TY - BOOK

T1 - Understanding Cancer Genome and Its Evolution by Next Generation Sequencing

AU - Hou, Yong

PY - 2016

Y1 - 2016

N2 - Cancer will cause 13 million deaths by the year of 2030, ranking the second leading cause ofdeath worldwide. Previous studies indicate that most of the cancers originate from cells thatacquired somatic mutations and evolved as Darwin Theory. Ten biological insights of cancerhave been summarized recently. Cutting-age technologies like next generation sequencing (NGS)enable exploring cancer genome and evolution much more efficiently. However, integratedcancer genome sequencing studies showed great inter-/intra-tumoral heterogeneity (ITH) andcomplex evolution patterns beyond the cancer biological knowledge we previously know.There is very limited knowledge of East Asia lung cancer genome except enrichment of EGFRmutations and lack of KRAS mutations. We carried out integrated genomic, transcriptomic andmethylomic analysis of 335 primary Chinese lung adenocarcinomas (LUAD) and 35corresponding lymph node metastases. We discovered novel recurrent mutated genes such asRHPN2, GLI3 and MRC2 and significant copy number variations (CNVs) in IQGAP3 that havenever been reported previously in The Cancer Genome Atlas (TCGA) study. To improve thevariation calling accuracy in the lymph node metastatic tumor, we also developed tumor purityestimating tool-MethylPurify. With the help of this tool, we found quite different mutationpattern in the lymph node metastatic tumor compared with the primary tumor, such as lack ofKRAS mutations and enrichment of TP53 mutations.To investigate the ITH and cancer evolution by NGS, we first developed high throughput singlecell sequencing (SCS) pipeline on whole exome and trascriptome and updated the pipeline aftersystematically reviewed the existed single cell whole genome amplification (WGA) and wholetranscriptome amplification methods. Using SCS pipeline we developed, we demonstrated thatcells in a primary colon tumor showed genetic mosaic during the evolution. More importantly,we also showed that subclonally mutated gene-SLC12A5 might play potential oncogenic role byin vitro study. In combining with SNP array, WGS and SCS, we provided a comprehensivedynamic molecular landscape of the indolent disease, acute disease, response to therapy andremission, and finally relapsed disease of a 29-year following up chronic lymphocyticleukaemia (CLL) patient. What’s more, we also demonstrated the feasibility of combining liquidbiopsy and SCS to analyse circulating tumor cells (CTCs) and infer the heterogeneity andevolution of solid tumors after relapsed. Taken together, we showed that NGS on cancers couldprovide novel biological insights of cancer genetics and SCS may serve as powerful tool toinvestigate the ITH and evolution of both primary tumor and metastatic/relapse tumor.

AB - Cancer will cause 13 million deaths by the year of 2030, ranking the second leading cause ofdeath worldwide. Previous studies indicate that most of the cancers originate from cells thatacquired somatic mutations and evolved as Darwin Theory. Ten biological insights of cancerhave been summarized recently. Cutting-age technologies like next generation sequencing (NGS)enable exploring cancer genome and evolution much more efficiently. However, integratedcancer genome sequencing studies showed great inter-/intra-tumoral heterogeneity (ITH) andcomplex evolution patterns beyond the cancer biological knowledge we previously know.There is very limited knowledge of East Asia lung cancer genome except enrichment of EGFRmutations and lack of KRAS mutations. We carried out integrated genomic, transcriptomic andmethylomic analysis of 335 primary Chinese lung adenocarcinomas (LUAD) and 35corresponding lymph node metastases. We discovered novel recurrent mutated genes such asRHPN2, GLI3 and MRC2 and significant copy number variations (CNVs) in IQGAP3 that havenever been reported previously in The Cancer Genome Atlas (TCGA) study. To improve thevariation calling accuracy in the lymph node metastatic tumor, we also developed tumor purityestimating tool-MethylPurify. With the help of this tool, we found quite different mutationpattern in the lymph node metastatic tumor compared with the primary tumor, such as lack ofKRAS mutations and enrichment of TP53 mutations.To investigate the ITH and cancer evolution by NGS, we first developed high throughput singlecell sequencing (SCS) pipeline on whole exome and trascriptome and updated the pipeline aftersystematically reviewed the existed single cell whole genome amplification (WGA) and wholetranscriptome amplification methods. Using SCS pipeline we developed, we demonstrated thatcells in a primary colon tumor showed genetic mosaic during the evolution. More importantly,we also showed that subclonally mutated gene-SLC12A5 might play potential oncogenic role byin vitro study. In combining with SNP array, WGS and SCS, we provided a comprehensivedynamic molecular landscape of the indolent disease, acute disease, response to therapy andremission, and finally relapsed disease of a 29-year following up chronic lymphocyticleukaemia (CLL) patient. What’s more, we also demonstrated the feasibility of combining liquidbiopsy and SCS to analyse circulating tumor cells (CTCs) and infer the heterogeneity andevolution of solid tumors after relapsed. Taken together, we showed that NGS on cancers couldprovide novel biological insights of cancer genetics and SCS may serve as powerful tool toinvestigate the ITH and evolution of both primary tumor and metastatic/relapse tumor.

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/fbp0ps/alma99122565281005763

M3 - Ph.D. thesis

BT - Understanding Cancer Genome and Its Evolution by Next Generation Sequencing

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -