Wang et al. have performed whole-exome sequencing of 15 pancreaticductal adenocarcinoma cell lines and matched normal tissue samples.Pancreatic cancer is one of the most lethal human cancers, claimingthe lives of 95% of patients within five years of diagnosis. Theauthors describe how their study uncovered widely varying mutationrates between the cell lines, and notably, a significantcorrelation between loss of one copy of the MLH1 gene, involved inDNA repair, and the rate of small insertions and deletions (called”indels”) in the genome of pancreatic cancer cell lines. Althoughloss of a copy of the chromosome region where MLH1 resides has beenwidely described in cancers, this is the first time that MLH1 hasbeen associated with indel mutation rate.
The whole-exomesequencing analysis showed how loss of one of the two copies of theMLH1 gene from the genome raised the rate of indel mutationsten-fold, which disrupted several well-known cancer genes,including TP53. References: Turajlic et al., Whole genome sequencing of matched primary andmetastatic acral melanomas. Genome Res. doi:10.1101/gr.125591.111 Wang et al., Whole-exome sequencing of human pancreatic cancers andcharacterization of genomic instability caused by MLH1haploinsufficiency and complete deficiency. Genome Res.doi:10.1101/gr.123109.111 2.
Circulating free DNA holds clues to cancer diagnosis and risk ofrelapse Despite recent advances that have improved breast cancer survivalrates, means of monitoring residual disease and the risk forrelapse with metastatic cancer have remained elusive. Circulatingfree DNA (cfDNA), present in the blood at low levels in healthyindividuals but elevated in patients suffering from differentcancers, has been suggested as a means of diagnosing disease.Because elevated cfDNA can also occur in benign disease, itsutility in the clinic has been limited and thus there has been noreliable method using blood to diagnose patients with primarybreast cancer or monitor relapse following treatment. However, cfDNA might still be a key to efficient and reliablediagnosis of breast cancer and effective monitoring of potentialfor relapse. Shaw and colleagues recognized that a genomic analysisof cfDNA could shed light on the genetic signatures of diseaseprogression. Semi Trailer Fifth Wheel
Utilizing genotyping technology that identifies singlenucleotide variations and copy number variations in cfDNA and theDNA of primary tumors, the research group was able to distinguishbetween healthy individuals and patients with breast cancer. “CfDNAanalysis can predict whether a patient has evidence of dormancy ornot, and intriguingly, may predict the onset of relapse,” said Dr.Jacqueline Shaw of the University of Leicester and lead author ofthe report. The research team’s analysis of patients on follow-up aftertreatment showed that even 12 years after diagnosis and despite noclinical evidence of disease reoccurrence, breast cancer patientsstill have cfDNA with genetic signatures of their primary cancer,suggesting dormancy of the cancer or minimal residual disease.Further cfDNA monitoring could predict relapse. “This should enableclinicians to target therapy earlier, at a time when disease ispotentially curable,” Shaw noted. Reference: Shaw et al., Genomic analysis of circulating cell free DNA infersbreast cancer dormancy. Special Fasteners Manufacturer
Genome Res. doi:10.1101/gr.123497.111 3. Epigenomic analyses shed new light on breast, colon, andprostate cancers Epigenetic modifications (cellular changes that alter geneexpression, phenotype, and disease by mechanisms other thanvariation in DNA sequence) are increasingly being recognized forplaying a role in diseases including cancer. Published in thisspecial issue of Genome Research are four studies that haveinvestigated the role of DNA methylation in cancer, a chemicalmodification of DNA associated with gene silencing, shedding newlight on the biology of breast cancer, colon cancer , and prostate cancer. Trailer Landing Legs Manufacturer
DNA methylation and chromatin (the DNA/protein complex thatregulates gene expression and DNA replication) are both know to bealtered in cancer, but little is known how these two factors play acoordinated role in cancer progression. In this issue, Hon et al.have used next-generation sequencing technology to investigate thisinterplay in breast cancer. Surprisingly, although they observedwidespread loss of DNA methylation that would be predicted toincrease gene expression, they find that the genes are silenced bythe formation of gene-repressing chromatin. This mechanism couldplay an important role in breast cancer progression by repressinggenes that normally suppress tumors. Colorectal cancer is a complex disease, classified into multiple subtypes by geneticand epigenetic alterations in the cancer genome.
