Genomic Tumor Profiling and Identification of Germline Cancer Predisposition Variants in a Pediatric Cohort
Cancer Genetics and Therapeutics
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Primary Categories:
- Cancer
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Secondary Categories:
- Cancer
Introduction:
The recent advancement and implementation of high throughput genomic profiling technologies in the clinical setting has advanced identification of underlying germline cancer predisposition variants in the pediatric population. Several studies now indicate that approximately 10-15% of pediatric cancers arise due to an underlying pediatric cancer predisposition syndrome (CPS).
Methods:
Clinical genomic tumor profiling for 927 pediatric patients was performed between August 2019-September 2024 using the Oncomine Childhood Cancer Research Assay, which targets 86 genes for hotspot DNA analysis, 44 genes for full-coding DNA analysis, 28 genes for amplifications, and RNA analysis for 91 genes involved in known fusions. The age range at time of tumor profiling was <1 month to 32 years (mean= 10 years). Indications for testing included hematologic malignancies (37%), central nervous system tumors (37%), solid tumors (25%), and germ cell tumors (<1%). Retrospective analysis was performed to identify Tier I and Tier II variants reported at a variant allele frequency concerning for being germline, prompting recommendation for genetic counseling and germline testing. Laboratory records and patient electronic medical records were reviewed to determine if follow up testing was pursued.
Results:
Of the 927 pediatric patients who underwent tumor profiling, 3.9% (n=36) had a clinical diagnosis or prior germline testing consistent with a known CPS. The clinical diagnoses included neurofibromatosis type 1 (NF1), 50% (n=18); transient abnormal myelopoiesis or myeloid leukemia associated with trisomy 21, 19.4% (n=7); neurofibromatosis type 2 (NF2), 8.3% (n=3); Li-Fraumeni syndrome (TP53), 8.3% (n=3); essential thrombocythemia (JAK2), 2.8% (n=1); retinoblastoma (RB1), 2.8% (n=1); rhabdoid tumor predisposition syndrome (SMARCB1), 2.8% (n=1); and tuberous sclerosis type 1 and 2 (TSC1, TSC2), 2.8% (n=1 for each gene).
An additional 9.2% (86/933) of patients had molecular findings prompting recommendation for genetic counseling and germline testing. Of these patients, 45.3% (n=39) had no documentation of follow up testing. For the remaining 47 patients, 76.6% (n=36) had follow up testing which did not identify a germline pathogenic variant, while 23.4% (n=11) of patients had follow up testing which identified a germline pathogenic variant consistent with a CPS. Three patients presenting with cystic nephroma (n=1) and Sertoli-Leydig cell tumor (n=2) were identified to have DICER1 pathogenic variants; 2 patients with anaplastic medulloblastoma (n=1) and choroid plexus carcinoma (n=1) had germline TP53 variants; 2 unrelated patients with large B-cell lymphoma had germline SH2D1A variants; 1 patient with dysembryoplastic neuroepithelial tumor had a germline PTPN11 variant; 1 patient with schwannoma had a germline LZTR1 variant; 1 patient with metastatic hepatoblastoma had a germline ASXL1 variant; 1 patient with glioblastoma had a tumor profile suggestive of constitutional mismatch repair deficiency (CMMRD), which was confirmed by identification of a germline homozygous MLH1 variant.
Conclusion:
This study demonstrates the utility of genomic tumor profiling to uncover cancer predisposition syndromes in a pediatric cancer cohort. Overall, 3.9% of patients (n=36) who underwent tumor profiling had a potential germline finding consistent with the patient’s clinical diagnosis or a priori germline testing. An additional 9.2% of patients had molecular findings concerning for a potential underlying CPS, in which 11 had a subsequent confirmed germline finding. The cumulative diagnostic yield for identifying a CPS was 5.1% (n=47/927). The diagnostic yield may be lower than reported frequencies in pediatric cancer cohorts due to the targeted nature of the panel employed, and thus, incomplete coverage of all known CPS genes. In addition, 39 patients had a molecular finding suspicious for a germline cancer predisposition, but no documentation of follow up testing being performed. This highlights the importance of genetic counseling following somatic testing to facilitate germline testing when appropriate, allowing for informed decision making, appropriate surveillance, and at-risk familial testing when desired.
