PGLFirst

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PGLFirstTM (FORMERLY PARAGANGLIOMA-PHEOCHROMOCYTOMA (PGL-PCC) SYNDROME PANEL) is a next generation sequencing panel that simultaneously analyzes 7 genes associated with an increased risk of developing paragangliomas and/or pheochromocytomas.

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Ambry utilizes next generation sequencing (NGS) to offer PGLFirst, a comprehensive non-syndromic hereditary PGL/PCC panel.  Genes on this panel include MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127. Full gene sequencing and gross deletion/duplication analysis is performed for all 7 genes. PGLNext is a comprehensive syndromic and non-syndromic hereditary PGL/PCC panel of 12 genes.  Specific Site Analysis is available for individual gene mutations identified in a family.

Disease Name 
Hereditary paraganglioma-pheochromocytoma syndrome
Neuroendocrine tumors
Paraganglioma
Pheochromocytoma
Disease Information 

Paragangliomas (PGLs) are often benign, neuroendocrine tumors of the autonomic nervous system originating from the external ganglia. Pheochromocytomas (PCCs) are paragangliomas that are confined to the adrenal medulla. PGLs are further subdivided into sympathetic and parasympathetic tumors, depending upon their site of origin. Sympathetic PGLs commonly hypersecrete catecholamines and are typically located in the chest, abdomen and pelvis. Parasympathetic PGLs are primarily non-secretory and occur along the nerves in the head, the neck, and the upper mediastinum (termed head and neck PGLs or HNPGLs).1,2

The prevalence of PGLs in the U.S. is 1 in 2,500 to 1 in 6,500, although this is likely an underestimate. The average age of diagnosis is between 40-50 years.2,3  Approximately 75% of PGL/PCCs are benign; however, morbidity and mortality are associated with high levels of circulating catecholamines, which can lead to hypertension and stroke.1,3  Published population studies have found that at least 10-30% individuals with PGL/PCCs have an inherited germline mutation in one of the known susceptibility genes.1,4-6

PGLFirst Genes:

MAX is a tumor suppressor gene associated with PCC susceptibility. In one study of twelve MAX mutation carriers with PCC, 25% of patients showed metastasis, suggesting that, similar to SDHB, MAX mutations are associated with an increased metastatic potential.7  The exact PCC lifetime risk is not yet established for MAX mutation carriers. Seemingly sporadic PCCs may be due to paternal transmission of the mutant allele.1,3,7

SDHA, SDHAF2, SDHB, SDHC, SDHD are all genes associated with hereditary PGL/PCC syndrome. Germline mutations in these genes have been associated with susceptibility to head and neck paragangliomas (HNPGLs), extra-adrenal PGLs/PCCs and, rarely, renal cell carcinoma (RCC) with gastrointestinal stromal tumors (Carney-Stratakis syndrome). SDHB-associated RCC can be of varied histology with reported cases of clear cell, papillary, granular, and mixed.9,10  The exact lifetime risk for PCC is not yet established for SDHB mutation carriers.11  The SDHD and SDHAF2 genes are subject to the effects of imprinting (parent-of-origin effects), and cancer risk is correlated with paternal transmission.12-14  Mutations in the SDHB and SDHD genes have also been associated with PTEN mutation-negative Cowden syndrome.15

TMEM127 is a proposed tumor suppressor gene associated with PGL/PCC susceptibility.16 TMEM127 mutations demonstrate an autosomal dominant pattern of inheritance with unknown penetrance.1,3 TMEM127-associated PCCs can present bilaterally or unilaterally, and may also be found in patients with no family history of PCC.11,16  One study reported TMEM127 mutations in 2 of 48 patients with PGL.16

Germline mutations in SDHD cause the highest susceptibility to head and neck paragangliomas, however, mutations in SDHB, SDHC, and SDHAF2 have also been reported in these patients.  Germline mutations in SDHB and MAX have the highest risk of malignancy.  Mutations in SDHAF2, SDHD, RET, and MAX cause the highest susceptibility to multiple or bilateral PGL/PCCs.  To note, MEN1, NF1, RET, and VHL mutations have also been found to be part of the hereditary PGL/PCC spectrum. 17

Testing Benefits & Indication 

Genetic testing algorithms exist, however, recent data and guidelines suggest that all individuals with a PGL or PCC should be offered diagnostic testing for hereditary PGL/PCC susceptibility. Increased surveillance and treatment is available for those found to carry a mutation.17

Common Red Flags for Hereditary Cancer

  • Cancer diagnosed at a younger age than expected for the general population (≤ 50 years, for most cancers)
  • Cancer diagnosed across generations, and in multiple generations within a family, especially when diagnosed younger than average (on the same side of the family)
  • Individual with multiple primary cancers (either in paired organs or in different organs)
  • A pattern of cancer in the family that is typical of a known cancer predisposition syndrome (e.g. malignant PGL and renal cell carcinoma with SDHB)

Benefits of Testing:
Identifying patients with an inherited susceptibility for PGL/PCC can help with medical management and risk assessment. For example, this information can:

  • Modify surveillance options and age of initial screening
  • Suggest specific risk-reduction measures
  • Clarify and stratify familial cancer risks, based on gene-specific associations
  • Offer treatment guidance
  • Identify at-risk family members
  • Provide guidance with new gene-specific treatment options and risk reduction measures as they emerge
Test Description 

PGLFirst analyzes 7 genes (MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127) by NGS or Sanger sequencing of all coding domains and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Additional Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Suspect variant calls are verified by Sanger sequencing. Gross deletion/duplication analysis is performed for the covered exons and untranslated regions of all 7 genes using read-depth from NGS data with confirmatory multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray. 

 

Mutation Detection Rate 

PGLFirst can detect >99.9% of described mutations in the included genes listed above, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
5419 PGLFirst 14-21
5450 PGLFirst reflex to PGLNext 14-42
5416 Single Site Analysis  7-14

 

Specialty 
Genes 
MAX
SDHB
SDHC
SDHD
SDHAF2
TMEM127
SDHA
References 
  1. Fishbein L and Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genetics. 2012;205(1-2):1-11. 
  2. Welander J, et al. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer. 2011;18(6):R253-76. 
  3. DeLellis RA. Pathology and genetics of tumours of endocrine organs. Lyon, France: IARC Press; 2004.
  4. Fishbein L, et al. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Annals of Surgical Oncology. 2013;20(5):1444-50. 
  5. Mannelli M, et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94(5):1541-7. 
  6. Mannelli M, et al. Subclinical phaeochromocytoma. Best Prac Res Clin Endocrinol Metab. 2012;26(4):507-15. 
  7. Comino-Mendez I, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43(7):663-7. 
  8. Carney JA and Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002;108(2):132-9. 
  9. Ricketts C, et al. Germline SDHB mutations and familial renal cell carcinoma. Journal of the National Cancer Institute. 2008;100(17):1260-2. 
  10. Vanharanta S, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet. 2004;74(1):153-9. 
  11. Ricketts CJ, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010;31(1):41-51. 
  12. Baysal BE. Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors. Biochim Biophys Acta. 2013;1827(5):573-7. 
  13. Hao HX, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325(5944):1139-42. 
  14. Kunst HP, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011;17(2):247-54. 
  15. Ni Y, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008;83(2):261-8. 
  16. Neumann HP, et al. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab. 2011;96(8):E1279-82. 
  17. Lenders JWM, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915-42.