Patient-led functional genomics identifies novel drivers of intrahepatic cholangiocarcinoma
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Date
27/06/2020Item status
Restricted AccessEmbargo end date
27/06/2021Author
Younger, Nicholas Thomas
Metadata
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a rare and universally lethal
malignancy arising in the liver. Incidence has steadily been increasing globally yet
effective therapeutics are lacking. Currently, gold standard treatment is complete
resection for which a minority of patients are suitable and recurrence rates post
resection are high. For the majority of patients unsuitable for surgery, standard
chemotherapeutic options extend life by only 3-6 months on average. As such there
is a pressing need to elucidate the genetic and molecular features of this
malignancy so as to inform the development of more effective therapies. To date, a
small but robust set of driver genes have been discovered and for some targeted
therapies in development, with mixed results in clinical trials.
This work aimed to extend the set of known driver genes by exploring the long tail
of infrequently mutated genes in patient sequencing data. Through computational
prediction and in vivo screening, a set of driver genes were uncovered which
cooperate with the more commonly encountered oncogenic RASG12 isoforms of
KRAS and NRAS. Validation studies in vivo confirmed that the membrane
cytoskeleton adaptor protein Merlin, encoded by NF2, and the canonical
transmembrane semaphorin receptor PLXNB2 encoded by PLXNB2 are tumour
suppressors occurring at low frequency in the patient population. Mutation of
these genes significantly accelerated disease progression and propagated
aggressive, invasive tumour phenotypes.