Two studiespublished in this issue investigate methylation and theclassification of colon cancers. The first of these studies, byHinoue et al., performed comprehensive DNA methylation profiling ofcolorectal tumor genomes. The group identified four distinct DNAmethylation subgroups of colorectal cancer, and provided newinsight into the role of DNA hypermethylation in gene silencingcritical for tumor suppression. The report by Xu and colleaguesalso delves into DNA hypermethylation in colorectal cancer,describing the mapping and comparison of DNA methylation profilesby genome sequencing.
The group found that certain sites of thegenome are prone to hypermethylation in colorectal cancer, with acertain class of tumors prone to even more extensivehypermethylation, suggesting specific defects in the control ofthis epigenetic modification. Chemical modification of chromatin, the complex of DNA and proteinthat packages the genome within the nucleus, also plays a criticalregulatory role in gene expression in healthy and disease states.In this issue, Valdes-Mora and colleagues have investigated theinterplay between a specific chromatin modification, H2A.Zacetylation, and other epigenetic modifications including DNAmethylation in prostate cancer. This work reconciles conflictingevidence in the field regarding the role of H2A.Z acetylation, andfurther shows for the first time that it is a critical modificationassociated with gene activity in normal cells, and epigeneticderegulation of genes in cancer. References: Hon et al., Global DNA hypomethylation coupled to repressivechromatin domain formation and gene silencing in breast cancer.Genome Res.
doi:10.1101/gr.125872.111 Hinoue et al., Genome-scale analysis of aberrant DNA methylation incolorectal cancer. Genome Res. doi:10.1101/gr.117523.110 Xu et al., Unique DNA methylome profiles in CpG island methylatorphenotype colon cancers. Genome Res. doi:10.1101/gr.122788.111 Vald s-Mora et al., Acetylation of H2A.Z is a key epigeneticmodification associated with gene deregulation and epigeneticremodeling in cancer.
Genome Res. doi:10.1101/gr.118919.110 4. Cutting-edge methods to detect the genes and networks that drivecancer The special Cancer Genomics issue of Genome Research also features cutting-edge methodological advances, includingthree reports that address the problem of identifying the genes,networks, and pathways that drive cancer. A significant challenge to the identification of geneticalterations that lead to cancer is the experimental determinationof which mutations are driving cancer and which mutations arerandom “passengers.” Further complicating discovery of drivers isthat driver mutations can target multiple cellular pathways andprocesses, and each cancer can present different mutations that aresufficient to disrupt critical pathways.
Two reports in this issue present new computational strategies tofinding biological pathways that are commonly disrupted by diversegenomic alterations. Vandin and colleagues developed a pair ofcomputational strategies collectively called Dendrix to spot groupsof genes that constitute “driver pathways.” Applying Dendrix tothree cancer studies, Vandin et al. successfully identify sets ofgenes that are mutated in large numbers of patients, includingwell-known cancer-related pathways such as Rb, p53, mTOR, and MAPK. Ciriello and colleagues have developed the Mutual ExclusivityModules in Cancer (MEMo) method to identify previously unrecognizedoncogenic pathways. Applying MEMo to datasets of genomicalterations in glioblastoma and ovarian cancer, MEMo successfullyidentified known oncogenic pathways and presented evidence for anew hypothesis for the striking genomic instability of ovariantumors.
Dendrix and MEMo will be particularly useful for theinterpretation of very large cancer genome sequencing studies, manycurrently underway. Also in this issue, Xiong et al. present Gene Set AssociationAnalysis (GSAA), a statistical framework that integrates andsimultaneously analyzes the two dominant strategies for identifyingsets of genes or pathways associated with disease: geneticvariation analysis and gene expression analysis. Applied to theanalysis of diseases such as glioblastoma, GSAA identified pathwaysknown to be associated with disease, and also predicted novelpathway associations such as the association of perturbations inthe ABC transporter family with glioblastoma.
References: Vandin et al., De novo discovery of mutated driver pathways incancer. Genome Res. doi:10.1101/gr.120477.111 Ciriello et al., Mutual exclusivity analysis identifies oncogenicnetwork modules. Genome Res. doi:10.1101/gr.125567.111 Xiong et al., Integrating genetic and gene expression evidence intogenome-wide association analysis of gene sets.
Genome Res.doi:10.1101/gr.124370.111 Additional References Citations.