At a cancer genomics seminar this week we heard from Michael Tomasson of the Siteman Cancer Center, whose interest is multiple myeloma (MM), a cancer of plasma cells characterized by renal failure with bone fractures. It’s also uncurable, with a 3-year average survival following diagnosis according to the American Cancer Society.
Why Did Patient X Do So Poorly?
Dr. Tomasson presented a case, which I’ll call Patient X, a 64-year-old man who presented with anemia and back pain. The anemia had been observed in 2003, when the patient was turned down as a blood donor. In 2004 he suffered a “pathological hip fracture” – in other words, a break from a light fall that shouldn’t have caused one. High IgA levels were observed in a blood sample, and a subsequent bone biopsy revealed 56% plasma cells. By a FISH assay the patient was found to be positive for the 4:14 translocation, which is associated with a poor prognosis in MM. The patient didn’t respond to “salvage Rx,” which I’m guessing is an aggressive chemotherapy, and died in 2005, just a year after diagnosis.
Epidemiology of Multiple Myeloma
Like many complex diseases, risk of MM increases with age; typical onset is between 65 and 70 years of age. It’s also more prevalent in African Americans. Recently, researchers discovered that virtually all multiple myeloma cases are preceded by “monocloncal gammopathy of uncertain significance (MGUS),” a common, age-related medical condition characterized by an accumulation of bone marrow plasma cells derived from a single abnormal clone. MGUS does not promise MM, however; only a small fraction (~1%) of MGUS-postitive individuals develop multiple myeloma.
Complex Genetics, Largely Unexplored
According to Dr. Tomasson, the known genetic abnormalities seen in MM fall into two categories. One is hyperdiploid amplification of odd-numbered chromosomes. The second category is what I’d call large-scale structural variation: the 4:14 translocation and large deletions of chromosome 13 are seen in ~85% of cases. There are other translocations (11q13, 6p21) involving IgH (heavy chain) genes that seem to be associated with better prognosis.
The known translocation (4:14) doesn’t appear to create a fusion protein (like BCR-ABL) but does result in dysregulation of numerous transcripts. The chromosome 13 deletion alleles vary between patients, but most seem to fall between 13q11 to 13q34, so any of 50+ genes could be affected. Dr. Tomasson showed a genome-wide Nimblegen aCGH plot, and it as apparent to the audience that there were numerous signals of interest – deletions on other chromosomes in addition to chromosome 13. Li Ding pointed out an apparent amplification of chromosome 7, which we’ve seen in other cancers. I asked whether or not telomere loss was characteristic in MM, because several of the chromosomes seemed to have deletions near the ends.
The bottom line is that there are lots of areas to explore. Chromosome 13 is certainly of interest, but so are the chromosomes involving known translocations. If someone were to zoom in to the sequence level (whole-genome sequencing), who knows what we might find? At present, multiple myeloma is incurable, representing 1% of cancer cases and 2% of all cancer deaths, so it seems like we have little to lose.