Pediatric Cancer Panel

Hereditary cancers in children have been observed in approximately 8-10% of diagnosed cancers (Coury et al. 2018. PubMed ID: 29750288). Hereditary cancers tend to occur at an earlier age (<45 years), ≥2 malignancies, consist of multiple affected family members including children, specific tumor types, children with excessive treatment toxicity, and can be associated with other congenital or other anomalies (Ripperger et al. 2017. PubMed ID: 28168833). The results of testing for a group of hereditary cancers can be important for counseling, screening, prevention, and treatment (Scollon et al. 2017. PubMed ID: 28357779; Coury et al. 2018. PubMed ID: 29750288).

This test analyzes genes involved in hereditary solid and hematologic cancer syndromes which are mostly inherited in an autosomal dominant manner. Several types of cancers may be found in a pedigree and this test may help in the differential diagnosis and rule out particular syndromes by simultaneously analyzing multiple genes involved in hereditary cancers.

Pediatric cancers in this panel include: Acute Myeloid Leukemia, Colorectal, Endocrine, Medulloblastoma, Meningioma, Neurological, Nevoid Basal Cell Carcinoma, Osteosarcoma, Paraganglioma and Pheochromocytoma, Polyposis, Renal, Retinoblastoma, Rhabdoid, Rhabdomyosarcoma, Sarcoma, and Wilms Tumor.

See individual gene test descriptions for detailed information on clinical features, molecular biology of gene products, and spectra of pathogenic variants.

Genes tested in this panel have been implicated in hereditary pediatric solid and hematologic cancers, and although individually these genes may be involved in a minority of cancers, the combination of highly, moderately, and mildly penetrant pathogenic variants may be responsible for a significant portion of hereditary cancers.

Clinical sensitivity for this panel is highly dependent on the type of cancer, specific ethnicity, and age of patients and is given based on more common hereditary cancer disorders found in children.

Familial Adenomatous Polyposis (FAP): Pathogenic APC sequence variants are found in >90% of individuals with FAP (Laken et al. 1999. PubMed ID: 10051640). Gross deletions/duplications have been reported in up to 12% of APC patients (Jasperson et al. 2017. PubMed ID: 20301519).

Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome: Constitutional Mismatch Repair Deficiency Syndrome is mainly caused by biallelic germline pathogenic variants in PMS2 and MSH6, and less frequently in MSH2 and MLH1 (Rana and Syngal. 2017. PubMed ID: 28327367).

Hereditary Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML): in a recent study, pathogenic variants were identified in 29% of families with predisposition to MDS/AML (Churpek et al. 2015. PubMed ID: 26492932). The gene panel used in this study, however, did not include ANKRD26, SAMD9L, SRP72, DDX41, or ETV6 suggesting that 29% is a minimum value. Also, since we do not know all pathogenic variants in the MDS/AML predisposition genes, sensitivity of this test should steadily improve. To date, large deletions/duplications have not been reported in the ANKRD26, CEBPA, DDX41, ETV6, SAMD9L, or SRP72 genes in patients with Hereditary MDS/AML. Large deletions/duplications and complex rearrangements have been reported in patients with GATA2, RUNX1, TERC, TERT, and TP53 related syndromes and comprise ~ 9%, 29%, 5%, 5%, and 5%, respectively, of the different pathogenic variants reported for these genes (Human Gene Mutation Database).

Hereditary Neuroblastoma: ALK and PHOX2B germline pathogenic variants account for 90% of hereditary neuroblastoma, with the majority being in the ALK gene (Fisher and Tweddle. 2012. PubMed ID: 22673527). Clinical sensitivity for KIF1B pathogenic variants is unknown at this time since relatively few individuals with these variants have been reported.

Hereditary Paraganglioma-Pheochromocytoma Syndrome: Although the majority of hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome tumors are sporadic (non-familial), approximately 13% of all PGL/PCC tumors are caused by germline pathogenic variants in known PGL/PCC syndrome genes (Welander et al. 2011. PubMed ID: 22041710).

Juvenile Polyposis Syndrome (JPS): This test is predicted to identify a pathogenic BMPR1A sequence variant in 11-22% and a pathogenic SMAD4 sequence variant in 20-26% of patients diagnosed with JPS. Deletion/duplication analysis is predicted to identify a BMPR1A pathogenic variant in 1-2% and a SMAD4 pathogenic variant in 2-9% of patients diagnosed with JPS (Larsen Haidle and Howe. 2017. PubMed ID: 20301642).

Li-Fraumeni Syndrome: Sequencing the TP53 gene can detect approximately 95% of patients with Li-Fraumeni syndrome. Deletions in the TP53 gene have been detected in 1% of Li-Fraumeni cases (Schneider et al. 2013. PubMed ID: 20301488).

Multiple Endocrine Neoplasia type 2 and Familial Medullary Thyroid Carcinoma: This test is predicted to detect pathogenic variants in >95% of cases (Marquard and Eng. 2015. PubMed ID: 20301434).

Peutz-Jeghers Syndrome: Approximately 55% of patients with a positive family history or 70% of patients with no family history of Peutz-Jeghers syndrome will be detected by STK11 sequencing. Approximately 45% of patients with a positive family history or 21% of patients with no family history of Peutz-Jeghers syndrome will have a pathogenic variant in STK11 by deletion analysis (McGarrity et al. 2016. PubMed ID: 20301443).

PTEN Hamartoma Syndrome: This test is predicted to detect causative PTEN pathogenic variants in ~80% of patients with Cowden syndrome (CS), ~65% of patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS) and ~20% of patients with Proteus syndrome (PS). Large deletions are predicted to be detected in ~11% of patients with BRRS, but the sensitivity is not known for other PTEN related disorders (Eng 2003. PubMed ID: 12938083).

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

The PHOX2B exon 3 polyalanine region is not covered.

This panel also includes testing for the inversion of exons 1-7 in MSH2.

Of note, Next Generation Sequencing analysis of the SDHA gene is technically challenging due to the presence of segmental duplications and paralogy. Therefore, analysis of CNVs in this region is not included in this test.

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is not typically included in this test but can be ordered separately using test code 6062, if desired.