Parallel sequencing to identify the causes of childhood cancer

Identification of mutations in specific genes responsible for cancer susceptibility impacts decisions about treatment of the affected child as well as allowing increased surveillance and prevention approaches in 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. To date the methods utilized to identify these cancer susceptibility mutations have typically required large numbers of families with similar patterns of cancer. However, this approach has a number of limitations and recent studies of children with apparently sporadic cancer demonstrate that as high as 50% may carry a cancer susceptibility mutation. In our first two years of funding from Alex’s Lemonade Stand through an Innovation Award we approached this problem by utilizing high throughput technology to perform DNA sequence analysis of a complete panel of cancer associated genes for inherited mutations as well as genome-wide test of changes in the number of copies of genes in DNA from families affected by unique patterns of childhood cancer. This project has been successful and our initial data suggests that families who have more then one child with cancer are most likely to have mutations detected. We also identified which group of genes yielded the highest likelihood of our finding a mutation. We worked successfully with three children’s cancer genetics programs in Texas (Baylor College of Medicine (BCM), MD Anderson Cancer Center and University of Texas Southwestern) to identify families and enroll in our research studies. The sequencing was done in collaboration with the Human Genome Sequencing Center at BCM. In this renewal, we propose to confirm our findings by enrolling an additional 48 families and more thoroughly sequencing and analyzing the type of genes in which we found mutations in the first phase. We will also incorporate newer technology to identify other types of changes in these genes which are not detected by sequencing. This project will provide information on the mechanism of genetic susceptibility to childhood cancer in these families and serve as a pilot for even larger scale sequencing of all coding regions in children with cancer in the general population.