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Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas

Overview of attention for article published in Genome Medicine, September 2018
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (83rd percentile)

Mentioned by

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20 tweeters
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1 Facebook page

Citations

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3 Dimensions

Readers on

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39 Mendeley
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Title
Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas
Published in
Genome Medicine, September 2018
DOI 10.1186/s13073-018-0579-5
Pubmed ID
Authors

Alexandra R. Buckley, Trey Ideker, Hannah Carter, Olivier Harismendy, Nicholas J. Schork

Abstract

Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi-allelic alterations are universally required for germline variation to influence tumor mutational profile is unclear. Here, we performed an exome-wide analysis of the frequency and functional effect of bi-allelic alterations in The Cancer Genome Atlas (TCGA). We integrated germline variant, somatic mutation, somatic methylation, and somatic copy number loss data from 7790 individuals from TCGA to identify germline and somatic bi-allelic alterations in all coding genes. We used linear models to test for association between mono- and bi-allelic alterations and somatic microsatellite instability (MSI) and somatic mutational signatures. We discovered significant enrichment of bi-allelic alterations in mismatch repair (MMR) genes and identified six bi-allelic carriers with elevated MSI, consistent with Lynch syndrome. In contrast, we find little evidence of an effect of mono-allelic germline variation on MSI. Using MSI burden and bi-allelic alteration status, we reclassify two variants of unknown significance in MSH6 as potentially pathogenic for Lynch syndrome. Extending our analysis of MSI to a set of 127 DNA damage repair (DDR) genes, we identified a novel association between methylation of SHPRH and MSI burden. We find that bi-allelic alterations are infrequent in TCGA but most frequently occur in BRCA1/2 and MMR genes. Our results support the idea that bi-allelic alteration is required for germline variation to influence tumor mutational profile. Overall, we demonstrate that integrating germline, somatic, and epigenetic alterations provides new understanding of somatic mutational profiles.

Twitter Demographics

The data shown below were collected from the profiles of 20 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 39 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 39 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 6 15%
Researcher 5 13%
Student > Bachelor 5 13%
Student > Doctoral Student 4 10%
Student > Master 4 10%
Other 9 23%
Unknown 6 15%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 12 31%
Agricultural and Biological Sciences 8 21%
Medicine and Dentistry 4 10%
Computer Science 2 5%
Nursing and Health Professions 1 3%
Other 3 8%
Unknown 9 23%

Attention Score in Context

This research output has an Altmetric Attention Score of 12. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 November 2018.
All research outputs
#1,805,645
of 16,951,449 outputs
Outputs from Genome Medicine
#436
of 1,130 outputs
Outputs of similar age
#45,627
of 279,685 outputs
Outputs of similar age from Genome Medicine
#1
of 1 outputs
Altmetric has tracked 16,951,449 research outputs across all sources so far. Compared to these this one has done well and is in the 89th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,130 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 23.5. This one has gotten more attention than average, scoring higher than 61% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 279,685 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 83% of its contemporaries.
We're also able to compare this research output to 1 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them