Literature Scan
New and noteworthy research from the
medical literature landscape
Order of Gene Mutation
Predicting What Cancer Will Do Next
Over the last decade, scientists have
gained a much greater understanding of
which genes acquire mutations in particular cancers. Now, new research is showing
that the order in which the mutations are
acquired could have a significant impact
on the cancer’s clinical features and response to therapy.
According to the findings from a recent
study led by Christina A. Ortmann, MD,
and David G. Kent, PhD, published in The
New England Journal of Medicine, a cancer’s
path changes depending on the order of certain “driver mutations.” Drs. Ortmann, Kent,
and colleagues analyzed blood samples
from 246 patients with myeloproliferative
neoplasms (MPNs) and discovered that
acquired mutations in the Janus kinase 2
(JAK2) or TET2 genes later determined the
clinical features, response to target therapy,
and clonal evolution of the disease.
“These findings are exciting because
we were able to study the very early stages
of cancer,” Dr. Kent told ASH Clinical
News. “We were able to show that the
disease develops differently depending on
which mutation comes first.”
MPNs – which develop into leukemia
in 5 to 10 percent of cases – lend themselves to this type of research because they
reflect earlier stages of development that
may not be accessible in other types of
cancer. Scientists are also able to identify
clonal populations that have enough cells
for genotypic and phenotypic analysis, Dr.
Kent pointed out.
One-tenth of the 246 patients had
mutations in both the JAK2 and TET2
genes; mutation order was determined by
genotyping hematopoietic colonies or using next-generation sequencing. Of these
patients, there were 12 samples in which
the TET2 mutated first, and 12 samples in
which the JAK2 mutation came first.
Then, through analysis of the patientderived clonal populations of stem and
progenitor cells, the researchers were
able to develop a model for the effects of
mutation order on the biology of MPNs:
When a TET2 mutation was acquired first,
expansion of hematopoietic stem and progenitor cells was favored, but expansion
of lineage-committed erythroid cells was
blocked until acquisition of a JAK2 mutation. By contrast, in JAK2-first patients,
there was an increase in the number of
megakaryocytic and erythroid cells, but
not expansion of hematopoietic stem
and progenitor cells until acquisition of a
TET2 mutation.
Mutation order also was associated
with several clinical features:
• Patients who acquired the TET2
mutation first were an average of 12.3
years older than those who acquired
the JAK2 mutation first (mean age at
diagnosis = 71.5 years vs. 59.2 years;
p = 0.04)
• JAK2-first mutation patients were
more likely to present with polycythemia vera than essential thrombocytopenia (p = 0.05)
• The disease was noticeable 10 years
earlier in people with JAK2-first
mutation (60.71 years vs. 71.17 years;
p = 0.002)
• Despite presenting at a younger age,
JAK2-first mutation patients were
more likely to have a thrombotic
event (p = 0.02)
The cells of JAK2-first patients had a
higher sensitivity to the anti-JAK2 drug
ruxolitinib. However, this sensitivity
did not necessarily translate into better
response from that medication.
According to Dr. Kent, the results of
the study demonstrate that “the order of
mutation acquisition can impact disease
pathogenesis. Patients with known mutations have distinct diseases depending on
which mutation came first.”
Knowing the mutation order of a
patient with MPN could potentially
guide physicians in treatment decisions –
particularly in understanding the timing
and presentation of thrombotic risk for
patients with the JAK2-first mutation.
“An understanding of mutation order
might improve the delivery of targeted
therapy to attenuate early driver events
that are present in the trunk of the
evolutionary tree of the tumor,” Charles
Swanton, MD, PhD, wrote in an editorial
accompanying the study by Drs. Ortmann
and Kent. “That is, driver mutations that
are present in all cells, influencing the
behavior of the whole tumor early in
evolution, would be targeted.” ●
References
• Ortmann C, Kent D, Nangalia J, et al. Effect of mutation order on
myeloproliferative neoplasms. N Engl J Med. 2015;372:601-12.
• Swanton C. Cancer evolution constrained by mutation order. N Engl J
Med. 2014;372:661-3.
Can Genetic Sequencing Provide Insights
into Disease and Hematopoiesis?
Sequencing of genomic data is increasingly becoming a
valuable tool in identifying disease etiology in diagnostically challenging cases, as one research team discovered
while evaluating a family who had multiple females with
macrocytic anemia. While multiple etiologies have been
implicated for the development of hematopoietic disorders,
many cases of abnormal blood cell production have no
discernable cause.
Using genetic sequencing, Vijay G. Sankaran, MD, and
his team were able to identify a dominant negative mutation in the aminolevulinic acid synthase (ALAS2) allele on
one X chromosome of the proband and other affected individuals in the family. In this case, the proband, or the first
affected individual in the family who prompted the genetic
study, was a 32-year-old woman with a history of atrial
septal defect and anemia with an unclear etiology since
childhood. Dominant negative mutations usually result in
an altered, often inactive, gene product.
Researchers believe this report, which was published
24
ASH Clinical News
in The Journal of Clinical Investigation, supports the use of
whole-exome sequencing as a tool for characterizing disease
etiology.
Macrocytic anemia, in which the red blood cells are
larger than normal, and dyserythropoiesis, a morphological hallmark of disordered maturation of blood cells, can be
found in a variety of inherited and acquired hematopoietic
disorders, including: congenital dyserythropoietic anemias
(CDAs), specific mitochondrial disorders, myelodysplastic
syndromes (MDS), and megaloblastic anemias. However,
in some cases the cause of the disorder is unclear.
Researchers hoped to provide more insight into mechanisms of abnormal blood cell production in patients by developing a greater understanding of the origin of these diseases.
After identifying the proband, Dr. Sankaran and colleagues believed that the 32-year-old woman, who was also
found to have dyserythropoiesis and iron overload, likely
had a congenital syndrome. However, the hematopathology
evaluation and genetic analysis of the most likely candidates
Bone marrow from the female
patient with macrocytic, dyserythropoietic anemia
FIGURE 1.
March 2015