NEW YORK – In a study of children, adolescents, and young adults (C-AYA) with solid tumors, researchers at the Cleveland Clinic have found that many carried pathogenic or likely pathogenic germline variants (P/LP) in known cancer-predisposing genes (KCPG), some of which suggested treatment with drugs already approved by the US Food and Drug Administration for adult patients.
There are much fewer targeted treatments for solid tumors in C-AYA patients compared to adult patients, the researchers noted in a study published on Tuesday in Nature Communications. And although germline genomic signature analysis has been used in these patients to study heritability, its impact on therapeutic decision-making has not been fully studied.
The researchers analyzed the germline DNA of 1,507 C-AYA patients with solid tumors and found that 12 percent of these patients carried germline P/LP variants in KCPG genes. Further, an additional 61 percent had germline pathogenic variants in non-KCPG genes, including PRKN, SMARCAL1, SMAD7, which the investigators referred to as candidate genes. When they conducted a drug-target analysis, they found that one-third of patients with germline P/LP variants had at least one druggable alteration, with more than half of them from the candidate gene group.
"Our findings emphasize the necessity for all C-AYA patients with solid tumors to be sent for genetics evaluation and gene testing," senior author Charis Eng said in a statement. "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 percent of patients with pathogenic and/or likely pathogenic variants."
She noted that the majority of available targeted therapies are meant for adults, but that the study found a significant number of the germline-altered genes in C-AYA solid tumors were targetable by FDA-approved drugs. "[This] presents an opportunity to harness drug repurposing to identify therapeutic options for C-AYA patients," Eng added.
In one of their analyses, the researchers looked for a germline genomic signature for each of the 12 tumor types they studied. They found that individuals with adrenocortical carcinoma and high-grade glioma tumors had the highest number of germline P/LP variants (combined KCPG and candidate genes) per sample, 3.6 and 2.8, respectively, compared to the overall 1.9 P/LP variants per sample.
The researchers had also observed that a broad spectrum of both KCPG and candidate genes were involved in C-AYA solid tumors, so they sought to determine if they converged on any common pathways. They found that the p53 pathway was the most affected, followed by the receptor tyrosine kinases and Ras pathway, and the Hippo pathway.
"Candidate genes were remarkably involved in the affected pathways," the authors wrote. "For example, in the RTK–RAS pathway, three out of 12 mutated genes were from the candidate gene group, including SHC1, ERBB3, and FLT3. The Hippo pathway had four affected candidate genes, CRB1, CRB2, HMCN1, and LATS1."
Finally, the researchers determined which of these variants could be treated with currently available therapies. Of the 1,507 patients in the cohort, 511 (34 percent) had at least one P/LP variant in a gene that was potentially druggable. More than 8 percent (127 patients) had KCPG P/LP variants, and an additional 25.5 percent (384 individuals) had P/LP variants in druggable candidate genes. For 72 individuals with KCPG P/LP variants and 89 with candidate genes P/LP variants, there were existing FDA-approved antineoplastic and immunomodulating-related compounds.