MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas
Background: Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase ( FH ) inactivation or occasionally by mediator complex subunit 12 ( MED12 ) mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivati...
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Published in | British journal of cancer Vol. 114; no. 12; pp. 1405 - 1411 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
14.06.2016
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Background:
Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (
FH
) inactivation or occasionally by mediator complex subunit 12 (
MED12
) mutations. The aim of this study was to analyse whether
MED12
mutations and
FH
inactivation are mutually exclusive and to determine the contribution of
MED12
mutations on HLRCC patients’ myomagenesis.
Methods:
MED12
exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients’ (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA).
Results:
Nine tumours from HLRCC patients harboured a somatic
MED12
mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were
MED12
mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients’
MED12
mutation-positive tumours clustered together with sporadic
MED12
mutation-positive tumours.
Conclusions:
Somatic
MED12
mutations and biallelic
FH
inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients’ uterine leiomyomas are caused by
FH
inactivation, but incidental tumours driven by somatic
MED12
mutations also occur. These
MED12
mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0007-0920 1532-1827 1532-1827 |
DOI: | 10.1038/bjc.2016.130 |