Page 397 - 2014 Printable Abstract Book
P. 397
interactions in the risk of subsequent cancer; (2) application of tumor sequencing technology in research
and clinical practice; and (3) on the application of sequencing for the detection of de novo mutations in
the germ line DNA of offspring of exposed individuals.
(SNE01) Evaluation of the risk of de novo variation in offspring due to parental radiation exposure in
the cohort of Japanese A-bomb survivors. Harry M. Cullings, Radiation Effects Research Foundation,
Hiroshima, Japan
While inherited genetic changes in offspring of irradiated parents have long been recognized in
animal experiments, they have never been convincingly demonstrated in observational studies of human
populations. The investigation of whether such de novo germ cell mutations occurred in the children of
the Japanese atomic bomb survivors, due to the parents’ exposure to ionizing radiation, was a major focus
of studies at the Atomic Bomb Casualty Commission (ABCC) beginning in the early years after its formation
in 1946, and has continued to the present day in the ABCC’s successor, the Radiation Effects Research
Foundation. A long succession of studies has been involved, with outcomes ranging from adverse
phenotypes exhibited in newborns and other untoward outcomes of pregnancy in the earliest study, to a
current clinical study of adult multifactorial diseases, but has yet to yield clear evidence of an increase in
mutations attributable to parents’ gonadal dose estimates. Although Nakamura and colleagues have
provided a resume of reasons why such mutations may not have been detectable to date, it has long been
expected that some effect, however small, might become manifest with the improvement of technology
to the point that the genome can be interrogated at the most detailed possible level. Molecular studies
to this end have been designed in recent years, and array comparative genomic hybridization (aCGH) using
densely spaced oligonucleotide probes has rapidly been supplanted by next-generation sequencing (NGS)
as the planned method. The associated studies, which are still being developed, must grapple with
bioinformatic and statistical challenges associated with the “calling” algorithms that identify apparent
changes as genomic differences between samples from related individuals, as such “calls” must be
confirmed with more focused methods such as Sanger sequencing. A key problem is that false-positive
error probabilities, while small in an absolute sense, may still greatly exceed the true mutation rate, and
may produce numbers of candidate mutations, when applied across the entire genome, that are too
numerous to confirm. Current challenges in the design of these experiments will be discussed.
(SNE02) The role of TP53 mutations in the origin and evolution of therapy-related AML. Terrence N.
3
4
2
1
1
1
Wong ; Giridharan Ramsingh ; Andrew L. Young ; Christopher A. Miller ; Waseem Touma ; Sharon Heath ;
3
1
4
5
Jack D. Baty ; Timothy J. Ley ; Todd Druley ; Daniel C. Link ; and Richard K. Wilson, Washington University
1
1
School of Medicine, St. Louis, MO ; University of Southern California Jane Anne Nohl Division of
2
Hematology, Los Angeles, CA ; Washington University in St. Louis, Department of Pediatrics, St. Louis,
4
3
MO ; Washington University in St. Louis, The Genome Institute, St. Louis, MO ; and Washington University
5
in St. Louis, Division of Biostatistics, St. Louis, MO
and clinical practice; and (3) on the application of sequencing for the detection of de novo mutations in
the germ line DNA of offspring of exposed individuals.
(SNE01) Evaluation of the risk of de novo variation in offspring due to parental radiation exposure in
the cohort of Japanese A-bomb survivors. Harry M. Cullings, Radiation Effects Research Foundation,
Hiroshima, Japan
While inherited genetic changes in offspring of irradiated parents have long been recognized in
animal experiments, they have never been convincingly demonstrated in observational studies of human
populations. The investigation of whether such de novo germ cell mutations occurred in the children of
the Japanese atomic bomb survivors, due to the parents’ exposure to ionizing radiation, was a major focus
of studies at the Atomic Bomb Casualty Commission (ABCC) beginning in the early years after its formation
in 1946, and has continued to the present day in the ABCC’s successor, the Radiation Effects Research
Foundation. A long succession of studies has been involved, with outcomes ranging from adverse
phenotypes exhibited in newborns and other untoward outcomes of pregnancy in the earliest study, to a
current clinical study of adult multifactorial diseases, but has yet to yield clear evidence of an increase in
mutations attributable to parents’ gonadal dose estimates. Although Nakamura and colleagues have
provided a resume of reasons why such mutations may not have been detectable to date, it has long been
expected that some effect, however small, might become manifest with the improvement of technology
to the point that the genome can be interrogated at the most detailed possible level. Molecular studies
to this end have been designed in recent years, and array comparative genomic hybridization (aCGH) using
densely spaced oligonucleotide probes has rapidly been supplanted by next-generation sequencing (NGS)
as the planned method. The associated studies, which are still being developed, must grapple with
bioinformatic and statistical challenges associated with the “calling” algorithms that identify apparent
changes as genomic differences between samples from related individuals, as such “calls” must be
confirmed with more focused methods such as Sanger sequencing. A key problem is that false-positive
error probabilities, while small in an absolute sense, may still greatly exceed the true mutation rate, and
may produce numbers of candidate mutations, when applied across the entire genome, that are too
numerous to confirm. Current challenges in the design of these experiments will be discussed.
(SNE02) The role of TP53 mutations in the origin and evolution of therapy-related AML. Terrence N.
3
4
2
1
1
1
Wong ; Giridharan Ramsingh ; Andrew L. Young ; Christopher A. Miller ; Waseem Touma ; Sharon Heath ;
3
1
4
5
Jack D. Baty ; Timothy J. Ley ; Todd Druley ; Daniel C. Link ; and Richard K. Wilson, Washington University
1
1
School of Medicine, St. Louis, MO ; University of Southern California Jane Anne Nohl Division of
2
Hematology, Los Angeles, CA ; Washington University in St. Louis, Department of Pediatrics, St. Louis,
4
3
MO ; Washington University in St. Louis, The Genome Institute, St. Louis, MO ; and Washington University
5
in St. Louis, Division of Biostatistics, St. Louis, MO
