Cancer genetics - the case of hepatocellular carcinoma Daniel Ho Department of Pathology HKU

Central dogma of biology Copy number alterations Mutations Structural variations Expressional alterations Epigenetic alerations Gain/loss of function Degradation https://www.ncbi.nlm.nih.gov/Class/MLACourse/Modules/MolBioReview/central_dogma.html

Somatic vs germline alterations https://www.ncbi.nlm.nih.gov/books/NBK21894/

What are oncogenes and proto-oncogenes? Oncogenes have the potential to cause tumor formation Proto-oncogenes are normal genes by default but acquire malignant functions when mutated or upregulated Typically dominant https://en.wikipedia.org/wiki/Oncogene

What are fusion genes? Philadelphia chromosome Consequence of chromosomal translocation Parts of chr 9 and 22 exchanged Formation of BCR-ABL fusion gene by joining BCR (22q11) and ABL (9q34) Commonly found in leukemia Detection by FISH

What are tumor suppressor genes? Gatekeeper for abnormal cellular events Knudson two-hit hypothesis Typically recessive Dominant negative or haploinsufficiency http://uvmgg.wikia.com/wiki/Tumor_suppressor

Cancer – inactive tumor suppressor and active oncogene http://cisncancer.org/research/what_we_know/advances/oncogenes.html

What are copy number alterations? Microarray NGS

Copy number alterations in HCC Recurrently amplified and deleted genes in HCC Shibata, T. & Aburatani, H. (2014) Exploration of liver cancer genomes Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.6

What are mutations? http://evolution.berkeley.edu/evolibrary/article/evo_20 http://www.vce.bioninja.com.au/aos-3-heredity/molecular-genetics/mutations.html

What are structural variaions? http://www.vce.bioninja.com.au/aos-3-heredity/molecular-genetics/mutations.html

Genomic alterations in HCC Totoki, et al. Nature Genetics. 2014

Genomic alterations in HCC Schulze, et al. Nature Genetics. 2015

Druggable mutations in HCC Ho, Chan, et al. Gut. doi:10.1136/gutjnl-2016-312734

Druggable mutations in HCC Ho, Chan, et al. Gut. doi:10.1136/gutjnl-2016-312734

Druggable mutations in HCC Ho, Chan, et al. Gut. doi:10.1136/gutjnl-2016-312734

Druggable mutations in HCC Ho, Chan, et al. Gut. doi:10.1136/gutjnl-2016-312734

Druggable mutations in HCC Ho, Chan, et al. Gut. doi:10.1136/gutjnl-2016-312734

Viral integration in cancers Chen, et al. Cancers. 2014.

HBV viral integration in HCC Sung, et al. Nature Genetics. 2012

HBV viral integration in HCC Chiu, Wong , et al. Journal of Hepatology. 2016 64, 1256-1264. DOI: (10.1016/j.jhep.2016.02.005)

HBV viral integration in HCC Chiu, Wong , et al. Journal of Hepatology. 2016 64, 1256-1264. DOI: (10.1016/j.jhep.2016.02.005)

HBV viral integration in HCC Chiu, Wong , et al. Journal of Hepatology. 2016 64, 1256-1264. DOI: (10.1016/j.jhep.2016.02.005)

Chimeric genomic fragment Strategy for viral integration detection Human HBV Chimeric genomic fragment (Soft-clipped reads)

Workflow of Virus-Clip Ho, et al. Oncotarget. 2015

Performance comparison of Virus-Clip with other existing tools Ho, et al. Oncotarget. 2015

Detecting transcriptomic alterations by differential gene expression analysis Ho, et al. Front Med. 2015

Molecular pathogenesis of HCC Multi-step accumulation of oncogenic alterations at multiple levels Ho, et al. Liver Cancer. 2016