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11 Cards in this Set

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Gerlinger et al

Genomic architecture and evolution of clear cell renal cell carcinomas define by multi-region signalling.

Tried to determine ccRCC subclonal architecture and discriminate early from late driver events and decipher mutational spectra that occur during the course of ccrCC evolution using ultra deep sequencing of exomes.

Found evidence of intratumour heterogeneity in the form of subclonal population that did not lead to saturation with the number of biopsies taken --> likely underestimated --> also likely underestimated as only looked at exomes (criticism).

73-75% of all driver mutations were subclonal with chromosome 3p loss and VHL gene aberations were the only ubiquitous events --> subclones appear to be regionally separated with divergent mutations, however parallel evolution was also shown to occur with certain tumour repressor mutations enriched amongst the different subclones (e.g. pTEN, SEDT2).

Shilen et al 2015

Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hyper mutated cancers.

looked at bi allelic mismatch repair deficiency in inherited cancers in children --> removes confounding action of other mutational processes.

exhibits a massive number of substitution mutations (>250 per mb) --> few copy number changes --> all hyper-mutated bMMRD cancers acquired early somatic mutations in DNA pol E and D.

therefore mechanism proposed --> errors in proof reading capacity of DNA pol results in mutations occurring during DNA replication with the MMR deficiency allowing for the mutation persistence and subsequent accumulation.

Mutational burden reaches but does not surpass ~20,000 exonic mutations in ~6 months --> implying a threshold comparable with cell survival --> potential mechanism to exploit therapeutically.

specific mutation signature associated with each of the common PolD and PolE mutations --> other tissues do no exhibit same mutational burden as have not acquired these pol mutations.

Gundem et al 2015

The evolutionary history of lethal metastatic prostate cancer.

Generally accepted that metastases origionate from a single tumor cell --> authors, however, found evidence of poly clonal seeding in human cancer patients.

Metastases to metastases spread: monoclonal seeding of daughter metastases or transfer of multiple clones between metastatic sites.

Spread and be branching or linear.

*evidence from the spread of multiple subclones carrying Androgen deprivation therapy resistance mutations suggesting tumour populations with a significant survival advantage are not confined to a specific organ site.

* Evidence of intraclonal co-operativity --> initial prostance cancer clones colonise the site and alter the micro environment to allow for the colonization by other subclones --> indicated by the colocation of specific subclones to multiple metastises.

* Also found that clones in close proxcimity are more similar --> were not able to specify if this was due to geographical proxcimity or tissue specific seeding?

Criticisms: cannot fully exclude the possibility that metastases are the result of undeleted subclones in the primary tumour.

the level of ITH may have affected the conclusions with further samples revealing that linear spread was infact branching.

Kandoth et al 2015

Mutational landscape and significance across 12 tumor types

- looked at point mutations and deletions from 3281 tumors across 12 tumor types as part of the TCGA Pan-cancer effort.

- By assuming that mutations in cancer genes are positivly selected for to maintain and create the neoplastic state, and therefor occur at an increased frequency within a pool of samples, they identified 127 significantly mutated genes (SMGs) --> potential targets for therapeutics.

SMGs are differentially mutated across and within cancer tyoes.

- each contains an average of 2 to 6 mutations, providing an indication of the amount required for oncogenesis.

- some are mutated at an increased frequency in specific tumor types e.g. SEDT2 in aCML, whilst others are more broadly acting e.g. TP53 mutations occured in 42% of samples.

- Some mutations of SMGs (14) are mutually exclusive e..g KRAS and NRAS, could be that they act through the same pathway so little benefit or could be an indicator of synthetic lethality.

Found that differential cancer types have different numbers of mutation (all higher than paediatric cancers, except AML), and mutation frequency in some instances may be clustered which could be the result of localised sequence context e.g. CpG islands or the location of a series of important driver mutations.

* Found a shift towards higher expression of SMGs vs non-synomous mutations using variant analysis.


Clustering analysis found 72% of tumors are adjacent to same tissue type, however this analysis only involved exome mutations and so may underestimate ITH.

Furthermore, the identification of SMGs does not differentiate between subclones and clonesand does nto involve regional sampling therefore may over or underestimate the proportion SMG frequency, i think that it is assumes that the power of the study overcomes this bias, however it directly conflicts with their assumption.

Ding et al 2010

Genome remodelling in basal-like breast cancer metastases and xenografts.

Basal like breast cancer is characterised by the absence of ER expression, the lack of ERBB2 gene amplification and a high mitotic index.

Whole Genome Sequencing of Primary tumor, metastasis and the xenograft (taken pretreatment).

Key question --> is fatal metastatic process driven by mutations that occur after the tumor arrives at the distant site or does the primary tumor generate cells with a complete repertoire of somatic mutations required for metastatic growth.

papers goal to look the ability of the xenograft taken from the primary tumour to grow in a metastatic fashion in a murine model and look for similarities to the human metastases.

