Understanding cancer-causing mutations found in lymphoma

Green Spleen Since scientists first sequenced a cancer genome a decade ago, hundreds of cancer genomes have been sequenced, each one revealing myriad genetic mutations.

But which ones are significant? How can we decide which mutations might be the best drug targets?

Dr Keisuke Horikawa and his team at The John Curtin School of Medical Research at ANU are tackling this problem by investigating which mutations out of thousands are responsible for lymphoma, which is a cancer of white blood cells.

“What I am trying to do is find meaning in cancer genetics. We find so many mutations, but we don’t know which mutations are the problem,” says Dr Horikawa.

Lymphoma is the fifth most common cancer in Australia. Over 5800 Australians are diagnosed each year. Recent advances in DNA sequencing found that lymphoma genomes are very complex. It’s therefore difficult to treat patients with lymphoma because each patient has a unique set of mutations.

Ninety-five per cent of lymphomas originate from B cells, which is a type of white blood cell. B cells make the antibodies necessary to fight infection, however sometimes accumulation of mutations in the B cell can cause cancer.

“There is limited understanding as to which mutation is changing B cell function,” says Dr Horikawa.

As the cost of sequencing genomes has plummeted it is now possible to take a tumour sample from a patient and sequence it. But just knowing which genes are mutated is not helpful, because we don’t know which mutations are significant.

The goal in cancer medicine is to target the problems caused by mutations with drugs, but the first challenge is to identify which mutations are the problem.

“We characterise each mutation, checking for potency and to see if they respond to specific drugs,” says Dr Horikawa.

Dr Horikawa and his team have been focusing their research on mutations which have been found to have strong links with lymphomas. They are studying two molecules, MYD88 and CARD11, which are signaling molecules, responsible for communicating between cells. They were surprised to find that introducing MYD88 and CARD11 mutations into normal B cells caused them to proliferate. However, this proliferation was self-limiting, meaning that several checkpoints held back B cell proliferation driven by these mutations.

As a result, Dr Horwika and his team began researching a potential inhibitor of CARD11 mutations. They found lymphoma with weak CARD11 mutation can be treated with Bruton Tyrosine Kinase (BTK) inhibitor. This drug is now part of a clinical trial.

As it becomes more cost-effective to sequence tumours of individual patients the knowledge of which mutations are significant will make it easier to create effective individual treatment plans for patients.

“I hope my research is used in the future for personalised medicine,” Dr Horikawa says.

Published in Research Highlights – The John Curtin School of Medical Research, ANU, May 2017.

 

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