Age-linked gene changes underlie therapy-related leukemia in cancer patients

Date: Dec-09-2014 A small proportion of cancer patients who receive radiotherapy or

chemotherapy can develop acute myeloid leukemia - an aggressive blood cancer with a

poor prognosis. Now, a new study suggests this is because of a build-up of age-related gene mutations in blood cells that resist treatment and then multiply at an

accelerated rate.

Contrary to what many believe, the leukemia that

sometimes follows cancer treatment may not be a result of chemo or radiotherapy but

due to accumulated, age-related mutations in cells that resist therapy and then

multiply rapidly.

The finding challenges the conventional idea that therapy-related acute

myeloid leukemia (AML) is a direct result of the cancer treatment.

Chemotherapy and radiation therapy fight cancer by inflicting a barrage of gene

changes that accumulate in the cancer cells, causing so much havoc that they die.

Unfortunately, for a small proportion of patients, this is followed by therapy-related AML.

In the US, there are about 18,000 new cases of AML every year, including 2,000

that follow exposure to chemotherapy or radiation therapy. Even with aggressive

treatment, therapy-related AML is almost always fatal.

Therapy-related AML typically develops 1-5 years after chemotherapy or radiation,

and the rate at which it occurs depends on the cancer being treated. For instance, 10% of patients with lymphoma that recurs following chemotherapy develop therapy-related AML. But in the case of breast cancer, only 0.1% of patients develop

therapy-related AML.

Now, in a new study published in the journal Nature, researchers at

Washington University School of Medicine in St. Louis, MO, challenge the idea that it

is the cancer treatment itself that causes therapy-related AML.

They suggest the findings will lead to new ways to research and predict

which patients are at risk of developing therapy-related AML, and also to prevent

it.

Build-up of P53 mutations followed by cancer treatment leads to AML

In their study, the researchers focus on a well-known cancer gene - P53. They find

that mutations to this gene accumulate in blood stem cells as a person gets older,

years before they are diagnosed with cancer.

P53 is a tumor suppressor gene - its normal function is to stop cells dividing

uncontrollably and to maintain the integrity of chromosome structures inside cells.

But when both copies of the gene are mutated, cancer can follow.

If and when a person with a build-up of P53 mutations in their blood stem cells

develops cancer, and then has chemotherapy or radiotherapy, the mutated cells are

more resistant to treatment and proliferate more quickly. It is this

sequence of events that can lead to AML, the authors argue.

"This is contrary to what physicians and scientists have

long accepted as fact," says senior author Dr. Richard K. Wilson, director of The Genome Institute at

Washington University.

In one part of the study, the team sequenced the genomes of 22 therapy-related AML

cases and found the genetic mutations in the leukemia cells of those patients were

similar in number and type as those found in AML patients who had not received

chemotherapy or radiation therapy - suggesting the cancer treatment was not to

blame.

In another part of the study, the researchers analyzed blood samples from 19

healthy people aged 68-89 years with no history of cancer or chemotherapy. To their

surprise, they found nearly 50% of them had mutations in one copy of the P53 gene -

suggesting these accumulate with age.

"Most of the time, these mutations are harmless because they only

affect one copy of the gene," says Dr. Wilson.

Bone marrow had P53 mutations years before therapy-related AML developed

These two findings caused the team to dig further. What was happening earlier in

people's lives? What is the exact P53 mutation that causes therapy-related AML years

later?

Blood stem cells are made in bone marrow. So, the researchers sourced and analyzed

bone marrow samples from seven patients with therapy-related AML whose samples had

been collected and stored before they developed the blood cancer between 3 and 6

years later.

In four of the seven samples, the team found very low levels of specific P53

mutations. It is possible that these P53 mutations were present in the other three

samples, but at levels too low to detect, say the researchers.

However, another possibility is that other age-related mutations may have played a

role in triggering therapy-related AML, they note. The team is already conducting

follow-up studies to look for other age-related mutations.

And finally, using mice, the researchers showed chemotherapy causes blood stem

cells with P53 mutations to divide more quickly - but this did not happen in blood

stem cells without P53 mutations.

In September of this year, Medical News Today learned of another study where

researchers uncovered a genetic network that fuels

AML and its precursor disease - myelodysplastic syndrome - paving the way for new

treatment strategies.

Written by Catharine Paddock PhD

Not to be reproduced without permission.

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Courtesy: Medical News Today Note: Any medical information available in this news section is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional.