Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care

Catherine Quindipan; Jennifer A Cotter; Jianling Ji; Wendy G Mitchell; Diana J Moke; Fariba Navid; Stefanie M Thomas; Michele VanHirtum-Das; Larry Wang; Sulagna C Saitta; Jaclyn A Biegel; Matthew C Hiemenz

doi:10.1016/j.pediatrneurol.2020.09.015

Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care

Pediatr Neurol. 2021 Jan:114:55-59. doi: 10.1016/j.pediatrneurol.2020.09.015. Epub 2020 Oct 2.

Affiliations

¹ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California. Electronic address: cquindipan@chla.usc.edu.
² Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, Keck School of Medicine at the University of Southern California, Los Angeles, California.
³ Division of Pediatric Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Keck School of Medicine at the University of Southern California, Los Angeles, California.
⁴ Department of Pediatrics, Keck School of Medicine at the University of Southern California, Los Angeles, California; Division of Hematology and Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
⁵ Division of Medical Genets, Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
⁶ Foundation Medicine, Cambridge, Massachusetts.

PMID: 33221597
DOI: 10.1016/j.pediatrneurol.2020.09.015

Abstract

Background: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders.

Methods: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention.

Results: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues.

Conclusions: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.

Keywords: Mosaicism; NGS; OncoKids; PIK3CA; PROS; Pediatric oncology; Segmental overgrowth.

MeSH terms

Adolescent
Adult
Child
Child, Preschool
Class I Phosphatidylinositol 3-Kinases*
Feasibility Studies
Genetic Testing* / methods
High-Throughput Nucleotide Sequencing* / methods
Humans
Medical Oncology* / methods
Mosaicism*
Nervous System Malformations / diagnosis*
Nervous System Malformations / genetics*
Pediatrics* / methods
Tissue Preservation
Young Adult

Substances

Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human