RESUMEN
Somatic mutation phasing informs our understanding of cancer-related events, like driver mutations. We generated linked-read whole genome sequencing data for 23 samples across disease stages from 14 multiple myeloma (MM) patients and systematically assigned somatic mutations to haplotypes using linked-reads. Here, we report the reconstructed cancer haplotypes and phase blocks from several MM samples and show how phase block length can be extended by integrating samples from the same individual. We also uncover phasing information in genes frequently mutated in MM, including DIS3 , HIST1H1E , KRAS , NRAS , and TP53 , phasing 79.4% of 20,705 high-confidence somatic mutations. In some cases, this enabled us to interpret clonal evolution models at higher resolution using pairs of phased somatic mutations. For example, our analysis of one patient suggested that two NRAS hotspot mutations occurred on the same haplotype but were independent events in different subclones. Given sufficient tumor purity and data quality, our framework illustrates how haplotype-aware analysis of somatic mutations in cancer can be beneficial for some cancer cases.
RESUMEN
ABSTRACT: Personalized cancer vaccines designed to target neoantigens represent a promising new treatment paradigm in oncology. In contrast to classical idiotype vaccines, we hypothesized that "polyvalent" vaccines could be engineered for the personalized treatment of follicular lymphoma (FL) using neoantigen discovery by combined whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Fifty-eight tumor samples from 57 patients with FL underwent WES and RNA-seq. Somatic and B-cell clonotype neoantigens were predicted and filtered to identify high-quality neoantigens. B-cell clonality was determined by the alignment of B-cell receptor (BCR) CDR3 regions from RNA-seq data, grouping at the protein level, and comparison with the BCR repertoire from healthy individuals using RNA-seq data. An average of 52 somatic mutations per patient (range, 2-172) were identified, and ≥2 (median, 15) high-quality neoantigens were predicted for 56 of 58 FL samples. The predicted neoantigen peptides were composed of missense mutations (77%), indels (9%), gene fusions (3%), and BCR sequences (11%). Building off of these preclinical analyses, we initiated a pilot clinical trial using personalized neoantigen vaccination combined with PD-1 blockade in patients with relapsed or refractory FL (#NCT03121677). Synthetic long peptide vaccines targeting predicted high-quality neoantigens were successfully synthesized for and administered to all 4 patients enrolled. Initial results demonstrate feasibility, safety, and potential immunologic and clinical responses. Our study suggests that a genomics-driven personalized cancer vaccine strategy is feasible for patients with FL, and this may overcome prior challenges in the field. This trial was registered at www.ClinicalTrials.gov as #NCT03121677.