondence should be addressed, at Early Detection
Branch, Executive Plaza North, Room 305, Division of Cancer
Prevention and Control, National Cancer Institute, National Institutes
of Health, Bethesda, MD 20892, USA. Fax: (301) 402-0816.
36
SRIVASTAVA AND ROSS1
With the increasing number of hereditary genes identified
and implicated in polyposis and non-polyposis types of colorectal cancer, it has now become possible to identify people
pre-disposed to colon cancer through genetic screening. However, this will account for less than 15% of all colorectal
carcinomas. Data accumulated thus far suggest that few of
these mutant gene products by themselves or in combination
may be fully predictive of cancer development. Thus, new
potential biomarkers (Table I) need to be investigated.
GENETIC SCREENING
The presence of certain abnormal hereditary genes, as in
familial adenomatous polyposis (Groden et al., 1991) and
HNPCC (Leach et al., 1993), may indicate increased susceptibility to genotoxic (or epi-genotoxic) ambient exposures. Patients harboring these dominant genetic traits also carry an
elevated risk for cancer. With these unique genetic characteristics, it would be possible to identify sub-populations and to
classify individuals on the basis of potential susceptibility
rather than simply on the basis of general risk factors. For
example, direct sequence analysis of retinoblastoma (Rb), p53,
DCC and mismatch repair genes could help predict a background risk of hereditary cancer and thereby identify a
sub-population to target using available screening tests such as
stool guaiac or sigmoidoscopy more effectively.
Another area where biomarkers could have a significant
impact is the selective screening of high-risk populations. For
disease of very low prevalence, even screening tests with
specificities as high as 95-98% would generate more falsepositives than true-positives. Positive predictive value is, in
other words, highly dependent on the underlying prevalence,
or population-based risk, of the disease. A potential way to
circumvent this is to selectively screen high-risk populations,
thus increasing pre-test prevalence. Some of the markers listed
in Table I and some carcinogen adducts could possibly be used
to improve upon this strategy. Other biological markers,
particularly oncogene mutations in persons exposed to known
carcinogens, may also significantly contribute to these efforts.
The potential benefits of the markers will depend on their
sensitivity and specificity. Before their large-scale applications,
the markers must be validated; i.e., a biomarker must measure
what it is intended to measure (Schatzkin et al., 1990).
Validation studies in humans should include determinations of
sensitivity, specificity and predictive value. Epidemiological
applications of such markers will require carefully designed
studies based on adequate sample size, control for salient
confounders (such as age, sex and ethnic variability) and an
understanding of the function of the marker. Eventually, with
the early detection of cancer using biomarkers, it would be
possible to determine whether the risk of rapid tumor progression was sufficient to justify the use of more invasive diagnostic
tests and/or aggressive prophylactic or therapeutic interventions.
Finally, the cost-effectiveness of the molecular approach to
early detection of cancer would require a careful evaluation on
a case-by-case basis. Since the molecular assays for a number
TABLE 1 - POTENTIAL BIOMARKERS FOR COLON CANCER
Marker
SamDle
ras mutations
p53 or other suppressor gene
mutations
Ploidy
Novel tyrosine kinases, telornerase
hMSH2, hMLH1, PMS1, PMS2
Tissue, colonic effluent
Tissue
Tissue
Tissue
Tissue, colonic effluent
of tumor markers are fairly specialized, the cost per assay is
much less if tumor markers are assayed in large numbers in a
centralized laboratory.
FUTURE DIRECTIONS
One of the objectives of the EDRN is to stimulate multiinstitutional, population-based collaborative studies and to
encourage collaboration toward the common goals of (i)
measuring the proportion of HNPCC cases among all colon
cancer cases and (ii) piggybacking epidemiological data onto
HNPCC cases to see if there are identifiable factors, including
dietary habits, affecting the selective expression or nonexpression of HNPCC-related genes.
It is hoped that the collaborative efforts of many institutions
will provide the adequate sample size and develop a useful
data base on family history and/or medical information on
participants.
A second objective relates to evolution of the basic research
needed for translation to be successful in developing RER
status for mass screening-ie., when and where to apply this
technology. Developing automated sequencing technologies is
of paramount importance for mass screening. We need to
improve techniques to detect mutations within individual cells
and to develop genotype/phenotype assays for mutational “hot
spots” in genes. More efforts should be focused on understanding the natural history of tumor progression for developing
intermediate end-points. Additional areas of high priority
research for early detection of HNPCC include: (i) the
development of a mismatch repair (MMR) gene mutational
data base in HNPCC; (ii) the development of a mechanism to
avoid reduplication of efforts; (iii) the development of consortium and international collaboration-q., BRCAl international collaboration,p53 mutational data base; (iv) the detection of technology priorities to include validation, automation
and cost-effectiveness; (v) the development of family registries
and epidemiological data bases; (vi) the effect of genes and
environment on age at onset of tumors in those with HNPCC;
(vii) the banking of patient materials for future studies and
(viii) the frequency and penetrance of mutations in HNPCC
and sporadic colon cancer.
CONCLUSIONS
In the era of technological advancement, one might see
invasive procedures become almost unnecessary for early
detection. We hope that the continuing developments in the
area of molecular biology may provide sensitive and specific
techniques for early diagnosis of cancer. For example, chromosomal aberrations in tumors may draw attention to potentially
significant genetic sites in precursor lesions. Observations of
genetic alterations, chromosomal breaks or altered DNA
methylation could identify a precursor or pre-malignant condition. Loss of DNA methylation is found in very early stages of
colon tumor progression (Goelz et al., 1985) and has been
shown to lead to mitotic disjunction by inhibiting chromosomal
condensation (Schmid et al., 1990).
The near-term benefit of studying biornarkers may lie in the
improvement of survival by detecting cancer cases at an early
stage rather than as potential targets for therapeutic intervention using tools that do not yet exist. Curative modalities
already exist for most tumors if discovered prior to the
development of invasive or metastatic potential. Oncogenes,
for example, may be used as biomarkers for early diagnosis of
cancer or may provide important prognostic information.
Many have already been shown to be associated with poor
survival. For example, over-expression of c-myc in head and
neck squamous cell carcinoma has been associated with
EARLY DETECTION RESEARCH PROGRAM
shorter survival compared with those with low levels of c-myc
protein (Field et a/.. 1989). A correlation has been found
between an altered c-myc gene and a poor short-term prognosis in 121 patients with breast cancer (Varley et al., 1987).
c-myc gene over-expression has also been shown to be correlated with breast cancers of poor prognosis (GuCrin et al.,
1988). In the longer term, interventions to stop or reverse
tumor progression may also improve survival and prognosis,
but these await new developments.
A note of caution is important: The use of genetic and
biological markers in a cancer prevention study implies 2
assumptions: (i) the marker-indicated cancer is likely to occur
and ( i i ) reduction of the marker is synonymous with control of
the disease. However, these assumptions may not be true for
many of the markers and events discussed above; thus, each
biomarker must be validated. Biomarkers may or may not be
disease-specific and may or may not lie directly along the
causal pathway. If not on the causal pathway, an intervention
may successfully block its expression but fail to block the
progression to malignancy; there may also be more than one
causal pathway. Intermediate markers may occur early or late
on the causal pathway so that a given successful intervention
may not change an intermediate marker, while another would,
37
depending on where in the cascade of genetic events each
marker occurred. Finally, we do not know the spontaneous
regression rate of molecular events, for it is conceivable that
some events occur and disappear.
None of these caveats is likely to be insurmountable, but
they must be taken into account as future studies are used to
validate intermediate end-points. Therefore, prospective studies on individual cancer sites correlating molecular and biochemical changes with clinical disease characteristics and
patient outcome and demographics should be carried out.
These points highlight the importance of establishing a bank of
normal cells and tissues and of pre-malignant and malignant
lesions to identify potential cellular and molecular markers for
early detection. Studies on the patterns of biochemical, cellular, genetic and molecular events on such prospectively collected cells and tissues may identify surrogate end-points for
prevention and a “candidate marker” for the detection of early
lesions. Matching these markers with an associated prospective data base of demographic information, exposure to potential carcinogens and risk factors on the subjects from whom
specimens have been obtained may aid in developing a new
generation of screening and early detection modalities.
