Identification of mutations in specific genes responsible for cancer susceptibility impacts decisions about
treatment of the patient as well as allowing increased surveillance and prevention approaches for at-risk family
members. In addition, knowledge of inherited predisposition to pediatric malignancies has provided important
insights into the mechanisms of cancer and potential therapeutic targets in both children and adults with cancer
in the general population. Current utilization of high-throughput sequencing methodologies for coding changes
has been focused on somatic mutations in tumor tissue, and conversely; genome-wide association studies of
cancer susceptibility have focused on common variations that individually have small impacts on cancer risk.
We propose a project at the intersection of these two different approaches. We plan to use massively parallel
sequence analyses of constitutional DNA from childhood cancer patients with medical and family history
suggestive of a cancer susceptibility syndrome. In Aim 1 we will focus on cohorts of families with consistent
and specific phenotypes, for example, probands with childhood sarcomas and second malignancies by age 40
where thorough analysis of well-characterized cancer-associated genes has been negative. The molecular
analyses of germline DNA will include two comprehensive approaches (1) capture of all coding exons followed
by sequencing at dense coverage to identify mutations pathogenic mutations (deletion, nonsense, frameshift or
splice site) that impact coding sequence (whole exome) and (2) whole genome sequencing of paired-ends
libraries at lower coverage to identify copy number changes and novel rearrangements. In Aim 2, we will carry
out informative statistical and bioinformatics analysis of rare or novel missense alleles, using original
methodology involving optimization of alignment depths for evolution-based studies of functionality. In Aim 3,
analyses of copy number change and rearrangement by whole genome sequencing will include an additional
cohort of subjects with childhood cancer and congenital anomalies or developmental delay to uncover novel
contiguous gene or rearrangement syndromes. Results from these initial cohorts will then be validated by
targeted sequencing of implicated genes in additional childhood cancer probands and families.
To complete this translational, cross-disciplinary project we include collaborators from pediatric cancer
genetics programs at Texas Children's Hospital, University of Texas MD Anderson Cancer Center and Health
Science Center at San Antonio and the Children's Hospital of Philadelphia, the Human Genome Sequencing
Center and the Department of Statistics at Rice University. The clinical centers enroll families from ethnically
diverse populations with linkage to medical data, and establishment of immortalized cell lines to facilitate the
generation of functionally and clinically relevant data. Our plan to thoroughly interrogate the constitutional
genome will advance the goals of the National Cancer Institute's Strategic Plan on gaining a fuller
understanding of the spectrum of genetic susceptibility to cancer in highly affected childhood cancer families.
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