Paper - Review

DOI: 10.1038/nature07943

Cancer
- unrestrained proliferation of cells
- invade beyond normal tissue boundary and metastasize
- abnormal clones of cells
- characterized by and caused by abnormalities of hereditary material

Damage DNA and generate mutations: cause cancer
e.g. Philadelphia translocation - chromosome 9 and 22

Introduction of total genomic DNA: human cancer-causing sequence change

Cancer is an evolutionary process
All cancers share a common pathogenesis.
Darwinian evolution is microenvironments provided by multicellular organism
Ongoing competition; most have limited abnormal growth potential

The catalogue of somatic mutations in a cancer genome
Cancer cell is a direct descendant of the fertilized egg. (Figure 1)

DNA sequence of cancer cell has acquired a set of differences.
Somatic mutations in a cancer cell encompass several distinct classes of DNA sequence change: insertion/deletion, rearrangement, copy number increase/reduction

Cancer cell may have completely new DNA sequences.
e.g. from virus

Compare to fertilized egg, cancer genome will also have acquired epigenetic changes: alter chromatin structure and gene expression

It should not be forgotten that another genome is harboured within cancer cell
e.g. mitochondria

Acquisition of somatic mutations in cancer genomes
Mutation found in a cancer genome accumulate over lifetime.
Ancestors of cancer were biologically normal; no phenotypic characteristics of cancer.
DNA in normal cells is continuously damaged by internal and external mutagens. Most of damage is repaired, but a small may be converted into fixed mutations and DNA replication itself.
Mutation rates increase by mutagenic exposures.
Somatic mutation rate is always higher during lineage.
Mutation acquisition need not be smooth. Predecessors of cancer suddenly acquire.

Driver and passenger mutations
Driver mutation: causally implicated in oncogenesis, 
Passenger mutation: has not conferred clonal growth advantage, has not contributed to cancer development.
Number of driver mutation - Central conceptual parameter
Engineering changes in functions is necessary to convert them into cancer.
Cancer have initially responded to treatment, but are now resistant; Existing as passengers in minor subclones until is changed by initiation of therapy; then, converted into driver and resistant subclone expands.

The repertoire of somatically mutated cancer genes
Identify driver mutation - a central aim of cancer research

Recurrent somatic mutation - strong evidence that contribution to cancer
Identify by their physical location; chromosomal translocations - transforming activity
Some mutation found in germ line: identified by genetic linkage analysis

Most of cancer genes or dominantly acting, i.e., mutation of just one allele is sufficient to contribute to cancer development.

Pattern differ between dominant and recessive cancer gene; diverse mutation types.
Activated through genomic rearrangement; rearranged cancer fusion genes - difficulty of identifying amidst jumble of passenger rearragements

Classification and treatment by presence of abnormal cancer gene; basis of presence of abnormalities involving specific cancer gene - development of new cancer therapy

Early systematic sequencing of cancer genomes
Provision of human genome sequence - offer new strategy and opportunity
Investigation of cancer genomes with DNA sequence itself

Copy number changes - several new amplified cacner gene
Point mutation of coding exons - new machanisms and cancer types 

Exposing the landscape of the cancer genome
general patterns and parameters of somatic mutation in cancer

Statistical evidence of many driver mutations; repertoire of somatically mutated human cancer genome

Prevalence and types of somatic mutation
Detected all indicates that these recurrences

Sequencing of cancer genomes in the future
Large-scale, systematic sequencing study: low throughput and high cost
All somatic mutation can be detected: randomly fragmenting cancer genome; sequencing large number of fragment - Full catalogue of somatic mutation

Second-generation sequencing technology - increase rapidly
- find full range of somatically genetic alteration
- identify subclone genetic diversity: drug-resistance mutations
∴ complete catalogue of somatic mutation

Coordinating the sequencing of cancer genomes
Maximize use of resource and harmonize the product
- International Cancer Genome Consortium (ICGC)
Comprehensively elucidate central questions
Identification of further potentially druggable cancer gene

---