Test Information Sheet

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Ilene George
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1 OncoGeneDx: Pediatric Tumor Panel Test Information Sheet Panel Gene List: ALK, APC, CDC73, DICER1, EPCAM*, MEN1, MLH1, MSH2, MSH6, NF1, NF2, PHOX2B*, PMS2, PRK1A, PTCH1, PTEN, RB1, RET*, SMCA4, SMCB1, STK11, SUFU, TP53, TSC1, TSC2, VHL, WT1 *Testing includes sequencing and deletion/duplication analysis for all genes except EPCAM (del/dup only), PHOX2B (seq only) and RET (seq only). Clinical Features: Approximately 1 in 285 children and adolescents will be diagnosed with cancer before age 20 which represents 1% of all new cancer diagnoses in the United States (ACS, 2014). While the majority of pediatric cancers and other are sporadic in nature, 5-10% of pediatric cancer cases are thought to be due to a hereditary predisposition (Zhang 2015). The proportion of cases due to hereditary predisposition varies considerably between cancer types (Zhang 2015, Plon 2005). In addition, certain benign tumors or other clinical features may also be suggestive of hereditary cancer predisposition. The features of a personal and/or family history of cancer that are suggestive of a hereditary cancer predisposition include: early age at diagnosis, multiple primary cancers in a single individual, rare cancers or tumors, and multiple relatives affected with the same type of cancer or related cancers spanning multiple generations. For some of the well-described hereditary conditions discussed below, clinical diagnostic criteria based on personal medical history and family history are available to help identify patients most likely to have a hereditary cancer. In many cases, however, patients do not meet the clinical diagnostic criteria or the criteria may overlap for multiple conditions, making it difficult to decide which genes should be tested and in what order. The OncoGeneDx Pediatric Tumor Panel offered at GeneDx includes analysis of 27 genes associated with hereditary predisposition s including Carney Complex (PRK1A) and other PRK1A-related disorders, Constitutional Mismatch Repair Deficiency (EPCAM, MLH1, MSH2, MSH6, PMS2), Familial Adenomatous Polyposis (APC), Gorlin /Nevoid Basal Cell Carcinoma (PTCH1), Heritable Retinoblastoma (RB1), hereditary neuroblastic tumor susceptibility (ALK, PHOX2B), Hyperparathyroidism-jaw Tumor (HPT-JT) and other CDC73-related disorders (CDC73), Li-Fraumeni (TP53), Multiple Endocrine Neoplasia type 1 (MEN1) and 2A/2B (RET), Neurofibromatosis type 1 (NF1) and 2 (NF2), Peutz-Jeghers (STK11), PTEN hamartoma tumor / Cowden (PTEN), Tuberous Sclerosis Complex (TSC1, TSC2), Von-Hippel Lindau disease (VHL) and WT1-related disorders (WT1). Newer genes that have been identified in association with pediatric onset have also been included in the panel. These genes include DICER1, SMCA4, SMCB1 and SUFU. Accurate risk assessment may be complicated by small numbers of patients, low penetrance Page 1 of 7, Updated: Dec-16

2 of pathogenic variants in these genes and/or ascertainment bias. Since the cancer risks are not yet well defined, no consensus guidelines for medical management are available for these genes. Inheritance Pattern: All of the genes on this panel are associated with autosomal dominant inheritance with the exception of Constitutional Mismatch Repair Deficiency (CMMR-D) which is inherited in an autosomal recessive manner. Test Methods: Genomic DNA from the submitted specimen was enriched for the complete coding region and splice site junctions of the genes on the panel using a proprietary targeted capture system developed by GeneDx. The products were sequenced on either an Illumina MiSeq or HiSeq instrument with 2x150 or 2x100 paired-end reads, respectively. The sequence was aligned to reference sequences based on human genome build GRCh37/UCSC hg19. Capillary sequencing was used to confirm all variants with clinical or uncertain significance and to analyze regions with inadequate coverage by Next Generation sequencing. If present, apparently homozygous variants were confirmed using alternate primer pairs to significantly reduce the possibility of allele drop-out. Concurrent deletion/duplication testing was performed for all relevant genes on the panel using either exon-level array CGH or MLPA. Confirmation of copy number changes was performed by MLPA, qpcr, or repeat acgh analysis. Data analysis was performed using gene-specific filtering. The array was designed to detect most single-exon deletions and duplications. For PHOX2B and RET, only sequencing was performed. In addition, polyalanine repeats for the commonly expanded region in exon 3 of PHOX2B are not resolved. For EPCAM, deletion/duplication analysis, but not sequencing, was performed. For PTEN, nucleotides c.-700 through c in the promoter region are also sequenced. Array CGH alterations were reported according to the International System for Human Cytogenetic Nomenclature (ISCN) guidelines. All sequence alterations are described according to the Human Genome Variation Society (HGVS) nomenclature guidelines. Benign and likely benign variants, if present, are not reported but are available upon request. Test Sensitivity: The clinical sensitivity of sequencing and deletion/duplication analysis of the 27 genes included in the OncoGeneDx Pediatric Tumor Panel depends in part on the patient s clinical phenotype and family history. In general, the sensitivity is highest for individuals with features suggestive of hereditary predisposition to cancer as outlined above. DNA sequencing will detect nucleotide substitutions and small insertions and deletions, while array CGH will detect exonlevel deletions and duplications. These methods are expected to be greater than 99% sensitive in detecting pathogenic variants identifiable by sequencing or array CGH. The likelihood of a false positive result is expected to be <1%. Sensitivity for NF2 is limited by somatic Page 2 of 7, Updated: Dec-16

3 mosaicism; therefore, testing of tumor tissue may be considered after a negative result in an apparently de novo patient with a high clinical suspicion of NF2. Technical Limitations: Neither sequencing nor exon-level acgh can reliably detect mosaicism, and cannot detect chromosomal aberrations. Deletions involving more than 20bp and insertions involving more than 10bp are not reliably detected by the sequencing methodology, and deletions or duplications of less than 250bp are not reliably detected by array CGH. Regions of certain genes have inherent sequence properties that yield suboptimal data, potentially impairing accuracy of the results. For instance, sequence and deletion/duplication analysis of PMS2 and NF1, among others, is complicated by the presence of pseudogenes or homologous sequences that involve multiple exons of this gene. In the absence of mrna/cdna studies, we cannot completely exclude the possibility of undetectable clinically significant variants in certain regions of these genes. False negatives may also occur in the setting of bone marrow transplantation, recent blood transfusion, or suboptimal DNA quality. In individuals with active leukemia or lymphoma or with known chronic myeloid or lymphoid (such as low grade MDS, CML, ET, P. vera, PMF, CLL), there is a possibility that testing of specimens containing leukocytes may detect an acquired somatic variant, resulting in a false positive result. In this situation, please contact one of our genetic counselors to discuss the utility of submitting an alternate specimen. Additionally, rare false negatives may occur when testing for a specific variant identified at a laboratory other than GeneDx if a positive control is not provided. Based on the specific array design and technology used, the reported coordinates of duplications and deletions at the exon or gene level can slightly differ among family members tested but, in general, relatives are expected to have the same copy number variant. The ability to detect genetic variants and naming conventions can differ among laboratories. ALK Gene Protein Inheritance Disease Associations ALK TYROSINE KINASE RECEPTOR Neuroblastic tumors APC ENOMATOUS POLYPOSIS COLI PROTEIN CDC73 PAFIBROMIN DICER1 ENDORIBONUCLEASE DICER Familial Adenomatous Polyposis (FAP)- associated condition: Colorectal, Duodenal or periampullary, Gastric, Thyroid, Pancreatic, Brain & Liver (Hepatoblastoma) cancers, Desmoid tumors, Gastrointestinal polyps Parathyroid cancer, Jaw fibromas, Renal tumors, Uterine tumors Pleuropulmonary blastoma, Multinodular thyroid goiter and Thyroid cancer, Cystic nephroma, Ovarian cancer (SLCT), Cervical embryonal rhabdomyosarcoma, among others Page 3 of 7, Updated: Dec-16

4 EPCAM EPITHELIAL CELL HESION MOLECULE MEN1 MENIN MLH1 MSH2 MSH6 DNA MISMATCH REPAIR PROTEIN MLH1 DNA MISMATCH REPAIR PROTEIN MSH2 DNA MISMATCH REPAIR PROTEIN MSH6 NF1 NEUROFIBROMIN NF2 MERLIN PHOX2B PMS2 PAIRED MESODERM HOMEOBOX PROTEIN 2B MISMATCH REPAIR ENDONUCLEASE PMS2 Lynch : Colorectal, Endometrial, Ovarian, Gastric Pancreatic, Biliary tract, Urinary tract, Small bowel & Brain cancer, Sebaceous Constitutional mismatch repair deficiency Multiple endocrine neoplasia type 1 (MEN1): Parathyroid tumors, Pancreatic neuroendocrine tumors, Pituitary tumors, Pheochromocytoma Lynch (LS): Colorectal, Endometrial, Ovarian, Gastric, Pancreatic, Biliary tract, Urinary tract, Small bowel & Brain cancer, Sebaceous Lynch (LS): Colorectal, Endometrial, Ovarian, Gastric, Urinary tract, Pancreatic, Biliary tract, Small bowel & Brain cancer, Sebaceous Lynch (LS): Colorectal, Endometrial, Ovarian, Gastric, Pancreatic, Biliary tract, Small bowel & Brain cancer, Sebaceous Neurofibromatosis type 1 (NF1) : Breast cancer, GIST, Optic nerve gliomas, Pheochromocytoma, MPNST, Neurofibromas, Brain tumors Neurofibromatosis type 2 (NF2) : Schwannomas - vestibular and other, Spinal tumors, Meningiomas Neuroblastic tumors Lynch (LS): Colorectal, Endometrial, Ovarian, Gastric, Pancreatic, Biliary tract, Urinary tract, Small bowel & Brain cancer, Sebaceous Page 4 of 7, Updated: Dec-16

5 PRK1A PTCH1 PTEN RB1 RET SMCA4 SMCB1 CAMP-DEPENDENT PROTEIN KINASE TYPE 1-ALPHA REGULATORY SUBUNIT PROTEIN PATCHED HOMOLOG 1 PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE 3- PHOSPHATASE AND DUAL-SPECIFICITY PROTEIN PHOSPHATASE PTEN RETINOBLASTOMA- ASSOCIATED PROTEIN PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET TRANSCRIPTION ACTIVATOR BRG1 SWI/SNF-RELATED MATRIX-ASSOCIATED ACTIN-DEPENDENT REGULATOR OF CHROMATIN SUBFAMILY B MEMBER 1 Test Information Sheet Thyroid cancer, Testicular tumors (LCCSCT), Myxomas, Psammomatous melanotic schwannomas (PMSs), Primary pigmented nodular adrenocortical disease, among others Gorlin : Basal cell carcinoma, Medulloblastoma, Fibromas, Jaw tumors (Ontogenic keratocysts) PTEN hamartoma tumor (PHTS): Breast, Thyroid, Endometrial, Colon, Melanoma & Renal cancer, Gastrointestinal polyps, Lhermitte Duclos Disease Hereditary Retinoblastoma: Retinoblastoma, Sarcoma, Leukemia, Melanoma, Pineoblastoma Multiple endocrine neoplasia type 2 (MEN2): Medullary thyroid cancer, Pheochromocytoma, Hyperparathyroidism Ovarian (SCCOHT) cancer, Rhabdoid tumors Rhabdoid tumors, Schwannomas Peutz-Jeghers Syndrome (PJS): Breast, STK11 Colorectal, Pancreatic, Gastric, Small SERINE/THREONINE- Bowel, Ovarian, Lung, Cervical & PROTEIN KINASE STK11 Endometrial cancer, Testicular tumors (LCCSCT), Gastrointestinal polyps SUFU SUPPRESSOR OF FUSED Medulloblastoma, Basal cell carcinoma, HOMOLOG Meningioma Li-Fraumeni (LFS): Breast TP53 cancer, Sarcoma, Brain cancer, CELLUL TUMOR Hematologic malignancies, ANTIGEN P53 Adrenocortical carcinoma, among others** TSC1 HAMTIN Tuberous sclerosis complex (TSC): Renal Page 5 of 7, Updated: Dec-16

