| The Laird-Offringa
laboratory is focused on identifying changes in
the genetic material (DNA) of lung cancer cells,
to help us understand how lung cancer develops,
and to use as markers for early detection. The
kind of molecular change we study is called DNA
methylation. DNA methylation is a chemical modification
of DNA that doesn’t change the genetic sequence,
but does change the way the DNA looks to a cell.
Excessive methylation leads to the silencing or
inactivation of genes. In cancer cells, DNA methylation
is now recognized as a key molecular mechanism
for the inactivation of so-called “tumor
suppressor genes”. If one thinks of the
genetic material as a very thick textbook, with
instructions for the cell, DNA methylation can
be thought of as post-it notes stuck to the beginning
of certain chapters, instructing these chapters
to be skipped. The pattern of methylation, or
the “methylation profile”, is not
the same for all types of cancer. Thus, abnormal
methylation changes could provide important insights
into the changes that lead to a particular kind
of cancer. In addition, they could yield powerful
biomarkers that may help the detection of different
kinds of cancer.
At USC, we have developed a sensitive, accurate,
automated DNA methylation analysis technique called
MethyLight®. It uses a robot to analyze large
numbers of samples per day, so that the presence
of methylation at many different genes can be
studied in a short amount of time. Using this
assay, we have recently identified genes that
are more highly methylated in lung adenocarcinoma
than in a healthy, non-cancerous section of the
lung of the same patient. Here we propose to examine
when these changes first occur: whether they are
present in atypicial adenomatous hyperplasia (AAH)
and/or bronchioalveolar carcinoma (BAC), which
are the pre-invasive lesions thought to precede
lung adenocarcinoma. In addition, we will carry
out detailed characterization of genes that specifically
become methylated as BAC transitions to invasive
adenocarcinoma. We are able to carry out such
studies through our collaboration with Dr. Keith
Kerr, a pathologist who is an expert in early
lung lesions such as AAH and BAC. He is giving
us access to a unique sample collection that he
has collected over many years. The proposed studies
will help clarify the molecular changes that cause
pre-invasive changes in the lung, and the subsequent
changes that cause progression to invasive lesions.
The identification of sequential changes in methylation
will provide insights that may be applicable to
the development of targeted drugs. In addition,
such DNA methylation changes will be powerful
markers for early detection and patient classification,
helping guide clinical decisions about treatment.
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