Question: TMB Tumor Mutation Burden
gravatar for abibioinformatics
2.9 years ago by
abibioinformatics10 wrote:


Can someone help me with the formulae or a tool to identify the Tumor Mutation Burden from a Whole Exome Sequence?



cancer burden mutation tumor exome • 7.4k views
ADD COMMENTlink modified 8 months ago by igor12k • written 2.9 years ago by abibioinformatics10

The TMB is defined as the total number of nonsynonymous mutations per coding area of a tumor genome. Initially, it was determined using whole exome sequencing, but due to the high costs and long turnaround time of this method, targeted panel sequencing is currently being explored to measure TMB.

samtools flagstat can be used for total base calculation.

ADD REPLYlink written 21 months ago by Shicheng Guo8.5k

It looks like that definition came from this paper:

As already mentioned in other answers here, it's frequently any mutations (not just nonsynonymous), so the definition is not very exact.

ADD REPLYlink written 9 months ago by igor12k
gravatar for Nicolas Rosewick
2.9 years ago by
Belgium, Brussels
Nicolas Rosewick9.3k wrote:

You can start by this paper :

In the method part :

TMB was defined as the number of somatic, coding, base substitution, and indel mutations per megabase of genome examined.

ADD COMMENTlink written 2.9 years ago by Nicolas Rosewick9.3k

I think the "number of mutations per magabase" could be a misleading estimate of TMB. The deeper you sequence the more mutations per magabase you find since you detect more and more variants with low allele frequency. Maybe one should weight a variant by its frequency in order to compute TMB. (NB, I just glanced through the paper.)

ADD REPLYlink written 2.9 years ago by dariober11k

I think they sequence to ridiculously high median depth (500X) so they might have started to saturate by then?

That having been said it's a crude metric for 2018 to say the least. I'm surprised it even has a name.

ADD REPLYlink modified 2.7 years ago • written 2.7 years ago by Jeremy Leipzig19k
gravatar for roy.granit
2.9 years ago by
roy.granit830 wrote:

Note that the human exome size is ~30Mb. So you can take the number of somatic mutations in a given tumor sample an divide that by 30 to obtain the Mut/Mb value (normally > 4-6 is considered 'hyper mutation')

Or maybe you can try this tool

ADD COMMENTlink written 2.9 years ago by roy.granit830

Instead of using 30 as denominator, I would use tools like GATK CallableLoci to get the exact number of bases.

ADD REPLYlink written 2.9 years ago by markus.riester510

I believe standard WXS capture sizes are around 50 mb. (eg; Agilent sure select)

ADD REPLYlink written 2.9 years ago by poisonAlien3.0k

I would go with either the GATK CallableLoci or the capture size , that should be the one in use rather than something arbitrary.

ADD REPLYlink written 2.7 years ago by ivivek_ngs5.0k
gravatar for igor
8 months ago by
United States
igor12k wrote:

Just to add a little more confusion to this topic, there is another method implemented in Varlociraptor:

Varlociraptor enables an uncertainty aware computation of the tumor mutational burden (TMB). TMB is usually defined as the number of somatic, non-synonymous coding mutations per megabase of the measured coding genome. ... the TMB is calculated as expected value over the posterior probabilities for each variant to be somatic. Hence, the TMB estimate properly considers the uncertainty in the data. Moreover, as we show a TMB estimate for each minimum allele frequency, it becomes possible to reason over the clonal structure of the tumor, instead of considering only a single overall number. We expect this to increase the predictive power of the TMB.

ADD COMMENTlink written 8 months ago by igor12k
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