6 cancer/tumors, CNS tumors, Hamartomatous tumors TSC2 TUBERIN Tuberous sclerosis complex (TSC): Renal cancer/tumors, CNS tumors, Hamartomatous tumors VHL VON HIPPEL-LINDAU DISEASE TUMOR SUPPRESSOR von Hippel-Lindau (VHL) disease: Renal cancer (clear cell), Pancreatic neuroendocrine tumors, Hemangioblastoma, Pheochromocytoma, Endolymphatic sac tumors WT1 WILMS TUMOR PROTEIN Wilms tumor Because of evolving and expanding phenotypes, this list of cancer/tumor types is not exhaustive. Gene specific risk for some of the cancers and other features listed are not well defined. ** High overall risk of cancer: 75% lifetime risk for males to develop cancer, nearly 100% risk for females. Abbreviations: Autosomal dominant Autosomal recessive CGH Comparative genomic hybridization GIST Gastrointestinal stromal tumor LCCSCT - Large cell-calcifying Sertoli cell tumors MLPA Multiplex ligation-dependent probe amplification MPNST - Malignant peripheral nerve sheath tumors SCCOHT - Small cell carcinoma of the ovary, hypercalcaemic type SLCT - Sertoli-Leydig cell tumor References: 1. Auber F et al. Management of Wilms tumors in Drash and Frasier s. Pediatric Blood & Cancer Jan 52(1):55-9. (PMID: ) 2. American Cancer Society. Special Section: Cancer in Children & Adolescents. Cancer Facts & Figures American Thyroid Association Bonadona V et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch. JAMA Jun;305(22): (PMID: ) 5. Bree AF et al. Consensus statement from the first international colloquium on basal cell nevus (BCNS). Am J Med Genet A Sep;155A(9): doi: /ajmg.a (PMID: ) 6. Correa R et al. Carney complex: an update. Eur J Endocrinol Oct;173(4):M (PMID: ) 7. Dome JS, Huff V. Wilms Tumor Overview Dec 19 [Updated 2013 Sep 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 8. Doros L, Schultz KA, Stewart DR, et al. DICER1-Related Disorders Apr 24. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 9. Durno CA, Holter S, Sherman PM, Gallinger S. The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations. Am J Gastroenterol Nov;105(11): (PMID ) 10. Evans DG et al. Genetic testing and screening g of individuals at risk of NF2. Clin Genet Nov;82(5): (PMID: ) 11. Evans DG, Farndon PA. Nevoid Basal Cell Carcinoma Syndrome Jun 20 [Updated 2015 Oct 1]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 12. Frantzen C, Klasson TD, Links TP, et al. Von Hippel-Lindau Syndrome May 17 [Updated 2015 Aug 6]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 13. Friedman JM. Neurofibromatosis Oct 2 [Updated 2014 Sep 4]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 14. Greengard EG, Park JR. ALK-Related Neuroblastic Tumor Susceptibility Jan 5 [Updated 2015 Apr 9]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 15. Jackson MA, Rich TA, Hu MI, et al. CDC73-Related Disorders Dec 31 [Updated 2015 Jan 15]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 16. Krueger DA et al. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol Oct;49(4): (PMID: ) 17. Lohmann DR, Gallie BL. Retinoblastoma Jul 18 [Updated 2015 Nov 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 18. Parsons DW et al. Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. Jama Oncology Jan 28. (PMID: ) 19. Plon SE and Nathanson K. Inherited Susceptibility for Pediatric Cancer. Cancer J Jul-Aug. (PMID: ) 20. Richards CS et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions Genet Med Apr;10(4): Page 6 of 7, Updated: Dec-16

7 21. Scott RH et al. Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Archives Of Disease In Childhood Dec 91(12): PMID: ( ) 22. Stratakis C et al. Clinical and Molecular Features of the Carney Complex: Diagnostic Criteria and Recommendations for Patient Evaluation J Clin Endocrinol Metab Sep;86(9): (PMID: ) 23. The Endocrine Society Weese-Mayer DE et al. An official ATS clinical policy statement: Congenital central hypoventilation : genetic basis, diagnosis, and management. Am J Respir Crit Care Med Mar 15;181(6): (PMID: ) 25. Weese-Mayer DE, Marazita ML, Rand CM, et al. Congenital Central Hypoventilation Syndrome Jan 28 [Updated 2014 Jan 30]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. 26. Weissman SM et al. Genetic counseling considerations in the evaluation of families for Lynch --a review.j Genet Couns Feb;20(1):5-19. (PMID: ) 27. Wimmer K and Kratz CP. Constitutional mismatch repair-deficiency. Haematologica May; 95(5): (PMID ) 28. Zhang J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. The New England Journal Of Medicine Nov 18. (PMID ) Page 7 of 7, Updated: Dec-16

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