The recent advancement and implementation of high throughput genomic profiling technologies in the clinical setting has advanced identification of underlying germline cancer predisposition variants in the pediatric population. Several studies now indicate that approximately 10-15% of pediatric cancers arise due to an underlying pediatric cancer predisposition syndrome (CPS).
Methods:
Clinical genomic tumor profiling for 927 pediatric patients was performed between August 2019-September 2024 using the Oncomine Childhood Cancer Research Assay, which targets 86 genes for hotspot DNA analysis, 44 genes for full-coding DNA analysis, 28 genes for amplifications, and RNA analysis for 91 genes involved in known fusions. The age range at time of tumor profiling was <1 month to 32 years (mean= 10 years). Indications for testing included hematologic malignancies (37%), central nervous system tumors (37%), solid tumors (25%), and germ cell tumors (<1%). Retrospective analysis was performed to identify Tier I and Tier II variants reported at a variant allele frequency concerning for being germline, prompting recommendation for genetic counseling and germline testing. Laboratory records and patient electronic medical records were reviewed to determine if follow up testing was pursued.
Results:
Of the 927 pediatric patients who underwent tumor profiling, 3.9% (n=36) had a clinical diagnosis or prior germline testing consistent with a known CPS. The clinical diagnoses included neurofibromatosis type 1 (NF1), 50% (n=18); transient abnormal myelopoiesis or myeloid leukemia associated with trisomy 21, 19.4% (n=7); neurofibromatosis type 2 (NF2), 8.3% (n=3); Li-Fraumeni syndrome (TP53), 8.3% (n=3); essential thrombocythemia (JAK2), 2.8% (n=1); retinoblastoma (RB1), 2.8% (n=1); rhabdoid tumor predisposition syndrome (SMARCB1), 2.8% (n=1); and tuberous sclerosis type 1 and 2 (TSC1, TSC2), 2.8% (n=1 for each gene).
An additional 9.2% (86/933) of patients had molecular findings prompting recommendation for genetic counseling and germline testing. Of these patients, 45.3% (n=39) had no documentation of follow up testing. For the remaining 47 patients, 76.6% (n=36) had follow up testing which did not identify a germline pathogenic variant, while 23.4% (n=11) of patients had follow up testing which identified a germline pathogenic variant consistent with a CPS. Three patients presenting with cystic nephroma (n=1) and Sertoli-Leydig cell tumor (n=2) were identified to have DICER1 pathogenic variants; 2 patients with anaplastic medulloblastoma (n=1) and choroid plexus carcinoma (n=1) had germline TP53 variants; 2 unrelated patients with large B-cell lymphoma had germline SH2D1A variants; 1 patient with dysembryoplastic neuroepithelial tumor had a germline PTPN11 variant; 1 patient with schwannoma had a germline LZTR1 variant; 1 patient with metastatic hepatoblastoma had a germline ASXL1 variant; 1 patient with glioblastoma had a tumor profile suggestive of constitutional mismatch repair deficiency (CMMRD), which was confirmed by identification of a germline homozygous MLH1 variant.
Conclusion:
This study demonstrates the utility of genomic tumor profiling to uncover cancer predisposition syndromes in a pediatric cancer cohort. Overall, 3.9% of patients (n=36) who underwent tumor profiling had a potential germline finding consistent with the patient’s clinical diagnosis or a priori germline testing. An additional 9.2% of patients had molecular findings concerning for a potential underlying CPS, in which 11 had a subsequent confirmed germline finding. The cumulative diagnostic yield for identifying a CPS was 5.1% (n=47/927). The diagnostic yield may be lower than reported frequencies in pediatric cancer cohorts due to the targeted nature of the panel employed, and thus, incomplete coverage of all known CPS genes. In addition, 39 patients had a molecular finding suspicious for a germline cancer predisposition, but no documentation of follow up testing being performed. This highlights the importance of genetic counseling following somatic testing to facilitate germline testing when appropriate, allowing for informed decision making, appropriate surveillance, and at-risk familial testing when desired.