Use Mosaic Chromosomal Alterations to ID New Approaches to Preventing CLL?

Mosaic chromosomal alterations are known to be strongly associated with future hematologic malignancies. Now, a team of oncologists and geneticists from Harvard Medical School and the Broad Institute of MIT and Harvard reports in Nature that they have uncovered specific mosaic chromosomal alterations that may be predictive for chronic lymphocytic leukemia (CLL), suggesting a new avenue for possible prevention of the disease.

Po-Ru Loh, PhD, an assistant professor in the Division of Genetics at Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues developed a new technique for detecting a mosaic chromosomal alterations, which involve clonal expansions of cells carrying mutations that affect large chunks of chromosomes. The team applied this technique to 151,202 participants in the UK Biobank. They then compiled an atlas of 8,342 mosaic chromosomal alterations, an order of magnitude larger than any previous study.

“The large size of this data set allowed us to find many interesting patterns in the data. The biggest surprise was that several subclasses of clonal expansions are actually strongly influenced by inherited genetic variants. That is, certain DNA mutations that are passed along from parents to children strongly increase the likelihood of clonal expansions later in one’s life,” Loh told Cancer Network.

By looking at cancer outcomes among UK Biobank participants, the researchers were able to replicate the finding that detectable mosaicism substantially increases risk of future blood cancer. Intriguingly, the current investigation also refined this observation by identifying specific mosaic events that drive this increase in risk.

CLL, which is a slowly progressing cancer, is preceded by clonal mosaicism for several years before disease progression, according to the researchers. They examined mosaic chromosomal alterations in patients who went on to develop CLL and found that many individuals with incident CLL exhibited clonality up to 6 years before diagnosis. The researchers also found that clonal fraction inversely correlated with time to malignancy. “We observed that duplication of chromosome 12 conferred over a hundred-fold increased risk of chronic lymphocytic leukemia,” explained Loh.

However, Loh said these findings must be viewed with caution in terms of their clinical implications. “First, CLL and blood cancer in general are rare diseases, so despite the large increases in risk, most people with mosaic events do not go on to develop blood cancers. Second, interventions still need to be developed to prevent high-risk individuals from getting CLL. Overall, this work is still upstream of clinical translation,” said Loh.

However, Loh emphasized that these findings significantly improve the understanding of the biology of clonal hematopoiesis, suggesting promising directions for future work. He noted that the results clearly demonstrate that clonal hematopoiesis is really a medley of quite different biological transformations, with widely variable prognoses. “We have now highlighted a few mosaic events that confer the largest risk of CLL, and our hope is that the knowledge that these events are often present years before progression will spur work in developing new preventions or treatments,” he said.