Journal Club; Wahida, Nat Rev Cancer, 6 Riddles for Precision Oncology

I love research and clinical applications in oncology that go beyond "the sequence" alone (e.g. recent unexpected work on chromothripsis, genomic instability, here, here.)  

Here's an excellent article with a broad view of molecular oncology and its current puzzles.  Find it in Nature Reviews Cancer, Wahida et al.  Find it here (subscription). 

I would summarize the six riddles as:

1. Timing.  Is it critical to start precision therapies early, before multiple driver pathways accumulate?
2. When is a mutation pathogenic?  Which of several, in a tumor, is the most important driver?  Why do some conditions (from adenomas to endometriosis - have "pathologic" mutations but are not cancer?
3. Are mutations tissue-tropic?   Such as BRAF having different impacts in different tissues of origin.
4. Which tumor clone should be targeted?  Are therapies "irrelevant" to some parts of the tumor?
5. Are the roles of age, sex, microbiome bigger than we suspect?
6. When, and based on what biomarkers, do we switch to immunotherapy?  What about specific mutations (epitopes) rather than gross tumor mutation burden?

See the first author's twitter here.  See his Twitter-summary ("tweetorial") of his article here.