COmpared somatic alterations between the three lineages.

metastases contained two denovo mutations and a large deletion not present in the primary tumor and was significantly enriched for 20 shared mutations (increased allele frequency).

The xenograft retained all the primary tumor mutations and displayed a mutational enrichment pattern that resembled the metastases.

* two large mutations encompassing CTNNA1, were present in all 3 lineages.

The distinct somatic aberation present in the xenograft and the metastases compared to the primary tumor suggests that the tumors may have arisen from a similar sub population of cells in the primary tumor --> alternativly it could be explained by convergent evolution of the metastases and the xenograft.

* criticisms, only looked at genomic data, RNA expression and fucntional characteristics may be completely different.

Study does not have a lot of power.

Ludmil et al 2015

Signatures of mutational processes in human cancer.

- mutational signatures are imprints left on the cancer genome by a mutational process e.g. carcinogen exposure --> goal is to identify the aetiology of a given cancer based on its mutational signature with potential implications for prevalence and treatment.

- multiple signatures can be active at one time leading to a jumbled composite signal --> this paper uses recent advaces in sequencing technology to decipher such noisy signals.

applying this approach (192 mutational subclasses) to the 30 types of cancer revealed 21 distinct validated mutational signatures.

*some cancers were found to have an higher mutational frequency than others --> attributable to ..........

Were able to bioinformatically associate mutational signatures with certain plausible metagenic processes

e.g. age (25/30 cancer types)

e.g. APOBEC family of cytadine deaminases converts C to uradine (a uracil homologue containign a ribose ring) --> part of the innate immune response against viruses and retrotransposons --> possible that these mutational signals result form colateral damage on the human genome from a response origionally directed at retrotransposing DNA elements or exogenous viruses (could represent a new mechanism for human carcinogenesis).

e.g. smoking --> causes bulky adjuncts from polycylic hydrocarbons that are removed by transcriptional-coupled NER resulting in C>A mutation on the transcriptional strand.

These mutational processes form signatures that are associated with different cancer types to different degrees. However, many of the mutational signatures do not have an established or proposed underlying mutational process or atieology.

Criticisms --> all of the conclusions drawn in the paper require experimental confirmation using model systems and known exposures and pertubations of DNA.

--> also doesn't correlate the contributions of each mutational signature with biological characteristics of each cancer; ranging from molecular profiling to epidemiology.

--> are certain cancer genes (*due to sequence context) at an increased likely hood of mutation in a given cancer type due to the activity of a specific process.

Localised hypermutation:

Kataegis --> associated with C>T and or C>G mutations in TpCpN regions --> implicating processed such as apobec enzyme activity --> ds breas increase likelyhood.

Ellis et al 2012 (S)

Sequenced pretreatment breast cancer biopsies in two studies of neoadjuvant inhibitor therapy to identify somatic alterations that correlated with positive and negative outcomes --> For example, MAPK1 mutated tumors show a good outcome whilst TP53 mutated tumors were resistant to treatment.

Discussed intertumour heterogeneity but left out ITH which may have confounded the occurance of significant diver mutations which they commented even the most frequent were relativly rare ~10% of cases.

Piazza et al 2012 (S)

aCML shares a number of clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion gene.

Here they performed exome sequencing to try and identify somatic alterations that could be used to differentiate (then defined by only negative characteristics) and possibly provide a therapeutic target (as aCML has a notoriously poor clinical prognosis).

Found SEDT2 alterations occurring in ~25% of cases --> all between codons 858 and 871. This paper showed that it was possible to use next generation sequencing to identify new oncogenic genes which in this instance have direct clinical application.

Did not use a comprehensive genomic e.,g. WGS or look at the transcriptme etc.

Stephens et al 2011 (S)

Used next generation sequencing to characteristic chromothripsis.

Hallmarks found in 2-3 % of cancers and 25% of bone cancers.

Shows that the text book model of cancer progression is not ubiquitous.

Analogous to re-assortment of influenza strains.

Would still require further river mutations, however tumor is anticipated to have a shorter latency.

Likely occurs while chromosomes are condense for mitosis, ionising ration etc. Another possibility is breakage fusion bridge cycle associated with telomere attrition.

Gerlinger et al 2012 (S)

Looked at samples from primary renal carcinomas and metastases using immunohistochemistry, mutational function analysis and profiling of mRNA expression.

63-69% of all somatic mutations are not detectable across every tumour region.

Also evidence of convergent phenotype evolution --> loss of function of different tumor supressors causing the small phenotype across an individual.

ITH likely underestimated with obvious implications for persioalised medicine and biomarker development.

Only looked at exome. SNP arrays were used.

Stephens et al 2012 (S)

looked at mutational signatures to find correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, including one present in 10% of tumors characterised by numerous mutations of cytosine at TpC dinucleotides.

To identify new cancer genes, we searched for non-random clustering of somatic mutations (assumption) in each of the 21,416 protein coding genes.

Aslso looked at copy number changes to identify new cancer genes, found 9 new ones.

Found few cancer genes of be commonly mutated and multiple somatic mutation processes operative.