Clone Wars: Catching Cancer Before it Starts?

A pair of studies recently published in The New England Journal of Medicine have uncovered an easily detectable “premalignant” state in the blood critical to the development of blood cancer. Taking two different approaches, both research groups arrived at the same conclusion: somatic mutations present in blood cancers leading to clonal hematopoiesis are rare in younger patients but increase in frequency with age and occur in at least 10 percent of older patients.

Individuals with these mutations were over 10 times more likely to go on to develop blood cancer in subsequent years. While most genetic research has focused on advanced cancers, the two new studies – one from Siddhartha Jaiswal, MD, PhD, and colleagues, and the other from Giulio Genovese, PhD, and colleagues – looked instead at somatic mutations in DNA samples collected from the blood of individuals not known to have cancer or blood disorders.

Dr. Jaiswal and co-authors looked specifically at 160 genes known to be recurrently mutated in blood malignancies, using genetic data from more than 17,000 blood samples. They detected mutations in 746 persons (4.3%), affecting 73 genes; the majority of the variants occurred in three genes: ASXL1, DNMT3A, or TET2. These mutations did indeed increase the likelihood of developing blood cancer (hazard ratio [HR] = 11.1; 95% CI 3.9-32.6), as well as all-cause mortality (HR=1.4; 95% CI 1.1-1.8), incident coronary heart disease (HR=2.0; 95% CI 1.2-3.4), and ischemic stroke (HR=2.6; 95% CI 1.4-4.8). Jaiswal et al. also observed a clear association between age and the frequency of these somatic mutations: occurring at a rate of 5.6 percent in persons aged 60 to 69 years and increasing to a rate of 18.4 percent in persons 90 years or older.

In the related paper, Dr. Genovese and co-authors discovered the “precancerous” state when looking at a different disease: the risk for schizophrenia. Analyzing data from whole-exome sequencing of DNA in blood samples from 12,380 persons (6,135 with psychiatric disorders and 6,245 healthy controls), the researchers found similar frequencies of age-dependent clonal hematopoiesis and predominant mutations in the same genes identified by Jaiswal et al. After following the medical histories of subjects with somatic mutations, researchers found that these persons had an almost 13-fold greater risk of subsequently developing a blood cancer (HR=12.9; 95% CI 5.8-28.7).

“Cancer is the end stage of the process,” said Dr. Jaiswal, from Massachusetts General Hospital. “By the time a cancer has become clinically detectable it has accumulated several mutations that have evolved over many years.” While there are no treatments currently available that would address this condition in otherwise healthy individuals, the discovery of these somatic mutations opens the door to entirely new directions for blood cancer research – toward early detection, and even early prevention.

References

  • Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoeisis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014 November 26. [Epub ahead of print]
  • Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014 November 26. [Epub ahead of print]

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