Accelerating Discovery of Functional Mutant Alleles in Cancer

Abstract

Most mutations in cancer are rare, which complicates the identifi cation of therapeutically signifi cant mutations and thus limits the clinical impact of genomic profi ling in patients with cancer. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identifi ed 1,165 statistically signifi cant hotspot mutations of which 80% arose in 1 in 1,000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population-scale mutant allele discovery illustrates how the identifi cation of driver mutations in cancer is far from complete. SIGnIFICAnCE: Our systematic computational, experimental, and clinical analysis of hotspot mutations in approximately 25,000 human cancers demonstrates that the long right tail of biologically and therapeutically signifi cant mutant alleles is still incompletely characterized. Sharing prospective genomic data will accelerate hotspot identifi cation, thereby expanding the reach of precision oncology in patients with cancer. Cancer Discov; 8(2);

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

“…Sequencing data were analysed as previously described to identify somatic single-nucleotide variants, small insertions and deletions, copy number alterations and structural arrangements 40 . Additionally, hotspot alterations were identified using an adaptation of a previously described method 41 applied to a cohort of 24,592 sequenced human cancers 42 . For gene level analysis, select genes within our targeted 341/410 MSK-IMPACT panel involved in the RTK/RAS/RAF, PIK3CA/AKT/MTOR, and cell cycle checkpoint pathways were selected using the KEGG pathway database 43 .…”

Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

“…24 Annotation was performed using canonical transcripts and publicly available databases dbSNPv150, 25 gnomADv2.0.2 (http://gnomad.broad institute.org/), 26 COSMICv74, 27 ClinVar(25-02-2018), 28 dbNSF Pv2.9.3 18 and known cancer Hotspots. 29 Loss of function (LoF) assessment was performed using the snpEff tool. SNVs/InDels were discarded as benign/likely benign/polymorphic based on population minor allele frequency (popmax) ≥0.1% from gnomAD database.…”

Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

“…13,14,17 A combination of mutation function predictors 30 was employed to define the potential functional impact of each missense SNV, as previously described. 13 Mutation hotspots were assigned according to Chang et al 31…”