Test Code ENDCP Hereditary Endocrine Cancer Panel, Varies

Ordering Guidance

Customization of this panel and single gene analysis for any gene present on this panel are available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. For more information see FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

Specimen Required

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated

Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Inherited Cancer Syndromes Patient Information (T519)

3. If not ordering electronically, complete, print, and send a Oncology Test Request (T729) with the specimen.

Secondary ID

614578

Useful For

Evaluating patients with a personal or family history suggestive of a hereditary endocrine tumor syndrome

Establishing a diagnosis of a hereditary endocrine tumor syndrome, allowing for targeted surveillance based on associated risks

Identifying genetic variants associated with increased risk for endocrine tumors, allowing for predictive testing and appropriate screening of at-risk family members

Special Instructions

Method Name

Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing.

Reporting Name

Hereditary Endocrine Cancer Panel

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Tumors occurring within the endocrine and neuroendocrine systems, including thyroid/parathyroid tumors, pituitary tumors, pheochromocytomas (PCC), and paragangliomas (PGL), may occasionally be caused by an underlying hereditary predisposition. Suspicion may be raised for a hereditary cause in families with a strong history of endocrine cancers, patients diagnosed with an endocrine cancer at an early age, patients with multiple primary endocrine cancer diagnoses, and patients with specific histological subtypes, such as medullary thyroid cancer.

The most common endocrine-related malignancy is thyroid cancer, with a lifetime risk of approximately 1.2%.(1,2) Papillary thyroid cancers are typically sporadic but can be seen in individuals or families with familial adenomatous polyposis (FAP) syndrome, caused by variants within the APC gene (cribriform-morular variant). Additionally, about 5% of cases of isolated papillary thyroid cancer cluster in a familial pattern; however, in most cases, no underlying genetic predisposition has yet been identified.(3-6)

Follicular and/or papillary thyroid cancers may be seen in families with PTEN hamartoma tumor syndrome (PHTS). Individuals with disease-causing PTEN variants have a 70-fold increased incidence of thyroid cancer compared to the general population.(7) Thyroid cancers with follicular or papillary features can also be seen in individuals with disease-causing DICER1 variants, as well as individuals with Carney complex, which is caused by disease-causing variants within the PRKAR1A gene.(8,9)

Approximately 25% of cases of medullary thyroid cancer (MTC) are caused by an inherited RET variant.(10) Some disease-causing RET variants are associated with only familial MTC, while others cause a syndrome called multiple endocrine neoplasia type 2 (MEN2). Individuals with MEN2 have a high risk for MTC and may also have other tumors of the endocrine/neuroendocrine system, including PGL, PCC, and parathyroid tumors.(11)

Parathyroid and pituitary tumors may be caused by disease-causing variants within MEN1, CDKN1B, and CDC73. The AIP gene is associated with hereditary predisposition for isolated pituitary adenomas.

PCC and PGL are rare neuroendocrine tumors, 30% of which may have an underlying hereditary predisposition.(12) The genes most frequently associated with increased risk for PGL/PCC are the succinate dehydrogenase-associated genes: SDHA, SDHAF2, SDHB, SDHC, and SDHD.

Germline alterations in the MAX gene are typically associated with increased risk for PCC, although some individuals have been identified with PGL. MAX variants occur in approximately 1% of patients with hereditary PGL/PCC syndromes.(13)

TMEM127 variants are most commonly associated with PCC and rarely PGL.(12) Alterations of TMEM127 account for approximately 2% of individuals with hereditary PGL/PCC (13).

Recent evidence suggests that disease-causing variants in FH increase risk for PGL/PCC.(14,15) Individuals with disease-causing FH variants also have a significantly increased risk for cutaneous or uterine leiomyomata and renal tumors.(16)

Alterations in VHL, NF1, and RET also increase risk for PGL/PCC in addition to other features and tumor types.(17)

The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with hereditary endocrine tumor syndromes.(17,18)

Reference Values

An interpretive report will be provided.

Interpretation

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(19) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletion-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction (PCR)-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. For details regarding the targeted genes analyzed or specific gene regions not routinely covered see Targeted Genes and Methodology Details for Hereditary Endocrine Cancer Panel.(Unpublished Mayo method)

Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Genes analyzed: AIP, APC (including promoters 1A and 1B), CDC73, CDKN1B, DICER1, FH, MAX, MEN1, NF1, PHOX2B, PRKAR1A, PTEN (including promoter), RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, TSC1, TSC2, VHL, and WRN

Day(s) Performed