- Mutations or
alterations in genes involved in cell respiration linked to development of
paragangliomas (PGLs) and pheochromocytomas (PCCs)
- Two rare
variations in previously known genes and two new candidate genes
- These tumors (PGL
and PCC) have the strongest hereditary component known till date.
Pheochromocytomas (PCC) and
paragangliomas (PGL) are rare neuroendocrine tumors. Many genes whose
alterations or mutations confer hereditary susceptibility to develop these
tumors are those that are involved in the Kreb's cycle (cell respiration
pathway). A team of researchers from the Spanish National Cancer Research
Center have identified rare pathological variations in known PGL/PCC
susceptible genes and also two new candidate genes that confer hereditary
susceptibility. The study was published in the journal Clinical Cancer Research.
Pheochromocytoma and ParagangliomaPheochromocytoma
(PCC) and paraganglioma (PGL) are
rare tumors that form from neuroendocrine cells. They are both generally benign
(do not grow a.k.a cancerous) but rarely they do undergo metastasis (spread to
other parts of the body). PCC develops in the adrenal gland and PGL in certain
nerve cells. Both tumors result in episodic or persistent high blood pressure.
Both PGL and PCC are not genetic in origin but the generally benign tumors becoming cancerous and spreading to
other parts of the body is associated to mutations in genes involved in the cell respiration cycle. The fact that up to 40% of individuals with PCC and/or PGL have a
hereditary background due to germ line mutations affecting one of thirteen
susceptibility genes makes these tumors have a stronger hereditary component
compared to other tumors.
Study lead, Alberto Cascón, mentioned "The identification of mutations in the Krebs cycle
genes is especially important given that the patients harboring them have a
greater likelihood of developing metastasis"
‘GOT2 and IDH3B genes possibly linked to hereditary predisposition to paragangliomas and pheochromocytomas.’
Basis of The Study
Nearly half of the genes linked to development
of PGG and PCC were linked to genes that play a role in the Kreb's cycle.
Variations in genes that code for SDH, FH and MDH2 leads to accumulation of
metabolites that lead to epigenetic (combination of environmental and genetic)
changes in the genome. The team
hypothesized that if tumors which had the same epigenetic changes but the
already known genes were not mutated, then there must be mutations in other
Kreb's cycle genes.
49 tumors from patients that had the same
epigenetic changes and did not show alterations in the thirteen known PCC/PGG susceptibility
genes were analyzed. Exome sequencing revealed two very rare pathological
variations in known PCC/PGL susceptibility genes (SDHC and IDH1).
The study also identified two new candidate
genes tat could possibly be involved in the hereditary predisposition to PCC
and PGL. One is a germ line mutation in the GOT2 gene and the other IDHB3 gene
both encoding enzymes for the Kreb's cycle.
The study strengthens the evidence for the
relevance of Kreb's cycle genes in the development of pheochromocytomas and
paragangliomas and also indicates that there may be several undiscovered genes
that may be involved.
The epigenetic changes in the genome as a
result of the gene mutations lead to dis-regulation of the enzyme levels. If
all the susceptibility genes are identified, the epigenetic changes may be
rewritten. In this case the DNA becomes hyper-methylated (additional methyl
groups are added, thereby silencing or altering gene function). To bring back
normal function the methyl groups may be removed.
Identifying all susceptibility genes also means
that the a person affected with these neuroendocrine tumors can track the tumor
and eliminate the risk of metastasis.
- Remacha, L., Comino-Méndez, I., Richter, S., Contreras, L., Currás-Freixes, M., Pita, G., . . . Cascon,
A. (2017). Targeted exome sequencing of Krebs cycle genes reveals candidate cancer predisposing mutations in pheochromocytomas and
paragangliomas. Clinical Cancer Research. doi:10.1158/1078-0432.ccr-16-2250
- Pheochromocytoma and
Paraganglioma-Patient Version - (https://www.cancer.gov/types/pheochromocytoma)