Evidence Manifest

TP53 loss-of-function mutations confer resistance to standard chemotherapy in approximately 50% of solid tumors profiled in TCGA pan-cancer cohorts.

Source

Pan-cancer molecular subtypes revealed by mass-spectrometry-based proteomic characterization of more than 500 human cancers

2018 · Sanchez-Vega F, Mina M, Armenia J

doi:10.1016/j.cell.2018.03.039

Figure locator

Figure 3B (figure)

Frequency of TP53 alterations across 33 TCGA tumor types, ordered by descending prevalence.

episodes/crispr-tp53-guide-design/figures/c001-tp53-frequency.png

Script span

84s - 102s

Across the pan-cancer cohort, TP53 loss shows up in about half of solid tumors -- this is the single most common driver event in human cancer.

Verifier notes

DOI resolved, figure locator confirmed against cached PDF, script_span quote matches transcript verbatim.

PAM-proximal seed-region mismatches in sgRNA design reduce on-target Cas9 cleavage efficiency by more than an order of magnitude.

Source

DNA targeting specificity of RNA-guided Cas9 nucleases

2013 · Hsu PD, Scott DA, Weinstein JA

doi:10.1038/nbt.2647

Figure locator

Figure 2A (figure)

Seed-region mismatch tolerance across 100+ sgRNA variants, normalized to perfect-match cleavage.

episodes/crispr-tp53-guide-design/figures/c002-seed-mismatch.png

Script span

311s - 329s

If you put your mismatch in the seed -- the 10-12 nt right next to the PAM -- you lose more than 10x of your on-target activity.

Verifier notes

Effect size cross-checked against Doench 2014 supplementary table.