In an article published online May 9 in Nature, the authors provide the first high-resolution view of the genomic landscape of human melanoma tumors.

Previous genetic analyses have focused on the exomes of many types of cancer tumors, concentrating on the tiny fraction of the genome that provides the genetic code for producing proteins.

Whole genomes contain a wealth of genetic information, and by sequencing and analyzing 25 metastatic melanoma tumors – a significant technical and computational feat – scientists can learn vastly more about the variety of genetic alterations that matter in melanoma.

When the scientists explored the whole genome data generated and analyzed at the Broad, they found that the rates of genetic mutations rose along with chronic sun exposure in patients, confirming the role of sun damage in disease development.

Proteins provide clues to outcomes

An international group of researchers report promising results with a test that may identify patients likely to benefit from first-line therapy with a particular drug combination.

Dr Oliver Gautschi from the Swiss Group for Clinical Cancer Research (SAKK), and collaborators from The Netherlands and the US company developing the test, conducted a retrospective analysis of two phase-II trials with a serum proteomic classifier called VeriStrat®. Their aim was to evaluate the prognostic value of the test in patients with advanced non-small cell lung cancer receiving first-line treatment with bevacizumab and erlotinib. VeriStrat® uses mass spectrometry to measure proteins in pre-treatment blood and assigns a result that correlates with outcome from treatment with a class of drugs known as EGFR inhibitors, which includes erlotinib and gefitinib. The test was initially developed and validated in patients who had already been treated with chemotherapy, and who then received an EGFR inhibitor in second line, Dr Gautschi explains.

The researchers used VeriStrat® to analyze blood samples from 117 patients previously enrolled in two phase II trials and compared the results to the patients’ progression-free survival and overall survival. The analysis showed that those classified by the test as likely to have better outcomes on EGFR inhibitor therapy did indeed live longer.

Micro RNA marks response to chemoprevention

Dr Celine Mascaux from the University of Colorado and collaborators report that the micro RNA miR-34c is a potential biomarker for histological response in lung cancer chemoprevention studies.  Chemoprevention is a way of preventing the development of cancer using medicines or other agents, including the prevention of cancer in at-risk individuals such as smokers.

Dr Mascaux and colleagues analyzed the expression of selected micro RNAs as potential surrogate biomarkers in a lung cancer chemoprevention trial that compared a drug called iloprost to placebo in 125 former or current smokers. In a recent study, oral iloprost has shown promise to prevent the development of lung cancer in high-risk people.

After analyzing 14 different micro RNAs from 496 lung biopsies, they found that change in the expression of a particular micro RNA — miR-34c — in follow-up biopsies was inversely correlated with histological response. Changes in the expression of this micro RNA may therefore be a quantitative biomarker of response in lung chemoprevention studies, they say.

RRM predicts shorter survival

Dr Giovanna Dal Bello and colleagues report that expression levels of ribonucleotide reductase subunit 2 (RRM2) predict shorter survival in patients whose non-small cell lung cancer had been surgically removed. In 82 patients, the Italian group found that RRM2 was an independent prognostic marker of shorter survival.

Epigenetic clues distinguish tumor types

Dr David Shames from a San Francisco, California-based biotechnology company and colleagues report that epithelial-like lung tumors, which have a better prognosis and exhibit greater sensitivity to inhibitors of the EGFR pathway, can be distinguished from mesenchymal-like tumors on the basis of global DNA methylation patterns.  DNA methylation is an important form of ‘epigenetic’ modification, which affects the expression of genes within cells.

Using cancer cell lines and surgically resected non-small cell lung cancer tumors, the researchers showed that patterns of DNA methylation can divide non-small cell lung cancer into two phenotypically distinct subtypes. Their work also provides proof of principle, they say, that “differences in DNA methylation can be used as a platform for predictive biomarker discovery and development.”

A promising biomarker of response to radiotherapy

In a further report, Dr Ioannis Trigonis from the Wolfson Molecular Imaging Centre and The Christie Hospital in Manchester, UK, describes the findings from an assessment of F-18 fluorothymidine (FLT), a tracer molecule used in PET scanning to measure tumor cell proliferation.

In the report, The researchers found that radiotherapy induced early significant decreases in tumor FLT uptake that varied across patients.  Their results indicate the potential of FLT PET to identify how well patients are responding to radiotherapy and guide therapeutic approaches, they say. More results will be presented at the meeting.

Already, information gleaned through whole-genome sequencing is pushing researchers to reclassify tumors based on their genetic makeup rather than their location in the body. Using “deep digital sequencing” these WashU scientists sequenced individual mutations in patients’ tumor samples more than 1,000 times each. This provides a read-out of the frequency of each mutation in a patient’s tumor genome and allowed the researchers to map the genetic evolution of cancer cells as the disease progressed.

They found that as cancer evolves, tumors acquire new mutations but always retain the original cluster of mutations that made the cells cancerous in the first place. Their discovery suggests that drugs targeted to cancer may be more effective if they are directed toward genetic changes that occur early in the course of cancer. Drugs that target mutations found exclusively in later-evolving cancer cells likely may not have much effect on the disease because they would not kill all the tumor cells.

In addition, the researchers have identified a series of mutations in the breast tumors that have corresponding small-molecule inhibitor drugs that target defective proteins. This finding indicates that for women who are not responding to aromatase inhibitors, treatment options may include combining conventional chemotherapy with the indicated small-molecule inhibitor.

The researchers felt it was important to show there could be therapeutic options available to patients who are resistant to aromatase inhibitors,” Mardis says. In the future, they think sequencing will contribute crucial information to determining the best treatment options for patients.”