title: Accumulation of Deleterious Passenger Mutations Is Associated with the Progression of Hepatocellular Carcinoma.
abstract: In hepatocellular carcinoma (HCC), somatic genome-wide DNA mutations are numerous, universal and heterogeneous. Some of these somatic mutations are drivers of the malignant process but the vast majority are passenger mutations. These passenger mutations can be deleterious to individual protein function but are tolerated by the cell or are offset by a survival advantage conferred by driver mutations. It is unknown if these somatic deleterious passenger mutations (DPMs) develop in the precancerous state of cirrhosis or if it is confined to HCC. Therefore, we studied four whole-exome sequencing datasets, including patients with non-cirrhotic liver (n = 12), cirrhosis without HCC (n = 6) and paired HCC with surrounding non-HCC liver (n = 74 paired samples), to identify DPMs. After filtering out putative germline mutations, we identified 187±22 DPMs per non-diseased tissue. DPMs number was associated with liver disease progressing to HCC, independent of the number of exonic mutations. Tumours contained significantly more DPMs compared to paired non-tumour tissue (258-293 per HCC exome). Cirrhosis- and HCC-associated DPMs do not occur predominantly in specific genes, chromosomes or biological pathways and the effect on tumour biology is presently unknown. Importantly, for the first time we have shown a significant increase in DPMs with HCC.
authors.affiliation: Centenary Institute, University of Sydney, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Budzinska
authors.affiliation: Centenary Institute, University of Sydney, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tu
authors.affiliation: Centenary Institute, University of Sydney, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: William M H
authors.initials: WM
authors.lastname: d'Avigdor
authors.affiliation: Centenary Institute, University of Sydney, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.affiliation: School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia.
authors.forename: Fabio
authors.initials: F
authors.lastname: Luciani
authors.affiliation: Centenary Institute, University of Sydney, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Shackel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult