Cancer genome sequencing

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Cancer genome sequencing is the whole genome sequencing of a single, homogeneous or heterogeneous group of cancer cells. It is a biochemical laboratory method for the characterization and identification of the DNA or RNA sequences of cancer cell(s).

Contents

Unlike whole genome (WG) sequencing which is typically from blood cells, such as J. Craig Venter's [1] and James D. Watson’s WG sequencing projects, [2] saliva, epithelial cells or bone - cancer genome sequencing involves direct sequencing of primary tumor tissue, adjacent or distal normal tissue, the tumor micro environment such as fibroblast/stromal cells, or metastatic tumor sites.

Similar to whole genome sequencing, the information generated from this technique include: identification of nucleotide bases (DNA or RNA), copy number and sequence variants, mutation status, and structural changes such as chromosomal translocations and fusion genes.

Cancer genome sequencing is not limited to WG sequencing and can also include exome, transcriptome, micronome sequencing, and end-sequence profiling. These methods can be used to quantify gene expression, miRNA expression, and identify alternative splicing events in addition to sequence data.

The first report of cancer genome sequencing appeared in 2006. In this study 13,023 genes were sequenced in 11 breast and 11 colorectal tumors. [3] A subsequent follow up was published in 2007 where the same group added just over 5,000 more genes and almost 8,000 transcript species to complete the exomes of 11 breast and colorectal tumors. [4] The first whole cancer genome to be sequenced was from cytogenetically normal acute myeloid leukaemia by Ley et al. in November 2008. [5] The first breast cancer tumor was sequenced by Shah et al. in October 2009, [6] the first lung and skin tumors by Pleasance et al. in January 2010, [7] [8] and the first prostate tumors by Berger et al. in February 2011. [9]

History

Historically, cancer genome sequencing efforts has been divided between transcriptome-based sequencing projects and DNA-centered efforts.

The Cancer Genome Anatomy Project (CGAP) was first funded in 1997 [10] with the goal of documenting the sequences of RNA transcripts in tumor cells. [11] As technology improved, the CGAP expanded its goals to include the determination of gene expression profiles of cancerous, precancerous and normal tissues. [12]

The CGAP published the largest publicly available collection of cancer expressed sequence tags in 2003. [13]

The Sanger Institute's Cancer Genome Project, first funded in 2005, focuses on DNA sequencing. It has published a census of genes causally implicated in cancer, [14] and a number of whole-genome resequencing screens for genes implicated in cancer. [15]

The International Cancer Genome Consortium (ICGC) was founded in 2007 with the goal of integrating available genomic, transcriptomic and epigenetic data from many different research groups. [16] [17] As of December 2011, the ICGC includes 45 committed projects and has data from 2,961 cancer genomes available. [16]

Societal Impact

The Complexity and Biology of Cancer

The process of tumorigenesis that transforms a normal cell to a cancerous cell involve a series of complex genetic and epigenetic changes. [18] [19] [20] Identification and characterization of all these changes can be accomplished through various cancer genome sequencing strategies.

The power of cancer genome sequencing lies in the heterogeneity of cancers and patients. Most cancers have a variety of subtypes and combined with these ‘cancer variants’ are the differences between a cancer subtype in one individual and in another individual. Cancer genome sequencing allows clinicians and oncologists to identify the specific and unique changes a patient has undergone to develop their cancer. Based on these changes, a personalized therapeutic strategy can be undertaken. [21] [22]

Clinical Relevance

A big contribution to cancer death and failed cancer treatment is clonal evolution at the cytogenetic level, for example as seen in acute myeloid leukaemia (AML). [23] [24] In a Nature study published in 2011, Ding et al. identified cellular fractions characterized by common mutational changes to illustrate the heterogeneity of a particular tumor pre- and post-treatment vs. normal blood in one individual. [25]

These cellular factions could only have been identified through cancer genome sequencing, showing the information that sequencing can yield, and the complexity and heterogeneity of a tumor within one individual.

