An unprecedented massive genome sequencing of multiple myeloma tumors of 38 people has uncovered previously unsuspected genes and pathways that may offer glimmers of hope for developing more effective drugs to treat this incurable blood cancer.
Although mapping the genes from so many people offers the most clues ever available on what might drive the development of this cancer, the researchers stress there is still a lot of work to do before we know which of the genes might make useful drug targets.
You can read about their work in a paper published online this week in the journal Nature.
First author Dr Michael Chapman, a hematologist working with the the Eli and Edythe L Broad Institute in Cambridge, Massachusetts, in the US, who also works at Addenbrooke’s Hospital in another Cambridge in the UK, told the press that:
“We’ve uncovered genes that had not been suspected in cancer in any way.”
“We’ve delineated perhaps entirely new pathways as being important in cancer,” he added.
As well uncovering new pathways – interlinked chemical reactions that lead to changes in cells – Chapman and colleagues found gene mutations not known about before, which they hope will give lots of scope for new research into multiple myeloma.
Co-senior author Dr Todd Golub, director of the Broad’s Cancer Program and Charles A Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute in Boston, Massachusetts, said the study was a good example of “how genetic analysis can help point the field in the right direction very dramatically”; but he also stressed there was still a lot of work to be done before we can point to useful new drug targets.
The research study has also been successful in other ways. Many processes that are now standard in cancer genome analysis were worked out in this project, said Golub.
Multiple myeloma is an incurable blood cancer of unknown cause that starts in the bone marrow, causing plasma cells to become malignant, whereupon they crowd out normal cells and attack solid bone. It is the second most common blood cancer in the US where about 20,000 Americans are diagnosed with the disease every year.
We know little about what causes multiple myeloma: it can arise in people with no known risk factors and no family history of the disease.
The chances of surviving more than five years after diagnosis is less than 40%, which is low compared to what we can expect from other types of cancer.
For their study, the researchers conducted a “massively parallel sequencing” of tumor genomes from 38 patients “and their comparison to matched normal DNAs”.
By sequencing so many people’s genomes, they were able to pick out which genes were significantly and recurrently mutated in ways that would not have been possible with a single genome, said Chapman, whose work is sponsored by a Clinician Scientist Fellowship from Leukaemia and Lymphoma Research.
The parallel sequencing revealed previously unknown pathways that include mutations in genes involved in RNA processing and protein translation (they found these in nearly half the patients), histone methylation (a process than switches DNA genes “on” and “off”), and also genes involved in blood coagulation.
Two of the genes, DIS3 and FAM46C, appear to play important roles in keeping RNA stable and able to translate into protein. Further studies should now investigate exactly what role they play in cancer and how they may be useful as treatment targets.
Golub, who is also an investigator at Howard Hughes Medical Institute, and professor of pediatrics at Harvard Medical School, said these genes, which were frequently mutated, “were not on anyone’s radar before when thinking about multiple myeloma specifically or cancer in general”.
“This shows that there are entirely new cancer-causing genes that are going to be discovered through these sequencing efforts,” he added.
One finding that may initiate treatment possibilities sooner is the discovery of mutations in the BRAF gene in a smaller number of multiple myeloma patients.
A further investigation showed that samples from 4% of 150 patients with multiple myeloma had BRAF mutations.
BRAF mutations have never come up in connection with multiple myeloma before, although they are implicated in other cancers such as melanoma and colon cancer. Drugs that target this gene are already showing promising results in melanoma patients, and with further studies, it may not take as long as with the other discoveries, to establish if targeting BRAF with these drugs is also as effective for multiple myeloma.
A pathway suggested by the study is the NF-κB pathway, which if switched on at the wrong time, activates genes that let cancer cells grow and divide unchecked. The pathway has come up in previous studies into multiple myeloma, but without finding out what events activated it.
Chapman and colleagues found 11 genes in this pathway that were altered in at least one of the tumor samples.
Although the genes on their own are not mutated at a high rate, looking at the pathways that link them, there is a higher chance of finding the events that drive the cancer, said co-senior author Dr Gad Getz, director of Cancer Genome Analysis at the Broad Institute.
Chapman attributes much of the success of the project to the close collaboration between cancer researchers and computational experts, which enabled them to “find things that would never have been discovered by traditional means or by sequencing single genomes,” he said.
All the data from the project is being made publicly available to cancer researchers worldwide.
Funding for the research came from the Multiple Myeloma Research Foundation and tissue samples came from the Multiple Myeloma Research Consortium tissue bank.
“Initial genome sequencing and analysis of multiple myeloma.”
Michael A. Chapman, Michael S. Lawrence, Jonathan J. Keats, Kristian Cibulskis, Carrie Sougnez, Anna C. Schinzel, Christina L. Harview, Jean-Philippe Brunet, Gregory J. Ahmann, Mazhar Adli, et al.
DOI:10.1038/nature09837
Additional source: Broad Institute (23 Mar 2011).
Written by: Catharine Paddock, PhD