RESEARCHERS DISCOVER A UNIQUE MOLECULAR PROFILE FOR LUNG CANCER

A team of researchers has found that the expression pattern of certain
microRNAs, or miRNAs, may predict tumor aggressiveness in some patients
with lung cancer. These findings indicate that miRNAs may represent a
new class of diagnostic and prognostic tools for lung cancer. The study
is a collaboration among researchers at The Ohio State University
Comprehensive Cancer Center, Columbus, Ohio; the Jikei University School
of Medicine, Tokyo, Japan; National Cancer Center Research Institute,
Tokyo, Japan; and the Center for Cancer Research at the National Cancer
Institute (NCI), which is part of the National Institutes of Health. The
study results appear in the March 13, 2006, issue of "Cancer Cell"*.

miRNAs are small segments of genetic material called ribonucleic acid,
or RNA, and are thought to control gene expression. Their actions could
change the expression of cancer-related genes within a cell and lead to
malignancies.

The researchers identified two miRNAs -- "has-mir-155" and
"has-let-7a-2" -- that could be used as prognostic indicators in
patients with adenocarcinoma, a malignancy of the mucous glands in the
lungs. High levels of "has-mir-155" or low levels of "has-let-7a-2" were
associated with poor prognosis. Specifically, overexpression of
"has-mir-155", or the signalling of the miRNA to change the amount of a
protein produced, was the most significant indicator of this prognosis,
independent of tumor stage. Although these miRNAs have been identified
in other cancers, this is the first evidence linking "has-mir-155" to
lung cancer.

A tumor with an overexpression of "has-mir-155" or reduced expression of
"has-let-7a-2" would indicate the need for aggressive chemotherapy or
radiation treatments. Other tumors that do not show high "has-mir-155"
or low "has-let-7a-2" levels are less aggressive, and those patients
might not require more therapy.

"This study is significant because it provides another tool for studying
prognosis that is independent of tumor stage," said Curtis Harris, M.D.,
chief of the Laboratory of Human Carcinogenesis at NCI and co-leader of
this study. "Following surgery, 50 to 60 percent of patients with stage
I lung cancer will develop metastatic disease within five years. This
may indicate that there are micrometastases that have not been detected
by imaging, scanning or pathology." Harris noted that "in the future, we
can use miRNAs and other biological predictors to select patients who
may need more aggressive treatment versus those who may not. Additional
studies confirming these results are the next step before incorporating
miRNA analysis into routine clinical practice."

Lung cancer is the leading cause of death due to cancer and is primarily
caused by exposure to tobacco smoke. Scientists seek to better
understand the mechanisms underlying this disease, and miRNAs may
provide a way to examine the regulation of cancer-related genes.

"miRNAs are going to be important biomarkers of not only diagnosis and
prognosis, but therapy, as well," said Harris. "The next step is to
identify the genes that the miRNAs are affecting; they could be used as
potential targets for developing novel therapies."

In the study, a total of 104 pairs of primary tumor tissues and
corresponding noncancerous lung tissues were examined. The tumor and
corresponding normal tissues were obtained from the same patient to
eliminate genetic differences between tumor and normal tissues.

Researchers focused primarily on the more common adenocarcinomas in
their analysis; adenocarcinomas and squamous cell carcinomas. Unlike
adenocarcinomas, squamous cell carcinomas form in the cells lining the
internal surfaces in the lung. These two tumor types are the most common
lung cancers and are referred to as non-small cell lung cancers (NSCLC).
In the study, adenocarcinomas of the lung comprised 63 percent of the
tumors studied and squamous cell carcinomas comprised 37 percent.

Patterns of miRNA expression in each tumor and normal tissue pair were
studied by microarray analysis. A microarray allows the measurement of
hundreds of miRNAs simultaneously in a single sample. Five miRNAs
displayed different expression levels in tumor tissues versus their
corresponding noncancerous controls and, thus, were selected for further
study. Upon statistical analysis, data showed that patients with high
"has-mir-155" or low "has-let-7a-2" had poorer survival than patients
showing low "has-mir-155" or high "has-let-7a-2" expression. The
difference in the prognosis of these two groups was highly statistically
significant.

After examining tissue from lung cancer patients, and following each
patient to see how long they lived, researchers found that miRNA
expression patterns were independent of tumor stage. When the scientists
combined all clinical and molecular factors, they found that a high
level of "has-mir-155" or a low level of "has-let-7a-2" was the most
significant prognostic factor for an unfavorable patient outcome.

"This is promising research and is the first study to link these miRNAs
to lung cancer," said Carlo Croce, M.D., chair of Molecular Virology,
Immunology and Medical Genetics at The Ohio State University and study
co-leader. "We are proposing that "has-mir-155" may be acting like an
oncogene in lung cancer." Oncogenes control cell growth and, when
mutated, can contribute to abnormal cell growth. "miRNAs control the
expression of a number of genes," noted Croce, "so if the miRNA is
altered, this could lead to the alteration of a number of genes
affecting malignant tumor growth. Although these results are
encouraging, further testing is required to demonstrate the validity of
using these markers for predicting patient outcomes."

Other types of cancers also have been shown to express specific miRNAs;
however, the exact role that miRNAs play in the development of human
cancers is unknown. A recent paper appearing in the "Proceedings of the
National Academy of Science" supports the observation that
cancer-related genes are regulated by miRNAs in solid tumors**.

For more information about cancer, visit the NCI Web site at
http://www.cancer.gov or call NCI's Cancer Information Service at
1-800-4-CANCER (1-800-422-6237).

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