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Exome Sequencing Reveals Recurrent Mutations with Prognostic Potential

NEW YORK (GenomeWeb) – In a study published online this week in the Journal of Clinical Oncology, an international team led by investigators in the UK described a set of genes that appear to offer prognostic clues for individuals with myeloma.

The researchers did exome sequencing on tumor and matched normal samples from more than 450 individuals with myeloma who'd been enrolled through the National Cancer Research Institute's Myeloma XI trial, a phase III clinical trial with intensive and non-intensive myeloma treatment arms that relied on data on patients' clinical outcomes, molecular cytogenetics, and more.

Among genes frequently mutated in the myeloma tumor samples, they saw several with apparent ties to unusually poor or beneficial outcomes. Coupled with clinical data on disease stage, mutation patterns in the gene set made it possible to pick up some 90 percent of the cases involving aggressive disease and earlier-than-usual death.

"We hope our study ultimately paves the way for genetic testing to pick out the minority of patients with myeloma with a poor prognosis, who might benefit from the most intensive possible treatment," senior author Gareth Morgan, a hematology and molecular pathology researcher at The Institute of Cancer Research in London, said in a statement.

In the past, approaches such as the international staging system (ISS) have been used to try to differentiate between myeloma patients who are expected to respond well to treatment and the minority of individuals with the blood and bone marrow cancer with lower-than-usual progression-free survival or overall survival, the researchers noted.

While molecular subtypes involving specific copy number changes or chromosomal translocations can refine predictions produced by the ISS to some extent, they added, it's expected that a clearer picture of the mutations present in myeloma tumors may help in finding still more prognostic indicators.

With that in mind, the team used Illumina paired-end sequencing to sequence the exomes of tumor and matched normal samples from 463 individuals with myeloma. The sequence data revealed recurrent mutations in 13 genes, including some significantly mutated genes that were only found in tumors from specific cytogenetically defined myeloma subgroups.

Many of the mutations fell in genes that may be amenable to targeted treatment, the researchers noted, including genes in the RAS/MAP kinase pathway — which were mutated in tumors from more than 43 percent of those tested — and genes from the NF-kappaB pathway.

As expected, factors such as disease stage, translocation patterns, and other cytogenetic features corresponded with overall survival times in the myeloma patients.

But the team also found mutations that coincided with better or worse outcomes. In the more than one-third of patients with CCND1 mutations in their tumors, for example, the two-year survival rate was just 38 percent. In contrast, some 80 percent of those without mutated CCND1 survived beyond two years.

Similarly, alterations in ATM, ATR, and TP53 genes appeared to be associated with poorer-than-usual outcomes, diminishing both progression-free survival and overall survival rates.

Meanwhile, mutations in ZNFHX4 also coincided with diminished progression-free survival time, the researchers reported, while alterations with IRF4 and EGR1 often turned up in tumor samples from those with better-than-usual outcomes.

By bringing such prognostically informative mutations together with disease-stage profiles and cytogenetic profiles, the study's authors developed a staging system called ISS-Mut that accurately predicted just over 80 percent of cases with early progression and 90 percent of cases with diminished overall survival times. 

"The detection of mutations can improve our ability to detect high-risk patients who experience relapse and die early," they wrote, "but who may benefit from specific therapeutic interventions."