Novel Prognostic Biomarkers Discovered in Specific Cancer Types

An analysis of breast cancer patient gene reveals that copy number alterations (CNAs) within cancer-causing genes is more likely to accurately indicate the severity of the disease (shown) than simply measuring how many of those genes are actually mutated to cause cancer (not shown).

Scientists at Cold Spring Harbor Laboratory (CSHL) have identified a specific class of biomarkers that can tell a lot about how aggressive a patient’s cancer will be.

“There are undoubtedly dozens or hundreds of mutations that cause cancer, and that can be found in almost any tumor,” said CSHL Fellow Jason Sheltzer, Ph.D. “That’s why it was surprising to discover that these mutations are pretty evenly distributed in early-stage benign cancer as well as in the really aggressive, highly-malignant cancers.”

In other words, the mutations that cause cancer don’t actually tell you all that much about who will end up surviving and who will end up dying from cancer.

That’s why Dr. Sheltzer set out to find other easily identifiable factors that can determine a cancer patient’s prognosis. According to a paper (“Systematic identification of mutations and copy number alterations associated with Cancer Patient Prognosis”) published in eLife, his team not only traced each patient’s outcome—whether it be recovery or tragedy—but also took a closer look at genetic sites commonly associated with cancer-causing mutations.

“Successful treatment decisions in cancer depend on the accurate assessment of patient risk. To improve our understanding of the molecular alterations that underlie deadly malignancies, we analyzed the genomic profiles of 17,879 tumors from patients with known outcomes. We find that mutations in almost all cancer driver genes contain remarkably little information on patient prognosis. However, copy number alterations (CNAs) in these same driver genes harbor significant prognostic power. Focal CNAs are associated with worse outcomes than broad alterations, and CNAs in many driver genes remain prognostic when controlling for stage, grade, TP53 status, and total aneuploidy,” wrote the investigators.

“By performing a meta-analysis across independent patient cohorts, we identify robust prognostic biomarkers in specific cancer types, and we demonstrate that a subset of these alterations also confer specific therapeutic vulnerabilities. In total, our analysis establishes a comprehensive resource for cancer biomarker identification and underscores the importance of gene copy number profiling in assessing clinical risk.”

“While there wasn’t very much of a difference in the types of mutations that benign and aggressive tumors had,” said Dr. Sheltzer, “when we looked at copy number changes in these same genes, we found a very significant difference.”

Normally, the genetic information in a human cell comes in two copies distributed among 23 pairs of chromosomes. However, cancer cells often gain or lose chromosomes.

“A lot of cancers instead of having two copies of a gene, will have three copies, four copies, five copies, or only one copy of a gene instead,” explained Dr. Sheltzer. “We looked at the relationship between these copy number alterations and what happens to cancer patients and found a strong relationship.”

He now hopes to launch a prospective analysis, closely studying new cancer patients for years after diagnosis. This could highlight which kinds of copy number changes are associated with which outcomes.

“That would be one of the first steps towards taking what we’ve learned and translating it into a clinically useful tool that could also provide patients with peace of mind,” said Dr. Sheltzer.

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