Abstract 08: Clinical exome sequencing in the diagnosis of pediatric cancer predisposition
Authors: Chang Vivian , Lee Hane , Davidson Tom , Dorrani Naghmeh , O'Leary Erin , Ganz Patricia A. , Nelson Stanley F. , Martinez-Agosto Julian A. 
Published: May 2015

Background: Currently, there are few guidelines on genetic testing of pediatric patients for cancer predisposition and on appropriate cancer surveillance recommendations once a genetic cancer predisposition is diagnosed. Previous research studies estimated that only about 5-10% of pediatric cancers are due to a heritable cause. However, this may be an underestimation of the true incidence in the pediatric population where most patients being diagnosed with cancer do not have a significant history of environmental risk exposures, such as smoking or ultra-violet sun exposure.

Methods: We have created a multi-disciplinary Pediatric Cancer Predisposition Clinic at the University of California, Los Angeles (UCLA) that serves dual research and clinical missions of taking care of pediatric patients at an increased risk of cancer due to a genetic condition and advancing our understanding of cancer predisposition. Each family meets with a pediatric geneticist, pediatric oncologist, and genetic counselor for pre- and post- test counseling. We also consider the medical and psychosocial effects of these analyses on not only the patient, but also the parents of our patients, as well as direct relatives, who are affected and may need cancer surveillance.

When indicated, we use Clinical Exome Sequencing (CES) through the UCLA Clinical Genomics Center, as our first-line diagnostic test due to the unusual presentation of the many inherited cancer susceptibility genes in childhood. This single test assays 95% of all protein-coding sequence of current clinically offered disease genes and is usually more efficient and cost-effective than single-gene or panel testing, and data are saved for re-interpretation. We then formulate individualized cancer surveillance recommendations and coordinate all tests with the family and general pediatrician.

Results: There were 32 patients evaluated in the first 14 months. The average age of the patients was 10 years. Thirty-one referrals were from within our institution. Two patients had a history of cancer and presented with known familial cancer predisposition syndromes (Rhabdoid tumor predisposition and Hereditary paraganglioma-pheochromocytoma syndromes). Six additional patients presented without a personal history of cancer but with a known genetic syndrome associated with an increased cancer risk (Gorlin, Bannayan-Riley-Ruvalcaba, Cowden, Li-Fraumeni, Beckwith-Wiedemann, and Von Hippel-Lindau syndromes). Four patients were referred with known familial mutations in the family and had positive confirmatory testing (Li-Fraumeni, Familial adenomatous polyposis, and two with Neurofibromatosis Type 1). One patient was referred with a known mutation in the family and had negative testing (Hyperparathyroidism-jaw tumor syndrome).

Nineteen patients had a family history indicative of familial early-onset cancer as well as a personal history of cancer and had CES was ordered. Of these, CES resulted in two reportable, likely pathogenic mutations in PTEN and NF-1. Four patients had no clinically significant genetic variants identified, 11 patients had variants of uncertain clinical significance, and two patients' results are pending.

Conclusion: More thorough and broad scale germline analyses are needed to accurately inform patients of inherited risk to cancer, as it is not always obvious based on clinical presentation or family history. Our findings demonstrate a significant number of genomic variants with uncertain but potentially relevant clinical significance that warrant further study. CES is already a routinely used tool for mendelian genetic syndromes, and its routine use in testing the germline genomes of children with cancer holds the promise to augment diagnosis, treatment, and screening, and to permit the exploration of early initiation of cancer prevention strategies of patients with high risk of cancer.

Citation Format: Vivian Chang, Hane Lee, Tom Davidson, Naghmeh Dorrani, Erin O'Leary, Patricia A. Ganz, Stanley F. Nelson, Julian A. Martinez-Agosto. Clinical exome sequencing in the diagnosis of pediatric cancer predisposition. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 08. doi:10.1158/1538-7445.CANSUSC14-08