TY - JOUR
T1 - Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma
AU - Cerecer-Gil, Nidia Y.
AU - Figuera, Luis E.
AU - Llamas, Francisco J.
AU - Lara, Mauricio
AU - Escamilla, José G.
AU - Ramos, Ruben
AU - Estrada, Gerardo
AU - Hussain, A. Karim
AU - Gaal, José
AU - Korpershoek, Esther
AU - De Krijger, Ronald R.
AU - Dinjens, Winand N.M.
AU - Devilee, Peter
AU - Bayley, Jean Pierre
PY - 2010/8/15
Y1 - 2010/8/15
N2 - Purpose: Paragangliomas of the head and neck are neuroendocrine tumors and are associated with germ line mutations of the tricarboxylic acid cycle-related genes SDHB, SDHC, SDHD, and SDHAF2. Hypoxia is important in most solid tumors, and was directly implicated in tumorigenesis over 40 years ago when it was shown that dwelling at high altitudes increases the incidence of carotid body hyperplasia and paragangliomas. Although recent research has now elucidated several pathways of hypoxia in paragangliomas, nothing is currently known of the genetics or of gene-environment interactions in high-altitude paraganglioma. We postulated that SDH mutations might play a role in these tumors. Experimental Design: Patients from a Mexican family, originating and resident in Guadalajara, were tested for mutations of SDHD, and subsequently, for mutations of SDHB followed by immunohistochemical confirmation of SDHB loss. Results: Two patients, born and resident at altitudes of between 1,560 and 2,240 m, were found to have head and neck paragangliomas, including a remarkably aggressive recurrent tumor. Mutation analysis identified a pathogenic missense mutation in exon 7 of SDHB, c.689G>A, p.Arg230His, and loss of the SDHB protein was confirmed by immunohistochemistry. Conclusions: This is the first report of a SDH gene mutation in paraganglioma at high altitude. A rapidly recurrent head and neck paraganglioma is a very rare finding in an SDH mutation carrier, suggesting a gene-environment interaction. Neither patient showed evidence of sympathetic paraganglioma.
AB - Purpose: Paragangliomas of the head and neck are neuroendocrine tumors and are associated with germ line mutations of the tricarboxylic acid cycle-related genes SDHB, SDHC, SDHD, and SDHAF2. Hypoxia is important in most solid tumors, and was directly implicated in tumorigenesis over 40 years ago when it was shown that dwelling at high altitudes increases the incidence of carotid body hyperplasia and paragangliomas. Although recent research has now elucidated several pathways of hypoxia in paragangliomas, nothing is currently known of the genetics or of gene-environment interactions in high-altitude paraganglioma. We postulated that SDH mutations might play a role in these tumors. Experimental Design: Patients from a Mexican family, originating and resident in Guadalajara, were tested for mutations of SDHD, and subsequently, for mutations of SDHB followed by immunohistochemical confirmation of SDHB loss. Results: Two patients, born and resident at altitudes of between 1,560 and 2,240 m, were found to have head and neck paragangliomas, including a remarkably aggressive recurrent tumor. Mutation analysis identified a pathogenic missense mutation in exon 7 of SDHB, c.689G>A, p.Arg230His, and loss of the SDHB protein was confirmed by immunohistochemistry. Conclusions: This is the first report of a SDH gene mutation in paraganglioma at high altitude. A rapidly recurrent head and neck paraganglioma is a very rare finding in an SDH mutation carrier, suggesting a gene-environment interaction. Neither patient showed evidence of sympathetic paraganglioma.
UR - http://www.scopus.com/inward/record.url?scp=77955761570&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-10-0637
DO - 10.1158/1078-0432.CCR-10-0637
M3 - Article
C2 - 20592014
AN - SCOPUS:77955761570
SN - 1078-0432
VL - 16
SP - 4148
EP - 4154
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -