Updated analysis: HGG subtyping to remove BRAF and include TP53

[jharenza]

What analysis module should be updated and why?

molecular-subtyping-HGG

1. Per discussion with @adamcresnick, we should remove the BRAF V600E subtyping from HGG and replace with TP53 subtypes for HGG, as TP53 is the top co-occurring gene with H3 mutations in DMGs. Neither are currently in WHO, but the latter may be able to inform clinical decision making.
2. We should remove LGG samples which contain histone mutations during the initial search for samples with histone mutations, since there have been recent reports of LGG with these mutations. (See literature below).

What changes need to be made? Please provide enough detail for another participant to make the update.

Step 1 - cleanup

• Remove the BRAF V600E subtypes - This is being done in Removing BRAF subtyping for HGG #856
• Remove LGG tumor samples which have histone mutations. - This is being done in Remove lgg histone mut hgg subtyping #851

Step 2 - annotate as TP53 altered if:

• There are two alterations (SNV+SNV, CNV+SNV)
• There is one alteration + cancer_predispositions == "Li-Fraumeni syndrome"
• There are no TP53 alterations, but cancer_predispositions == "Li-Fraumeni syndrome" and TP53 classifier score for matched RNA-Seq > 0.5
• There are one of TP53 activating mutations R273C and R248W (see literature below)

Step 3 - assess and potentially annotate as TP53 altered if:

• There is an SNV or Focal CNV loss and TP53 classifier score for matched RNA-Seq > 0.5
• There is an SNV or Focal CNV gain and TP53 classifier score for matched RNA-Seq < 0.5 (indicating activating mutation) and TP53 expression is high

What input data should be used? Which data were used in the version being updated?

pbta-snv-consensus-mutation.maf.tsv.gz
https://github.com/AlexsLemonade/OpenPBTA-analysis/blob/master/analyses/tp53_nf1_score/results/pbta-gene-expression-rsem-fpkm-collapsed.stranded_classifier_scores.tsv
https://github.com/AlexsLemonade/OpenPBTA-analysis/blob/master/analyses/tp53_nf1_score/results/pbta-gene-expression-rsem-fpkm-collapsed.polya_classifier_scores.tsv

When do you expect the revised analysis will be completed?

2-4 days

Who will complete the updated analysis?

@kgaonkar6

Relevant literature

Tectal Low-Grade Glioma with H3 K27M Mutation
Pediatric low-grade glioma in the era of molecular diagnostics

p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM

Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy

[jharenza]

@kgaonkar6 - I imagine a table of lesions consisting of the TP53 SNV, TP53 classifier score, TP53 FPKM, TP53 loss, TP53 gain

[kgaonkar6]

In #837 the TP53 annotation PR, we are missing annotation corresponding to Step3 from this PR:

Step 3 - assess and potentially annotate as TP53 altered if:

There is an SNV or Focal CNV loss and TP53 classifier score for matched RNA-Seq > 0.5
There is an SNV or Focal CNV gain and TP53 classifier score for matched RNA-Seq < 0.5 (indicating activating mutation) >and TP53 expression is high

is this specific to HGG samples?

If not I can add these conditions to the annotation criteria in #837 since I think we wanted the exact annotation from #837 to be added to the samples in HGG here , right? @jharenza.

[kgaonkar6]

This seems to be completed now, ok from @jharenza to close?

[jharenza]

yes!