NEW YORK – Researchers at Memorial Sloan Kettering Cancer Center have explored the broader use of germline testing for pediatric cancer patients, demonstrating that such testing can provide a fuller picture of patients' diagnoses and identify their relatives' cancer risks.
In a paper published in Nature Cancer on Monday, the researchers conducted matched tumor-normal DNA sequencing on 751 pediatric cancer patients treated at MSK and found that 18 percent, or 138 patients, harbored one or more pathogenic or likely pathogenic germline mutation.
"Germline findings identified in our study informed clinical care in different ways, by helping us better understand some individuals' cancer diagnosis, risk for subsequent cancers, guidance for screening additional cancers, and cascade testing in families," Michael Walsh, one of the corresponding authors of the study and a geneticist and pediatric oncologist at MSK, said in an email. "We are offering this at our center for all patients in a clinical research context and recognize this is not available at all centers, but the field is clearly moving in this direction and we hope our data will help inform the expansion of this testing."
MSK researchers have conducted previous studies on germline mutations in adult cancer patients. One study conducted germline testing using MSK-IMPACT on "early-onset" patients with cancers that usually occur more frequently in older patients like breast, colon, or kidney cancer, and on "young-adult" patients with cancers that more commonly occur in children. The early-onset patients were more likely to harbor germline mutations (21 percent), compared to the young-adult cancer patients (13 percent).
Another study using MSK-IMPACT found that about 2,000 of 12,000 advanced cancer patients tested harbored germline mutations, and about 1,000 of these had therapeutic significance.
In the latest pediatric study, 13 percent, or 99 patients, had genetic variants in moderate- and high-penetrance dominant genes. Among the identified mutations, 34 percent were unexpected findings based on the patients' diagnoses and familial cancer history.
Patients were tested using the MSK-IMPACT next-generation sequencing panel, which can identify mutations in 468 genes, and the researchers conducted a germline analysis of 88 genes. The study covered several different cancer types, including sarcoma, neuroblastoma, central nervous system (CNS) tumors, retinoblastoma, and other rare solid tumors.
The team consulted the MSK Clinical Genetics Service, a molecular tumor board, and followed the patients for about a year after conducting genomic profiling, but they did not follow patients through treatment. Of the patients found to harbor a germline mutation, 76 percent went to an appointment with the MSK Clinical Genetics Service for genetic counseling.
Walsh and his colleagues noted that germline testing is usually recommended for patients based on their tumor type, but when testing patients regardless of tumor type, they found "a substantial number of patients" with moderate- or high-penetrance variants in "unexpected genes," they wrote.
"Broad pan-cancer predisposition testing is a key part of research to appreciate the full spectrum associated with many germline mutations, but it also has increasing clinical utility for many patients," the authors wrote.
Germline variants were found in 49 percent of patients with retinoblastoma, 21 percent of patients with CNS tumors, 15 percent of patients with neuroblastoma, 12 percent of patients with sarcoma, and 19 percent of patients with other tumor types.
The most common mutations in high- or moderate-penetrance genes were in RB1 (found in 4 percent of patients), NF1 (1 percent) and TP53 (1 percent) in patients with retinoblastoma and those with a prior clinical diagnoses of NF1- or Li Fraumeni syndrome (LFS)-associated tumors. About 3 percent of patients had variants in DNA damage repair genes, 1.6 percent had mutations in the RAS–MEK or mTOR–PTEN pathway, and 1 percent had variants in metabolic pathways related to cancer.
The study authors noted that their research does not represent a truly unselected cohort because it is based on pediatric cancer patients treated at MSK. Walsh further explained in an email that no cancer center has a truly unbiased dataset, and that MSK tends to see more pediatric patients with neuroblastoma, retinoblastoma, and osteosarcoma.
The authors also acknowledged the limitations of its MSK-IMPACT test and other NGS assays, noting that many patients in the study who had negative results from MSK-IMPACT still received genetic counseling for genetic disorders or mutations that NGS cannot detect.
"In fact, more patients with negative results (116) were seen [by Clinical Genetics Service] than patients with positive results (105)," the authors wrote. "NGS-based assays are not designed to detect imprinting disorders or disorders of telomere biology in patients without a detectable mutation in a gene included on the panel."
Among genetic diseases that were not identified by MSK-IMPACT in this study was the growth disorder Beckwith–Wiedemann syndrome, identified in four patients. Another patient had an NF1 P variant mutation that was below the level of detection by NGS and needed specific NF1 testing to identify. The authors suggested combining multiple tests in these cases, like NGS and RNA sequencing, to detect all types of genetic variants.
Although the researchers did not follow these patients through treatment, they noted that the number of molecularly guided targeted therapies for children is continuing to grow. Germline data can also inform treatment and dosing decisions and help predict which patients will experience increased therapeutic toxicity.
Another clinical implication of broader germline testing is cascade testing for a patient's family, which the authors said could "multiply the benefits of detecting a germline mutation" beyond the patient.
If family members are also tested for germline mutations, they can receive better cancer surveillance, risk-reducing interventions, and reproductive planning help based on those findings. However, the researchers noted that uptake of cascade testing remains low. Previous studies have shown only about half of at-risk family members will undergo cascade testing, and the researchers noted that the rate of cascade testing was similarly low in their study.
In total, 21 percent of patients had at least one relative undergo cascade testing. That led to the detection of 27 mutation carriers who were not previously aware of their status. Only in 14 cases there was previous documentation of a family member's mutation.
The likelihood that a family member would undergo cascade testing in this study was associated with the penetrance of the mutation detected and varied by gene. About 37 percent of patients with high- or moderate-penetrance variants had at least one family member undergo cascade testing, compared to 15 percent of those with a low-penetrance or autosomal recessive variant, the researchers found.
Finally, the researchers explored the cost-effectiveness of broadly providing germline testing to pediatric cancer patients. They noted that while the area was not well studied and required a longer follow-up than in this study, the benefits of early detection and effective, targeted treatment could over time make up for the high upfront costs of DNA sequencing.
"Potential cost savings exist through cancer screening and early detection, prevention, [preimplantation genetic testing], and potentially more effective therapeutics; however, there are also significant costs associated with each of these in addition to the costs of sequencing and clinical genetics visits," the authors wrote.