ctDNA tumor mutation burden

Question

[anlinli.napert]

Is ctDNA tumor mutation burden (TMB) (PMID: 30867242) defined as the same as the blood-based TMB (PMID: 30082870)?

Article PMID 30867242: https://www.ncbi.nlm.nih.gov/pubmed/30867242

Article PMID 30082870: https://www.ncbi.nlm.nih.gov/pubmed/30082870

Advanced thanks for answering!

Answer 1

[Kevin Blighe]

You can assume that it is generally the same - yes.

The caveat(s):

• ctDNA will be fragmented; therefore, the ctDNA TMB calculation can be regarded as a best estimate of the true TMB
• ctDNA will only reflect tumour clones that are actively shedding material into the circulatory system, either via apoptosis or necrosis
• Some tumour clones may likely be replicating at higher rates than others; thus, the ctDNA TMB calculation may be biased for the mutation profile for these particular clones.

Kevin

[anlinli.napert]

Dear Kevin,

Thank you very much for your answer!！

I still have a question regarding the association of ctDNA TMB with the entire tumor heterogeneity. As you answered, "the ctDNA TMB calculation can be regarded as a best estimate of the true TMB", but "ctDNA will only reflect tumour clones that are actively shedding material into the circulatory system, either via apoptosis or necrosis".

I am not sure but I found it paradoxical. If the ctDNA only reflects partial tumour clones, why many articles said ctDNA TMB could reflect more comprehensive tumor heterogeneity then tissue-based TMB? Although ctDNA TMB could concurrently capture mutations from both primary and metastatic sites, but they only reflect mutations shed in the blood.

Regards, Anlin Li

[Kevin Blighe]

Perhaps they mean that ctDNA TMB is a better prognostic tool, as it can be simply extracted from blood and is therefore non-invasive, and also considering the fact that ctDNA that's detected may reflect a dominant or metastasising clone.

Generally, though, 'TMB' is a 'catch all' term that refers to different ways of summarising mutation numbers and frequency. There is no standard way of calculating TMB