Comprehensive Cancer Genomic Projects

The two main projects focused on complete cancer characterization in individuals, heavily involving sequencing include the Cancer Genome Project, based at the Wellcome Trust Sanger Institute and the Cancer Genome Atlas funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). Combined with these efforts, the International Cancer Genome Consortium (a larger organization) is a voluntary scientific organization that provides a forum for collaboration among the world's leading cancer and genomic researchers.

Cancer Genome Project (CGP)

The Cancer Genome Projects goal is to identify sequence variants and mutations critical in the development of human cancers. The project involves the systematic screening of coding genes and flanking splice junctions of all genes in the human genome for acquired mutations in human cancers. To investigate these events, the discovery sample set will include DNA from primary tumor, normal tissue (from the same individuals) and cancer cell lines. All results from this project are amalgamated and stored within the COSMIC cancer database. COSMIC also includes mutational data published in scientific literature.

The Cancer Genome Atlas (TCGA)

The TCGA is a multi-institutional effort to understand the molecular basis of cancer through genome analysis technologies, including large-scale genome sequencing techniques. Hundreds of samples are being collected, sequenced and analyzed. Currently the cancer tissue being collected include: central nervous system, breast, gastrointestinal, gynecologic, head and neck, hematologic, thoracic, and urologic.

The components of the TCGA research network include: Biospecimen Core Resources, Genome Characterization Centers, Genome Sequencing Centers, Proteome Characterization Centers, a Data Coordinating Center, and Genome Data Analysis Centers. Each cancer type will undergo comprehensive genomic characterization and analysis. The data and information generated is freely available through the projects TCGA data portal.

International Cancer Genome Consortium (ICGC)

The ICGC’s goal is “To obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in 50 different tumor types and/or subtypes which are of clinical and societal importance across the globe”. [16]

Technologies and platforms

2nd Generation Sequencing 2nd Generation Sequencing.png
2nd Generation Sequencing
3rd Generation Sequencing 3rd Generation Sequencing.png
3rd Generation Sequencing

Cancer genome sequencing utilizes the same technology involved in whole genome sequencing. The history of sequencing has come a long way, originating in 1977 by two independent groups - Fredrick Sanger’s enzymatic didoxy DNA sequencing technique [26] and the Allen Maxam and Walter Gilbert chemical degradation technique. [27] Following these landmark papers, over 20 years later ‘Second Generation’ high-throughput next generation sequencing (HT-NGS) was born followed by ‘Third Generation HT-NGS technology’ in 2010. [28] The figures to the right illustrate the general biological pipeline and companies involved in second and third generation HT-NGS sequencing.

Three major second generation platforms include Roche/454 Pyro-sequencing, ABI/SOLiD sequencing by ligation, and Illumina’s bridge amplification sequencing technology. Three major third generation platforms include Pacific Biosciences Single Molecule Real Time (SMRT) sequencing, Oxford Nanopore sequencing, and Ion semiconductor sequencing.

Data Analysis

The work-flow of the sequencing of a tumor from biopsy to treatment recommendation. Cancer genome sequencing workflow.png
The work-flow of the sequencing of a tumor from biopsy to treatment recommendation.

As with any genome sequencing project, the reads must be assembled to form a representation of the chromosomes being sequenced. With cancer genomes, this is usually done by aligning the reads to the human reference genome.

Since even non-cancerous cells accumulate somatic mutations, it is necessary to compare sequence of the tumor to a matched normal tissue in order to discover which mutations are unique to the cancer. In some cancers, such as leukemia, it is not practical to match the cancer sample to a normal tissue, so a different non-cancerous tissue must be used. [25]

It has been estimated that discovery of all somatic mutations in a tumor would require 30-fold sequencing coverage of the tumor genome and a matched normal tissue. [29] By comparison, the original draft of the human genome had approximately 65-fold coverage. [30] To facilitate further improvement in somatic mutation detection in cancer, the Sequencing Quality Control Phase 2 Consortium has established a pair of tumor-normal cell lines as community reference samples and data sets for the benchmarking of cancer mutation detections. [31]


A major goal of cancer genome sequencing is to identify driver mutations: genetic changes which increase the mutation rate in the cell, leading to more rapid tumor evolution and metastasis. [32] It is difficult to determine driver mutations from DNA sequence alone; but drivers tend to be the most commonly shared mutations amongst tumors, cluster around known oncogenes, and are tend to be non-silent. [29] Passenger mutations, which are not important in the progression of the disease, are randomly distributed throughout the genome. It has been estimated that the average tumor carries c.a. 80 somatic mutations, fewer than 15 of which are expected to be drivers. [33]

A personal-genomics analysis requires further functional characterization of the detected mutant genes, and the development of a basic model of the origin and progression of the tumor. This analysis can be used to make pharmacological treatment recommendations. [21] [22] As of February 2012, this has only been done for patients clinical trials designed to assess the personal genomics approach to cancer treatment. [22]

Limitations

A large-scale screen for somatic mutations in breast and colorectal tumors showed that many low-frequency mutations each make small contribution to cell survival. [33] If cell survival is determined by many mutations of small effect, it is unlikely that genome sequencing will uncover a single "Achilles heel" target for anti-cancer drugs. However, somatic mutations tend to cluster in a limited number of signalling pathways, [29] [33] [34] which are potential treatment targets.

Cancers are heterogeneous populations of cells. When sequence data is derived from a whole tumor, information about the differences in sequence and expression pattern between cells is lost. [35] This difficulty can be ameliorated by single-cell analysis.

Clinically significant properties of tumors, including drug resistance, are sometimes caused by large-scale rearrangements of the genome, rather than single mutations. [36] In this case, information about single nucleotide variants will be of limited utility. [35]

Cancer genome sequencing can be used to provide clinically relevant information in patients with rare or novel tumor types. Translating sequence information into a clinical treatment plan is highly complicated, requires experts of many different fields, and is not guaranteed to lead to an effective treatment plan. [21] [22]

Incidentalome

The incidentalome is the set of detected genomic variants not related to the cancer under study. [37] (The term is a play on the name incidentaloma, which designates tumors and growths detected on whole-body imaging by coincidence). [38] The detection of such variants may result in additional measures such as further testing or lifestyle management. [37]

See also

Related Research Articles

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">Neoplasm</span> Abnormal mass of tissue as a result of abnormal growth or division of cells

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, when it may be called a tumour or tumor.

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

<span class="mw-page-title-main">Bert Vogelstein</span> American oncologist (born 1949)

Bert Vogelstein is director of the Ludwig Center, Clayton Professor of Oncology and Pathology and a Howard Hughes Medical Institute investigator at The Johns Hopkins Medical School and Sidney Kimmel Comprehensive Cancer Center. A pioneer in the field of cancer genomics, his studies on colorectal cancers revealed that they result from the sequential accumulation of mutations in oncogenes and tumor suppressor genes. These studies now form the paradigm for modern cancer research and provided the basis for the notion of the somatic evolution of cancer.

<span class="mw-page-title-main">Oncogenomics</span> Sub-field of genomics

Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.

The Cancer Genome Project is part of the cancer, aging, and somatic mutation research based at the Wellcome Trust Sanger Institute in the United Kingdom. It aims to identify sequence variants/mutations critical in the development of human cancers. Like The Cancer Genome Atlas project within the United States, the Cancer Genome Project represents an effort in the War on Cancer to improve cancer diagnosis, treatment, and prevention through a better understanding of the molecular basis of the disease. The Cancer Genome Project was launched by Michael Stratton in 2000, and Peter Campbell is now the group leader of the project. The project works to combine knowledge of the human genome sequence with high throughput mutation detection techniques.

