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How Do Molecular Diagnostics Work?

How Do Molecular Diagnostics Work?

Clinicians used to categorize cancer cells according to the appearance of their pathology using a microscope. New technology allows a much more refined and exact approach to diagnosing cancer.

Tests evaluate how genes and proteins are interacting in a cell by analyzing activity patterns in cancerous or precancerous cells. The cancer-related gene activity is separated from other activity in the cell. An analysis uncovers sets of changes and captures this information as expression patterns, or "molecular signatures."

By evaluating these patterns and changes, researchers have discovered that cancers named according to the organ in which the cancerous cells reside are in fact many different types of cancer. Studies have shown that what had been considered a single type of cancer based on how the cells looked under a microscope was really two, three, or even more subtypes, and each had a distinct gene expression pattern.

Protein Isoforms

Our bodies have developed elaborate mechanisms to modify proteins, creating many protein variants called isoforms, both to increase the diversity of functions and to regulate the activities of proteins. Isoforms represent a new class of diagnostic biomarkers.

About 8% of these isoforms are generated during the process of transcribing the coding genes into mRNA. Over 90% of protein isoforms are created through posttranslational modifications (PTMs) after genes have been transcribed to RNA and RNA then translated to proteins. Some of the common PTM's that have been implicated in cancers are phosphorylation, sulfation, acetylation methylation and hydroxylation.

Recent scientific evidence is demonstrating that the differentiation and quantification of individual protein isoforms could improve insights into disease diagnosis and management.


Assays have been designed to access and capitalize on these untapped protein isoform biomarkers.

Image courtesy of Target Discovery      

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Examples of molecular diagnostics in use today

Non-Hodgkin's lymphoma

Using a chip that contained fragments of 18,000 genes, researchers discovered two distinct cancer subtypes in a blood cancer called diffuse large B cell lymphoma-the most common subtype of non-Hodgkin's lymphoma.

These cancers subtypes looked the same under the microscope, but had different patterns of gene activity. The subtypes were different in other ways, too. For one thing, they arose from different kinds of cells. Tumor cells of one cancer subtype arose from less differentiated lymphocytes, while the other subtype arose from more differentiated lymphocytes.

Later, another gene chip analysis yielded a third and then fourth subtype of diffuse large B cell lymphoma. Researchers also found 17 genes that were strongly related to survival.

A formula was created to predict response to chemotherapy based on the expression patterns of these 17 genes. This formula divided B cell lymphoma patients into four groups. Two of the groups had about 72% survival rates five years after diagnosis. The third group had a 34% survival rate, and the fourth had a 15% survival rate.


The 17-gene predictor formula identified patients with the poorest prognosis better than any other method.

As a result, patients predicted to have poor outcomes can be identified correctly early in treatment and receive more aggressive therapies right away instead of waiting until standard therapies fail.

Image courtesy of the National Cancer Institute  
Breast Cancer

Molecular tests are being offered by several companies, including Genomic Health, Agendia and AviaraDx to help identify a breast cancer patient's risk of disease recurrence and/or the likelihood of it becoming metastatic.

These multigene assays are performed on tissue specimens taken from the primary tumor and utilize molecular methods such as reverse transcriptase polymerase chain reaction (RT-PCR) to determine gene expression. Depending on the pattern of gene expression, the patient's risk for recurrence is calculated. In the case of Genomic Health's Oncotype DX test, the assay is also predictive of response to chemotherapy.

Stomach Cancer

Comparing gene activity patterns in normal stomach tissue and tissue from stomach tumors, researchers found that the tumor tissue, but not the normal tissue, expressed a gene called PLA2G2A. They also found that cancer patients with high expression levels of PLA2G2A were more likely to survive for five years, compared with patients whose tumors produced lower levels.

Lung Cancer

Using microarrays, researchers discovered that the most common type of lung cancer called lung adenocarcinoma is actually four distinct types of cancer, each with its own gene expression pattern.

  Image courtesyof the National Cancer Institute  
Colorectal Cancer

Recently, colorectal cancer patients who harbor KRAS mutations were shown to have no response to antibody-based EGFR therapies such as cetuximab and panitumumab.

Mutated KRAS genes have been detected in about 40% of metastatic colorectal cancers. A new clinical laboratory test is now commercially available that identifies colorectal cancer (CRC) patients who may be resistant to EGFR-targeted monoclonal antibody therapies.

Reminder: What are tumor markers?

Molecular diagnosis allows for the identification of tumor markers that are used in the detection, diagnosis, treatment, and monitoring of some types of cancer.

Tumor markers are substances found in the blood, urine, or tissues produced by tumor cells or other cells in the body in response to cancer or certain benign conditions. For more information about tumor markers, please go to the CISN fact sheet called Tumor Markers. (coming soon)

Molecular diagnostics and drug metabolism

Along with cancer diagnosis, molecular diagnostics impact cancer treatment. Microarrays are being applied to pharmacogenomics-an area of research that studies why certain drugs work in combination with particular genetic expression patterns but not with others-to design new drugs that target cancer cells and do not affect normal ones.

Drugs are broken down in the body by proteins, and not all of these proteins are identical from person to person. The genetic variations, called SNPs, can result in subtle differences in proteins that translate to major differences in how the protein functions.

For example, as many as 40% of people have a SNP that causes a deficiency in a protein called cytochrome P450 CYP2C9, which is important to drug metabolism. Deficiencies in this protein can impair the metabolism of as many as 1 in 5 medications currently on the market, such as Tamoxifen, which is used in many ER+ breast cancer patients.

An example of an approved cancer therapy that uses molecular diagnostics

The Food and Drug Administration approved Herceptin in late 1998 as a therapy for women who test positive for high levels of the Her-2/neu protein, about 25 to 30% of all breast cancer patients.

Herceptin was developed using pharmacogenomics. In the 1980s, researchers discovered that some women who had particularly fast-growing breast cancers expressed extra copies of a gene called Her-2/neu. The genes were producing many copies of a protein that appeared to be driving the growth of the cancer cells.


In the early 1990s, an antibody was developed that latches onto the Her-2/neu proteins on the surface of a cancer cell.

It stops the proteins from spurring on cancer-cell growth, and this stop signal can also halt propagation of survival signals wit

Image courtesy of the National Cancer Institute      

Some women who were given the experimental antibody saw their cancer growth slow or stop altogether when their Herceptin treatment was combined with chemotherapy.





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