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5.5 years ago
CY
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We found a gene (TSC2) mutated with low VAF (around 7%) in 3/4 brain tumor patients. Although the sample size is limited, 3/4 patients is hard to be concidence. Besides, this gene is known to be a tumor suppressor preventing cells from growing too fast.
However, the low VAF makes it less unlikely to be a tumor suppressor (not a truncal mutation).
We found such case a bit contradictory. Can anyone share some comments on this and what can we do to make furthur investigation? Thanks in advance.
...but there are undoubtedly 1000s of other genes that have missense variants. too. and present in all of your samples, no? Are you only focusing on this gene based on its history?
What is the biopsy of study? If you are looking at a primary tumour, then 7% could still be a driver. If you're looking at a metastatic sample, then 7% is a bit far-fetched...
Other genes does not seem to be interesting based on their VAF and population frequency. Only this gene looks weird based on its situation above. Why do you think whether it is primary or metastatic makes such difference in terms of VAF?
What I thought is just the opposite: The variant in primary tumor has to have high VAF to be a driver (driver has to be a truncal mutation). However, The variant in metastatic tumor with a low VAF is unlikely to be a driver as well, could be a branch mutation before or after the metastasis. Am I right?
I was thinking along the lines of the primary tumour having many clones, any one of which may harbour a driver mutation that 'drives' metastasis. If you look at the bulk biopsy of the primary, a driver mutation in just 1 clone may come back with a low VAF when you look at it.
When you then look at your metastatic sample, the VAF should greatly increase if your metastatic sample was derived from the particular clone of interest.
I published some simple data on this years ago for matched primary and met in breast cancer. We got it out really late, so, only made PLOS ONE: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115346
I may be completely wrong in my logic...
I think the logic is reasonable. Anyway, it turns out that all samples are primary. We still can't believe it is a drive with such low VAF. Guess only way to confirm is validating the variant on more sample.
I guess that it may be that way (low VAF) if the primarty tumour exhibits a high level of genomic instability and is very heterogeneous. So, the original driver mutation may have become 'diluted'. Perhaps you could look to see if there are mutations in CIN signature genes, too, which would indicate genomic instability.
There are so many factors going into this, though. With cancer, every possible combination of events must exist due to the nature of cancer itself.