Program:
The development of neoplasia is characterized by genomic instability,
which generates the diversity necessary for a cancer cell to escape from
inherent restraints on growth. One form of genomic instability results
from malfunction of the DNA mismatch repair system (DNA MMR). This
results in the accumulation of mutations, particularly at simple
repetitive sequences called microsatellites, and results in a phenotype
that has been termed the replication error (RER) phenotype or
microsatellite instability (MI).
The DNA MMR system involves a large number of proteins, and this is not
yet fully characterized. Inactivation of several of these genes,
including hMSH2, hMLH1, hPMS2, and hMLH6 have been found in sporadic
colorectal tumors with the RER phenotype. Importantly, four major genes
associated with DNA MMR have been implicated in the causation of
hereditary nonpolyposis colorectal cancer (HNPCC), including hMSH2,
hMLH1, hPMS2, and possibly hPMS1. HNPCC accounts for approximately 3%
of all colorectal cancers, although this could be an underestimate due
to inadequate data and a failure to appreciate all of the human DNA MMR
genes.
MI or the RER phenotype may be found in varying degrees within a cancer.
Approximately 12- 15% of colorectal cancers have a degree of MI similar
to that associated with HNPCC tumors. Another 15-20% of colorectal
cancers have a OminorO form of MI, which has led to confusion in
defining the phenotype. Other cancers including those from the stomach,
pancreas, endometrium, prostate, breast and lung also show MI in a
significant proportion of those tumors. The mechanisms responsible for
MI in most tumors is incompletely understood, but there is no evidence
that it is necessarily associated with germline mutations in any of the
known DNA MMR genes linked to HNPCC. There is evidence that tumors with
MI may behave differently from other tumors in that organ without MI.
However, the full potential of using tests for MI or the RER phenotype
has not been realized due to the lack of agreement on the definition of
this phenotype.
The objective of the workshop is to develop criteria for defining
RER/MI. The workshop will address methodologic issues, including sample
collection, assay protocol, genomic targets, and quality control. The
workshop will evaluate the biological implications of RER in
carcinogenesis, and the role of RER/MI in prognosis and the assessment
of therapeutic interventions. The following issues will be specifically
addressed by the workshop.
Issue 1:How is RER/MI defined? The idiosyncratic use of criteria has
led to controversy, and if data are to be pooled from laboratories, the
definitions must be standardized.
Issue 2: What are the pathological and biological differences between
RER+ and RER- tumors? Are sporadic RER+ tumors similar to tumors
associated with HNPCC?
Issue 3: Does the diagnosis of an RER+ colorectal tumor indicate that a
patient is at increased risk to develop another cancer?
Issue 4: Does the appearance of an RER+ phenotype in a non-neoplastic
tissue indicate an increased risk for development of cancer?
Issue 5: Are there populations who should be screened for germline
mutations in one of the DNA MMR genes associated with HNPCC?
Issue 6: Does the RER+ phenotype in a colorectal cancer indicate a
better prognosis? Is there a difference whether this occurs in a
sporadic tumor or in HNPCC?
Issue 7: Can a reliable, standardized test for RER be developed that can
be used in the community? How would this be used?
Issue 8: What is the therapeutic significance of RER? Can this
information be used to explain resistance to certain forms of treatment
such as chemotherapy or radiation therapy? Can the RER phenotype be
used to justify withholding certain types of therapy?
Issue 9: What do we know of the interaction between the MMR genes and
the environment?
Issue 10: What kinds of animal models or in vitro models should be used
to study the biological implications of RER in carcinogenesis?
Registration :
No registration fee required
Deadline for Abstracts: contact Dr. Sudhir Srivastava at SrivastS@dcpcepn.nci.nih.gov
Email for Requests and Registration: SrivastS@dcpcepn.nci.nih.gov