Myeloproliferative neoplasm mutations can occur decades before cancer develops

Genetic mutations linked to myeloproliferative neoplasms (MPN) develop during childhood or even before birth, according to a new study.

Research by the Wellcome Sanger Institute and University of Cambridge, UK, traced the genetic origins of MPN in ten individuals by studying bone marrow and blood samples. They found there may be opportunities to detect cancer warning signs much earlier than usual.

The researchers say their findings, presented at the American Society of Hematology Annual Meeting in December 2020, suggest that genetic testing could help identify people at risk for cancer much earlier than current methods allow.

Senior study author Dr Jyoti Nangalia, of the Wellcome Sanger Institute and University of Cambridge, said: “Our preliminary findings show these cancer driver mutations were often acquired in childhood, many decades before the cancer diagnosis.

“Our results finally answer the common question posed by patients, ‘How long has this cancer been growing?’ as we were able to study how these particular cancers developed over the entire lifetime of individual patients.”

Dr Nangalia and her team analysed bone marrow and blood samples from 10 people with Philadelphia chromosome-negative MPNs.

In most patients, this cancer is driven by the JAK2-V617F mutation. The researchers traced the ancestry of different blood cells and were able to estimate when each patient acquired this and other important mutations.

They established that the first cancer-linked mutations emerged as early as a few weeks after conception, and up to the first decade of childhood, even though the cancer often did not develop until decades later.

Dr Nangalia said: “We were not expecting this. In fact, in one patient, the JAK2 mutation was acquired more than 50 years before their diagnosis.”

She said that some cancer-linked mutations are found in healthy individuals as they age but ageing alone does not drive the growth of cancer. It takes a long time for the clones to grow and occasionally growing clones pick up additional cancer-linked mutations.

“For these patients, we calculated how many of these cancer clones would have been present in the past, and our results suggest that these clones may have been detectable up to ten to 40 years before diagnosis,” said Dr Nangalia.

“In addition to detecting the mutations, the rate at which the mutated clones grew was also very important in determining whether, and when, cancer develops.”

The researchers say they now want to understand the factors that influence the different rates of cancer growth. They hope to determine if there are ways to intervene and slow the growth of cells with cancer-linked mutations.

Source:

Williams N, Lee J, Moore L, Baxter JE, Hewinson J, Dawson KJ, Menzies A, Godfrey AL, Green AR, Campbell PJ, Nangalia J. (2020) “Driver Mutation Acquisition in Utero and Childhood Followed By Lifelong Clonal Evolution Underlie Myeloproliferative Neoplasms”.  American Society of Hematology Annual Meeting, December 2020.

Link: https://ash.confex.com/ash/2020/webprogram/Paper143813.html