REFERENCES
Bos. J.L., FEARON,
E.R., HAMILTON,
S.R., VERLAAN-DE
VRIES.M., colorectal cancer: an updated review. Gastroenterology, 104,1535-1549
VAN BOOM,J.H., VANDER EB,A.J. and VOGELSTEIN,
B., Prevalence of (1993).
ras gene mutations in human colorectal cancers. Nature (Lond.), 327, LYNCH,H.T., WATSON,P., LANSPA,S.J., MARCUS,J., SMYRK,T.,
293-297 (1987).
FITZGIBBONS,
R.J., JR., KRIEGLER,
M. and LYNCH,
J.F., Natural history
BRONNER,
C.E., BAKER,S.M., MORRISON,
P.T., WARREN,G., SMITH, of colorectal cancer in hereditary nonpolyposis colorectal cancer
C., LIPFORD,J. and (Lynch syndromes I and 11). Dis. Colon Rectum, 31,372-377 (1988).
L.G., LESCOE,M.K., KANE, M., EARABINO,
LINDBLOM,
A,, Mutation in the DNA mismatch repair gene homo- MILLER,B.A., RIES, L.A.G., HANKEY,
B.F., KOSARY,C.L., FEUER,
logue hMLHl is associated with hereditary non-polyposis colon E.J., BORING,
C.C. and EDWARDS,
B.K.. Section I: Overview. In: SEER
cancer. Nature (Lond.),368,258-261 (1994).
cancer statistics review: 1973-1990, National Cancer Institute, NIH
FEARON,
E.R., CHO,K.R., NIGRO,J.M., KERN,S.E., SIMONS.
J.W., Publ. 93-2789, Bethesda, MD (1993).
S.R., PREISINGER,
A.C., THOMAS,G., NICOLAIDES,
RUPPERT,J.M., HAMILTON,
N.C. and 17 OTHERS,
Mutations of two PMS homologues
KINZLER,
K.W. and VOGELSTEIN,
B., Identification of a chromosome
in hereditary nonpolyposis colon cancer. Nature (Lond.), 371, 75-80
18q gene that is altered in colorectal cancers. Science, 247, 49-56
(1994).
(1990).
PAPADOPOULOS,
N., NICOLAIDES,
N.C., WEI, Y.F., RUBEN,S.M..
FIELD,
J.K., SPANDIDOS.
D.A., STELL.P.M., VAUGHAN,
E.D., EVAN, CARTER,K.C., ROSEN,C.A., HASELTINE,
W.A., FLEISCHMANN,
R.D.,
G.I. and MOORE,J.P., Elevated expression of the c-myc oncoprotein FRASER,C.M. and ADAMS,M.D., Mutation of a mutL homolog in
correlates with poor prognosis in head and neck squamous cell hereditary colon cancer. Science, 263,1625-1629 (1994).
carcinoma. Oncogene. 4,1463-1468 (1989).
PETERSEN,
G.M., SLACK.J. and NAKAMURA,
Y., Screening guidelines
GOELZ,S.E., VOGELSTEIN,
B., HAMILTON, S.R. and FEINBERG,
A.P., and premorbid diagnosis of familial adenomatous polyposis using
Hypomethylation of DNA from benign and malignant human colon linkage. Gastroenterology.100,1658-1664 (1991).
neoplasm. Science, 228,187-190 (1985).
PRAGER,E.O., SWINTON,
N.W., YOUNG,J.L., VEIDENHEIMER,
M.C.
GRODEN,
J. and 22 OTHERS,
Identification and characterization of the and CORMAN,
M.L., Follow-up study of patients with benign mucosal
familial adenomatous polyposis coli gene. Cell, 66,589-600 (1991).
polyps discovered by proctosigmoidoscopy. Dis. Colon Rectum, 17,
GUERIN,M., BARROIS.
