219Effective targeted cancer therapeutic development depends upon distinguishing
disease-associated ‘driver’ mutations, which have causative roles in pathogenesis of
malignancy, from ‘passenger’ mutations, which are dispensable for cancer initiation
and maintenance. Translational studies of clinically active targeted therapeutics can
defi nitively discriminate driver from passenger lesions and provide valuable insights
into human cancer biology.
Hematological Cancer Risk Inferred from Blood DNA Sequence
Detectable clonal expansions most frequently involved somatic mutations in three
genes (DNMT3A, ASXL1, and TET2) have been implicated in hematologic can-
cers. A study has shown that clonal hematopoiesis is a strong risk factor for subse-
quent hematologic cancer as ~42 % of hematologic cancers in this cohort arose in
persons who had clonality at the time of DNA sampling, >6 months before a fi rst
diagnosis of cancer (Genovese et al. 2014 ). Clonal hematopoiesis with somatic
mutations is readily detected by means of DNA sequencing, is increasingly com-
mon as people age, and is associated with increased risks of hematologic cancer and
death. A subset of the genes that are mutated in patients with myeloid cancers is
frequently mutated in apparently healthy persons; these mutations may represent
characteristic early events in the development of hematologic cancers.
In the future, it may be possible to refi ne DNA analysis to develop strategies for
early detection and prevention of hematologic cancer. DNA analysis will offer three
important capabilities: ascertaining high-risk states, monitoring progression or
remission of these states, and follow-up of transforming mutations before clinically
apparent illness. The following research directions could bring DNA sequencing for
clonal hematopoiesis closer to clinical usefulness:
- Some somatic mutations are likely to be associated with a particularly high risk
of subsequent cancer; larger studies could identify such mutations. - Single-cell analyses might identify high-risk combinations of mutations occur-
ring in the same cells. - Sequencing of specifi c cell types might identify mutation and cell-type combina-
tions with higher predictive value. - Initial detection of clonal hematopoiesis might justify periodic screening for the
presence of cooperating mutations at low allele frequencies that could presage
cancer.
Large clinical studies will be needed to evaluate these possibilities. DNA
sequencing, by improving our ability to predict future disease in asymptomatic per-
sons, may eventually replace the traditional demarcation between illness and health
with a continuum of ascertainable genomic states that are associated with elevated
risks of illness.
Cancer Prognosis