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Cancer outcome depends on complex interactions between many mutations

Cancer outcome depends on complex interactions between many mutations, experts highlighted at the Molecular Analysis for Personalised therapy (MAP) Congress, held 13-14 October in Zurich, Switzerland.

The 2017 meeting focused on two aspects of so-called precision medicine: the complexity of the molecular mechanisms that lead to cancer progression, and the use of technologies to decipher this complexity.

Commenting on the first topic, Prof Fabrice André, co-chair for ESMO of the MAP meeting and Chair of the ESMO Translational Research and Personalised Medicine Working Group, said: “We know now that some cancers need several mutations to grow. Patient outcomes depend on the complex interactions between these mutations.”

During cancer progression, DNA alterations appear randomly in cancer cells. Only the alterations conferring a survival advantage to the cancer cells are 'kept', following the well-known process of natural selection. The survival advantage of a new alteration depends on the alterations already present in the cancer – called ‘evolutionary dependencies’.

A study presented at the MAP Congress aimed to discover these dependencies between alterations and to understand how they affect cancer response to medicines. (1, 2) The researchers looked for patterns in the occurrence of alterations in more than 6,000 patients who had been genetically profiled by The Cancer Genome Atlas (TCGA) consortium. Next, they checked whether the patterns had an impact on how cancer cell lines responded to medicines.

“We found evidence supporting the existence of hundreds of evolutionary dependencies between alterations in cancer,” said lead author Dr Marco Mina, University of Lausanne, Switzerland. “We also found evidence that these evolutionary dependencies affect the response of cancer cell lines to therapy.”

Mina said: “Dependencies between alterations should be considered when deciding on patient therapy as they can have a dramatic impact on response.”

“This study illustrates how the co-occurrence of several mutations can lead to cancer progression,” said André. “Predicting outcome cannot be based on a single mutation. What is important is the overall landscape of mutations.”

Regarding the second topic of technology, André said that scientists know how to sequence DNA; the issues requiring more knowledge are how to transform raw sequencing data into biological information, and how to interpret the clinical meaning of the biological data.

When it comes to transforming raw sequencing data, researchers at the MAP Congress showed how an algorithm they developed, called Excavator2, expands the number of copy number alterations that can be identified by small targeted sequencing panels, and therefore could be targeted for cancer treatment. (3)

Lead author Dr Luca Mazzarella, European Institute of Oncology, Milan, Italy, said: “Our method enhances the identification of alterations, thereby increasing the chances of finding targeted treatments for patients.”

André said: “This study is an example of how we can use bioinformatic tools to fine-tune the analysis of genome sequences.”

“For the third year in a row, the MAP Congress addresses an actual need from the medical and scientific community, who did not benefit, until then, from a place for exchange on personalised medicine,” outlined Prof. Patrice Viens, UNICANER President. “Thanks to a strong partnership between Unicancer, ESMO and Cancer Research UK (CRUK), this meeting has now become a major event in this domain. We are looking forward to welcoming it again in Paris next year.”

The MAP meeting is a joint initiative of the European Society for Medical Oncology (ESMO), Cancer Research UK and Unicancer. It gathers medical oncologists, academics, regulators, industry research and development scientists to explore how to make the best use of genome sequencing data to improve personalised treatment of cancer patients.