M., TERRIER,
M.J., SPIELMA”,M. and RIOU, 322-324 (1974).
G., Overexpression of either c-myc or c-erb B-2inerc protooncogenes in SCHATZKIN,
A,, FREEDMAN,
L.. SCHIFFMAN,
M. and DAWSEY,S.,
human breast carcinoma: correlation with poor prognosis. Oncogene Validation of intermediate end points in cancer research. J. nut.
Res., 3,21-23 (1988).
Cancerbist., 82, 1746-1752 (1990).
HOLLSTEIN, M., SIDRANSKY,
D., VOGELSTEIN,
B. and HARRIS,
C.C., p53 SCHMID,
M., HAFF,T. and GRUNER,
D., 5-azacytidine-induced undermutations in human cancers. Science, 253,49-53 (1991).
condensation in human chromosomes. Hum. Genet., 67, 257-263
KINZLER,
K.W., NILBERT,M.C.. VOGELSTEIN,
B., BRYAN,
T.M., LEVY, (1990).
D.B., SMITH,K.J., PREISINGER,
A.C., HAMILTON,
S.R., HEDGE,P. and SIMONS,B.D., MORRISON,
A.S., LEV,R. and VERHOEK-OFTEDAHL, W.,
MARKHAM,
A., Identification of a gene located at chromosome 5q21 Relationship of polyps to cancer of the large intestine. J. nut. Cancer
that is mutated in colorectal cancers. Science, 251,1366-1370 (1991).
Qsi., 84,962-966 (1992).
LEACH,F.S., NICOLAIDES,
N.C., PAPADOPOULOS,
N., LIU. B., JEN.J., SMART,
C.R., CHU,K.C., CONLEY,
V.L., HENSON,
D.E.. POMMERENKE,
PARSONS,R.,PELTOMAKI,
P., SISTONEN,
P., AALTONEN,
L.A. and F.P. and SRIVASTAVA,
S., Cancer screening and early detection. In: J.F.
NYSTROM-LAHTI,
M., Mutations of a mutS homolog in hereditary Holland, E. Frei 111, R.C. Bast, Jr., D.W., Kufe, D.L. Morton and R.R.
nonpolyposis colorectal cancer. Cdl, 75,1215-1235 (1993).
Weichselbaum (eds.), Cancer medicine, pp. 408-431, Lea and Febiger.
LOTFI,A.M., SPENCER,
R.J., TLSTRUP.
D.M. and MELTON,L.J., 111, Philadelphia (1991).
Colorectal polyps and the risk of subsequent carcinoma. M q o Clin. VARLEY,
J.M., SWALLOW,
J.E., BREAMMAR,
W.J., WHI-ITAKER.
J.L. and
Proc., 61,337-343 (1986).
WALKEK,
R.A., Alterations to either c-erb-B-2 (neu) or c-myc protoonLYNCH.
H.T., SCHUELKE,
G.S., WELLS,I.C., CHENG,S.C., KIMBERLING, cogenes in breast carcinoma correlate with poor short term prognosis.
W.J., BISCONE,
K.A., LYNCH,
J.F. and DANES,
B.S., Hereditary ovarian Oncogene, 1,423-430 (1987).
carcinoma. Biomarker studies. Cancer, 55,410415 (1985).
VOGELSTEIN,
B., FEARSON,
E.R., HAMILTON,
S.R., KERN,S.E., PREISLYNCH,H.T.. SMYRK,
T.C., WATSON,P., LANSPA,S.J., LYNCH,J.F., TNGER, A.C., LEPPERT,
M., NAKAMURA,
Y., WHITE,R., SMITS,A.M.
LYNCH,P.M., CAVALIERI,
R.J. and BOLAND,
C.R., Genetics, natural and Bos, J.L., Genetic alterations during colorectal-tumor develophistory, tumor spectrum, and pathology of hereditary nonpolyposis ment. New Engl. J. Med., 319,525-532 (1988).
Документ
Категория
Без категории
Просмотров
2
Размер файла
430 Кб
Теги
380
1/--страниц
Пожаловаться на содержимое документа