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

2. Central dogma of biology
Copy number alterations
Mutations
Structural variations
Expressional alterations
Epigenetic alerations
Gain/loss of function
Degradation

3. Somatic vs germline alterations

4. 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

5. 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

6. What are tumor suppressor genes?
Gatekeeper for abnormal cellular events
Knudson two-hit hypothesis
Typically recessive
Dominant negative or haploinsufficiency

7. Cancer – inactive tumor suppressor and active oncogene

8. What are copy number alterations?
Microarray
NGS

9. 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: /nrgastro

10. What are mutations?

11. What are structural variaions?

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

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

14. Druggable mutations in HCC
Ho, Chan, et al. Gut. doi: /gutjnl

15. Druggable mutations in HCC
Ho, Chan, et al. Gut. doi: /gutjnl

16. Druggable mutations in HCC
Ho, Chan, et al. Gut. doi: /gutjnl

17. Druggable mutations in HCC
Ho, Chan, et al. Gut. doi: /gutjnl

18. Druggable mutations in HCC
Ho, Chan, et al. Gut. doi: /gutjnl

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

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

21. HBV viral integration in HCC
Chiu, Wong , et al. Journal of Hepatology.  , DOI: ( /j.jhep )

22. HBV viral integration in HCC
Chiu, Wong , et al. Journal of Hepatology.  , DOI: ( /j.jhep )

23. HBV viral integration in HCC
Chiu, Wong , et al. Journal of Hepatology.  , DOI: ( /j.jhep )

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

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

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

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

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