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Investigators at Children’s Hospital Los Angeles (CHLA) have developed a liquid biopsy for solid tumors that could help deliver a specific diagnosis when a tissue biopsy is not feasible. The test looks at cell-free (cf) DNA from plasma to detect genome-wide copy number alterations (CNAs) and gene fusions.

The first version of the test, launched in November 2022, evaluates chromosomal copy number changes in blood samples, cerebrospinal fluid, and the aqueous humor of the eye to aid in the diagnosis of solid tumors, brain tumors, and retinoblastoma, respectively.

Their study findings were published last week in npj Precision Oncology.

“This is one of the first clinically validated liquid biopsy tests to be launched at a pediatric academic medical center,” says Jaclyn Biegel, PhD, senior author of the paper, and Chief of Genomic Medicine and Director of the Center for Personalized Medicine at CHLA.

A specific test for pediatric tumors is required because the genetics of adult tumors differ from those in children. Adult tumors tend to be caused by mutations, which most liquid biopsy tests have been developed specifically to identify. However, pediatric tumors arising from mutations are less common. In children, copy number changes—losing or having extra copies of one or more genes—or rearrangements of genes that result in gene fusions, are more characteristic.

“We created a test that may be helpful in making a diagnosis, determining prognosis, and potentially identifying an effective therapy for children with solid tumors,” says Fariba Navid, MD, Medical Director of Clinical Research in CHLA’s Cancer and Blood Disease Institute. Navid is co-senior author of this study.

For this study, the CHLA team combined Low-Pass Whole Genome Sequencing (LP-WGS) with targeted sequencing of cfDNA from plasma to detect copy number changes, as well as mutations, and gene fusions. With LP-WGS researchers load many samples onto a sequencer at once, so that each receives a small amount of sequencing. As a result, LC-WGS can be applied to many samples at low cost.

This is a key feature, since an infant or young child has a smaller blood volume, so the assays must be scaled down to accommodate this difference.

A total of 143 plasma samples were analyzed from 19 controls and 73 patients, including 44 bone or soft-tissue sarcomas and 12 renal, 10 germ cell, five hepatic, and two thyroid tumors. cfDNA was isolated from plasma collected at diagnosis, during and after therapy, and/or at relapse.

There was a high concordance of CNAs identified by LP-WGS to CNAs detected by chromosomal microarray analysis in the matching tumors. Mutations identified using  CHLA’s proprietary next-generation sequencing (NGS) panel, OncoKids, were also detected by LP-WGS of ctDNA in 14 of 26 plasma samples. Further, the team developed a hybridization-based capture panel to target EWSR1 and FOXO1 fusions from patients with Ewing sarcoma or alveolar rhabdomyosarcoma (ARMS), respectively.

To create this test, the researchers collaborated with other clinical teams and research investigators at CHLA including Jesse Berry, MD, Director of Ocular Oncology and CHLA’s Retinoblastoma Program, as well as investigators involved in Oncology, Neurosurgery and Pathology and Laboratory Medicine

The next version of the clinical assay, available in about six months, will include detection of mutations and gene fusions.

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