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Cause of SDH Cancers

The Root of the Problem

SDH cancers occur as a result of a problem with the function of the Succinate Dehydrogenase (SDH) gene complex.  SDH is a tumor suppressor gene which prevents the cells from growing and dividing in an uncontrolled way. Incorrect function of the SDH gene complex results in the accumulation of too much succinate. Excess succinate causes an abnormal build-up of another protein called Hypoxia-Inducible Factor (HIF).  HIF stimulates the cells to divide and the production of blood vessels in cancers such as Gastrointestinal Stromal Tumors (GIST), Pheochromocytomas (PCCs), Paragangliomas (PGLs), Pulmonary chondromas (PCs), Renal Cell Carcinomas (RCCs), and Pituitary Neuroendocrine tumors (PitNETs). It is a hallmark of SDH-deficient cancers to have an absence of the SDH protein on the tumor surface. Application of a staining reagent can determine the presence or absence of the SDH protein. Samples that stain negative for the presence of the protein are called SDH-deficient. 

The Pathology Process

The first step in obtaining a diagnosis involves the pathologist examining the visual features of tumor sample under a microscope. When an SDH gene mutation is suspected, immunohistochemical (IHC) staining can be performed to test for either the presence of absence of the SDH protein on the cell surface.  Absence of the SDH protein (SDH-deficiency), indicates that there is a problem with the function of the SDH gene complex.  IHC staining is the not the same as SDH gene mutation testing. SDH gene mutation analysis usually requires that a sample be sent to an outside lab. 

Cancers in which a driver mutation has not yet been identified are labeled as being wild-type (WT).  The term wild-type indicates that the genome resembles that of the normal, non-mutated version common in nature. Once a driver mutation is identified, wild-type tumors should thereafter be described according to their driver mutation: i.e., SDH-def GIST, SDH-def Paraganglioma, etc. and continuing to refer to the tumor as wild-type is an inaccurate misnomer.

Tumor tissue can be utilized for identification of a somatic (non-hereditary) mutation which is present only within the tumor itself; however, either a blood or saliva sample is required for identification of a (hereditary) germline mutation which is present in every cell in your body. The majority of patients have germline mutations.  When a pathogenic germline SDH mutation is identified, genetic counseling is recommended for the patient and their first degree relatives. Follow this link for assistance finding a genetic counselor. 

Types of SDH Cancers:

 

Gastrointestinal Stromal Tumor

 

Gastrointestinal stromal tumors (GIST) can be caused by a dysfunction of the SDH gene. These tumors, frequently diagnosed in children and young adults, are classified as sarcomas with neuroendocrine-like features. The primary tumor is almost always located in/on the stomach.  GIST patients with dysfunction of the SDH gene should be referred for genetic counseling.

Follow this link to read the SDH-deficient GIST Fact Sheet on the Life Raft Group

website.

 

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Pheochromocytoma/

Paraganglioma

 

 

Pheochromocytomas are paragangliomas that occur in the adrenal gland.  These neuroendocrine tumors can be associated with the presence of an SDH gene mutation.  It is recommend that individuals diagnosed with pheochromotomas (PCCs) and paragaongliomas (PGLs) be referred for genetic testing and family genetic counseling.

 

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Carney-Stratakis Dyad

 

 

Carney-Stratakis syndrome, a combination of familial paraganglioma and gastrointestinal stromal tumor (GIST) can occur in association with having a mutation in one of the SDH subunits. GIST and Paraganglioma patients with germline SDH gene mutations should participate in surveillance screening for both types of tumors.  Genetic counseling for the patient and family members is recommended.

 

 

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Renal Cell Carcinoma

 

Despite the low incidence of an SDH mutation as the cause of renal cell carcinoma (RCC), patients diagnosed at a young age, having tumors in both kidneys, or having a pheochromocytoma/paraganglioma should be considered for SDH mutation testing. A majority of SDH-deficient kidney cancer patients have a germline mutation in SDH subunit A, B, C, or D.  Those with an SDH mutation should be offered genetic testing and family genetic counseling.

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Carney Triad

 

 

The combination of GIST, paraganglioma, and pulmonary chondroma is known as Carney Triad; and the combination of any two of the three possible tumors is referred to as incomplete Carney triad. There is no known SDH gene subunit mutation associated with Carney triad; which is felt to be caused by dysfunction of the SDH gene complex as a whole due to an exterior factor known as an epigenetic change.  Carney Triad is not inherited and family counseling for family members is not indicated.

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Pituitary Adenoma/

Pituitary Neuroendocrine Tumor

 

The term 'pituitary adenoma' is being gradually replaced by the term 'PitNET' (pituitary neuroendocrine tumor).  Genetic analyses in in PitNET patients is a good first step to determine if the tumor is isolated to the pituitary or is part of a multi-organ tumor syndrome.  Young age at onset or a family history is suggestive of syndromic disease.  merging clinical syndromes. Endocrinologists should act in partnership with geneticists to optimise the management of PitNET patients.

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Understanding SDH-deficient Cancer pathology
SDH-def cancer decision trees
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