Researchers have completed the first comprehensive analysis combining full genomic sequencing and gene expression profiles of more than 1,300 patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS).

The research is being presented today during the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando. 

AML and MDS are blood cancers that undermine the body’s ability to make healthy blood cells.

While previous research has identified the roles of various individual genes in these diseases and their subtypes, the new study is the first to take an unbiased, genome-wide approach to illuminate the links between genes, gene expression, the physical form of cancer cells, and patient outcomes.

“Treating these diseases is a challenge because subtypes present different features,” said lead study author Ilaria Iacobucci, PhD, ofSt. Jude Children’s Research Hospital. “Our study provides a much richer understanding of these subtypes, akin to a dictionary of all the genomic alterations.

It also underscores the value of having comprehensive genomic information at the start of treatment to remove uncertainty and help clinicians better understand a patient’s outlook.”

The researchers analysed blood and bone marrow samples from 598 adults with AML and 706 adults with MDS.

In addition to sequencing all DNA, they also sequenced RNA, an indicator of which genes are being actively expressed and which are altered by chromosomal rearrangements, a common feature in AML.

They then combined these data with information on health outcomes and the physical features of each patient’s cancer.

In addition to confirming known genetic subtypes driven by chromosomal lesions or mutations, the results shed light on previously unknown associations.

For example, the researchers found pairs of genetic alterations that seem to change a patient’s prognosis when they occur together, such as combinatorial mutations in NPM1 and cohesin genes that confer good prognosis.

Conversely, mutations and structural variants of RUNX1 in association to overexpression of MN1 have a very poor outcome.

They also discovered unexpected genetic similarities among cancers that are morphologically different from each other, underscoring how genetic analysis combined with standard approaches provides a more complete picture than analysis of morphology alone. 

These insights have important implications for both cancer research and clinical decision making, researchers say.

At a basic level, having a dictionary-like genetic reference for AML and MDS subtypes will be useful for future research into how these diseases develop and how they might be targeted with new drugs.

From a clinical perspective, the study suggests full-genome sequencing is not only feasible but useful for identifying disease subtypes and prognosis in order to tailor the course of treatment to each patient’s disease – an approach known as precision medicine.

“This is the sort of dataset that’s going to prove invaluable to precision medicine efforts,” said Dr. Iacobucci. “As we have seen in lymphoid malignancies, the study shows the power of integrated genome and transcriptome sequencing to identify new disease subgroups of clinical significance not evident on conventional pathologic and molecular analysis.”

Researchers from the Munich Leukemia Laboratory have recently sequenced DNA and RNA from more than 4,500 patients as part of a broader effort to move whole genome and transcriptome sequencing from the laboratory into the clinic for diagnosis and targeted treatment.

Source: American Society of Hematology

Watch the press conference here.

Watch our interview with Dr Charles Mullighan here.