The Cancer Genome Atlas (TCGA) is a project to catalogue the genetic mutations responsible for cancer using genome sequencing and bioinformatics. The overarching goal was to apply high-throughput genome analysis techniques to improve the ability to diagnose, treat, and prevent cancer through a better understanding of the genetic basis of the disease.

<span class="mw-page-title-main">MCC (gene)</span> Protein-coding gene in the species Homo sapiens

Colorectal mutant cancer protein is a protein that in humans is encoded by the MCC gene.

<span class="mw-page-title-main">BCAS1</span> Protein-coding gene in the species Homo sapiens

Breast carcinoma-amplified sequence 1 is a protein that in humans is encoded by the BCAS1 gene.

Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.

<span class="mw-page-title-main">Whole genome sequencing</span> Determining nearly the entirety of the DNA sequence of an organisms genome at a single time

Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's chromosomal DNA as well as DNA contained in the mitochondria and, for plants, in the chloroplast.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours and within tumours. A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication: whenever a cell divides, a few mutations are acquired—leading to a diverse population of cancer cells. The heterogeneity of cancer cells introduces significant challenges in designing effective treatment strategies. However, research into understanding and characterizing heterogeneity can allow for a better understanding of the causes and progression of disease. In turn, this has the potential to guide the creation of more refined treatment strategies that incorporate knowledge of heterogeneity to yield higher efficacy.

The Cancer Genome Anatomy Project (CGAP), created by the National Cancer Institute (NCI) in 1997 and introduced by Al Gore, is an online database on normal, pre-cancerous and cancerous genomes. It also provides tools for viewing and analysis of the data, allowing for identification of genes involved in various aspects of tumor progression. The goal of CGAP is to characterize cancer at a molecular level by providing a platform with readily accessible updated data and a set of tools such that researchers can easily relate their findings to existing knowledge. There is also a focus on development of software tools that improve the usage of large and complex datasets. The project is directed by Daniela S. Gerhard, and includes sub-projects or initiatives, with notable ones including the Cancer Chromosome Aberration Project (CCAP) and the Genetic Annotation Initiative (GAI). CGAP contributes to many databases and organisations such as the NCBI contribute to CGAP's databases.

<span class="mw-page-title-main">Circulating tumor DNA</span> Tumor-derived fragmented DNA in the bloodstream

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that is not associated with cells. ctDNA should not be confused with cell-free DNA (cfDNA), a broader term which describes DNA that is freely circulating in the bloodstream, but is not necessarily of tumor origin. Because ctDNA may reflect the entire tumor genome, it has gained traction for its potential clinical utility; "liquid biopsies" in the form of blood draws may be taken at various time points to monitor tumor progression throughout the treatment regimen.

<span class="mw-page-title-main">LINE1</span> Group of transposable elements

LINE1 is a family of related class I transposable elements in the DNA of some organisms, classified with the long interspersed elements (LINEs). L1 transposons comprise approximately 17% of the human genome. These active L1s can interrupt the genome through insertions, deletions, rearrangements, and copy number variations. L1 activity has contributed to the instability and evolution of genomes and is tightly regulated in the germline by DNA methylation, histone modifications, and piRNA. L1s can further impact genome variation through mispairing and unequal crossing over during meiosis due to its repetitive DNA sequences.

Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.

Personalized onco-genomics (POG) is the field of oncology and genomics that is focused on using whole genome analysis to make personalized clinical treatment decisions. The program was devised at British Columbia's BC Cancer Agency and is currently being led by Marco Marra and Janessa Laskin. Genome instability has been identified as one of the underlying hallmarks of cancer. The genetic diversity of cancer cells promotes multiple other cancer hallmark functions that help them survive in their microenvironment and eventually metastasise. The pronounced genomic heterogeneity of tumours has led researchers to develop an approach that assesses each individual's cancer to identify targeted therapies that can halt cancer growth. Identification of these "drivers" and corresponding medications used to possibly halt these pathways are important in cancer treatment.

<span class="mw-page-title-main">Cancer pharmacogenomics</span>

Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.

References

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