MED12is recurrently mutated in Middle Eastern colorectal cancer.
OBJECTIVE
Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognising the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients.


METHODS
In the discovery phase of the study, we conducted whole genome sequencing of tumour and corresponding germline DNA in 27 patients with CRC. In addition to known driver mutations, we identified threeMED12somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequenceMED12and other candidate genes in a larger sample of 400 patients with CRC and confirmed the enrichment for recurrentMED12mutations.


RESULTS
In order to gain insight into a plausible biological mechanism for the potential role ofMED12mutations in CRC, we studied CRC cell lines that differ substantially in the expression level ofMED12, and found the latter to be correlated inversely with transforming growth factor (TGF)-β signalling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated whenMED12expression was experimentally manipulated.


CONCLUSIONS
Our data expand the recently described role ofMED12as a tumour suppressor in other cancers to include CRC, and suggest TGF-β signalling as a potential mediator of this effect.
Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Abdul K
AK
Siraj
Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Tariq
T
Masoodi
Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Rong
R
Bu
Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Poyil
P
Pratheeshkumar
Department of Surgery and Colorectal Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Nasser
N
Al-Sanea
Department of Surgery and Colorectal Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Luai H
LH
Ashari
Department of Surgery and Colorectal Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Alaa
A
Abduljabbar
Department of Surgery and Colorectal Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Samar
S
Alhomoud
Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Fouad
F
Al-Dayel
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Fowzan S
FS
Alkuraya
Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Khawla S
http://orcid.org/0000-0002-8430-6693
KS
Al-Kuraya
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D008877:Middle East; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000235:genetics*
D014408:Biomarkers, Tumor; C460107:MED12 protein, human; D056892:Mediator Complex; D016212:Transforming Growth Factor beta
COLORECTAL CANCER; COLORECTAL CANCER GENES; MUTATION SCREENING