Germline Genomic Profiling of Young Patients With Cancer Shows Treatment Opportunities

A study published this week found that germline testing of pediatric and young adult patients with cancer demonstrates that some tumors have actionable genetic variants.

Despite recommendations to refer and screen adult patients with certain types of tumors for germline testing, actual analysis remains low. Screening pediatric patients is even less common, although these young patients often have variants that can be targeted by currently available therapies, according to a study published this week.

The study, published in Nature Communications, evaluated germline mutations in children, adolescents, and young adults (C-AYA) with solid tumors.

Little is known about the spectrum, frequency, and implications of these germline variants in pediatric patients. Researchers led by Charis Eng, MD, PhD, who directs the Cleveland Clinic's Genomic Medicine Institute, evaluated germline mutations in solid tumors, all among patients younger than 29 years, from Cleveland Clinic and St. Jude Children's Research Hospital.

Fifty of the patients were prospectively enrolled from Cleveland Clinic, with 14 tumor types; bone and soft tissue sarcomas were the most common.

The authors also analyzed germline exome data from 1457 patients with solid tumors from the St. Jude dataset and combined it with the Cleveland data.

The combined dataset included 1507 patients with a median (SD) age of 6.41 (5.8) years, consisting of 1182 children (50.7% females; median age, 5.2  years), 164 adolescents (59.1% males; median age, 16.8 years ), 20 young adults (75% males; median age, 21 years), and 141 whose age was not specific, but who had diagnosed solid tumors and were under 29 years of age. In the combined set, the most observed malignancies included central nervous system tumors in 323 patients (21.4%), followed by Wilms tumors in 207 (13.7%), neuroblastomatas in 190 (12.6%), and rhabdomyosarcomas in 134 (8.9%).

Twelve percent of the 1507 patients carried germline pathogenic and/or likely pathogenic variants in known cancer-predisposing (KCPG) genes while an additional 61% had germline pathogenic variants in non-KCPG genes, including PRKN, SMARCAL1, and SMAD7. Although germline variants existed across a broad gene spectrum, pathway analysis showed a convergence around p53.

The researchers also conducted a drug-target network analysis to determine if the pathogenic and/or likely pathogenic germline variants detected were located within genes that could potentially be targeted by drug therapies; the analysis found that 34% of the patients had at least 1 pathogenic and/or likely pathogenic variant on a gene that could be targeted. Furthermore, one-third of the 34% had variants that can be targeted by existing FDA-approved drugs, although the majority of such drugs are only approved for adult use. Their findings show that there is "an opportunity to harness drug repurposing to identify therapeutic options for C-AYA patients," Eng said in a statement.

It is the largest such study of its kind, the researchers said.

"Our findings emphasize the necessity for all C-AYA patients with solid tumors to be sent for genetics evaluation and gene testing," Eng stated. "Adult guidelines, particularly family history, are typically used to recognize C-AYA patients with possible heritable cancer, but studies have found a family history of cancer in only about 40% of patients with pathogenic and/or likely pathogenic variants."

In an email to The American Journal of Managed Care®, Eng said the type of analysis her institution conducted is translatable, writing, "Clinical exomes are available. However, once you have exome information, a gene panel of the genes we uncovered can be designed, and this is very easy for a clinical lab. In other words, our research can be quickly translated to routine clinical care. However, it is vital that any germline gene testing must be accompanied by pre-test and post-test genetic counseling."


Akhavanfard, S., Padmanabhan, R., Yehia, L. et al. Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors. Nat Commun. 2020;11;2206 doi: 10.1038/s41467-020-16067-1.