impact of recurrent SNVs?

Question

[mangfu100]

Hi all

I am analyzing exome sequencing data for bladder cancer.

I ran somatic mutation detection tools and got a hundred of mutations in my storage. In order to classify which genes harboring variants are the most critical to target cancer, I think that genes that the most recurrently detected from my samples are the one that have the most dominant effects in my analysis. (Of course, I already removed any artifacts or non-relevant mutations).

It is very obvious that the most frequently mutated genes are the most important to corresponding cancer.

However, I tried to find relevant paper that are able to prove my evidence, but I can't.

I would appreciate it if someone who already have relevant article or paper about my issue, share with me the information.

[John]

Unfortunately with cancer it"s not so clear as this.

Most cancers show mutations in the genes that protect against cancer - https://en.wikipedia.org/wiki/Tumor_suppressor_gene

In other words, 8 cancerous bladder samples could have 8 totally different mechanisms for how the cancer started, but all share mutations in the common tumor suppressor genes.

So looking at the most frequently mutated genes might not be the best way to detect the really important causes.

Are your bladders all from a family (genetically inherited), or from the same kind of well-defined bladder cancer? Otherwise, this kind of study is going to be really really tricky without a LOT of samples and some really hardcore statistics.

[mangfu100]

My sample is not a family. However, they are very specific same cancer type.

[John]

Well thats good then - perhaps a comparison of your most frequently mutated genes against other bladder cancer frequently mutated genes (and frequently mutated genes in all cancers) would find you a good candidate.

But for the kind of certainty you would want for a publication, the project begins here, not ends :)

[monukmr98]

Hi mangfu100

I have confusion regarding mutational artifacts. what are these artifacts. please help to make this concept clear to me.

regards

Answer 1

[Christian]

Looking for recurrently mutated genes is the major rational behind all large-scale cancer sequencing projects (TCGA, ICGC), so it shouldn't be too hard to justify this approach. However, to be on the safe side, you should adjust for local mutation rates in case your cohort is large enough (see MuSiC or MutSig).

[DG]

This. Doing mutational analysis to find genes with recurrent mutations is what is driving most large-scale cancer studies these days, because you will find deleterious mutations in the same genes (sometimes you find the same mutations) over and over again. Comparing to other data sets is always helpful (if the same genes are known tumor suppressors, oncogenes, or recurrently mutated in other cancers for instance that is good secondary evidence of their importance) as is some exploration of the function and pathways those genes are in.

8 Samples is relatively small, but it also depends on the subtype of bladder cancer you are dealing with. If it is quite a rare cancer, or in an understudied population group, you may be able to publish in a decent journal even with a small sample size. But the stats will be underpowered.