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Abstract
Somatic mutations in cancer can result in neoantigens against which patients can be vaccinated. The quest for tumor specific neoantigens has yielded no targets that are common to all tumors, yet foreign to healthy cells. Single base pair substitutions (SNVs) at best can alter 1 amino acid which can result in a neoantigen; with the exception of rare site-specific oncogenic driver mutations (such as RAS) such mutations are private. Here, we describe a source of common neoantigens induced by frame shift mutations, based on analysis of 10,186 TCGA tumor samples. We find that these frame shift mutations can produce long neoantigens. These are completely new to the body, and indeed recent evidence suggests that frame shifts can be highly immunogenic. We report that many different frame shift mutations converge to the same small set of 3′ neo open reading frame peptides (NOPs), all encoded by the Neo-ORFeome. We find that a fixed set of only 1,244 neo-peptides in as much as 30% of all TCGA cancer patients. For some tumor classes this is higher; e.g. for colon and cervical cancer, peptides derived from only ten genes (saturated at 90 peptides) can be applied to 39% of all patients. 50% of all TCGA patients can be achieved at saturation (using all those peptides in the library found more than once). A pre-fabricated library of vaccines (peptide, RNA or DNA) based on this set can provide off the shelf, quality certified, ‘personalized’ vaccines within hours, saving months of vaccine preparation. This is crucial for critically ill cancer patients with short average survival expectancy after diagnosis.
Highlights
The concept of utilizing the immune system to battle cancer is very attractive and studied extensively
The list of genes most commonly represented in the cohort and containing such frame shift mutations is headed nearly exclusively by tumor driver genes, such as NF1, RB, BRCA2 (Fig. 1b and Table S2) whose whole or partial loss of function apparently contributes to tumorigenesis
Alignment of the translated NOP products onto the protein sequence reveals that a wide array of different frame shift mutations translate in a common downstream stretch of neo open reading frame peptides (‘NOPs’), as dictated by the −1 and +1 alternative reading frames
Summary
Received: 12 October 2018 Accepted: 14 February 2019 Published: xx xx xxxx neoantigens in up to 50% of cancer patients. We report that frame shift mutations, which are mostly unique among patients and tumors, converge to neo open reading frame peptides (NOPs) from their translation products, that result in common neoantigens in large groups of cancer patients. For the 341–410 genes assessed in this cohort, we obtained strikingly similar results in terms of genes frequently affected by frame shifts and the NOPs that they create (Supplementary Fig. S5) Even within this limited set of genes, 86% of the library peptides (in genes targeted by MSK-IMPACT) were encountered in the patient set. We have identified that various frame shift mutations can result in a source for common neo open reading frame peptides, suitable as pre-synthesized vaccines This discovery, potentially combined with checkpoint inhibition, holds promise for future treatment strategies to help instruct our own immune system to defeat cancer
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