Unique genomic and neoepitope landscapes across tumors: a study across time, tissues, and space within a single lynch syndrome patient

Tanya N. Phung,Elizabeth Lenkiewicz,Smriti Malasi,Amit Sharma,Michael T. Barrett,Karen S. Anderson,Melissa A. Wilson,Barbara A. Pockaj

doi:10.1038/s41598-020-68939-7

Tanya N. Phung, Elizabeth Lenkiewicz + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-68939-7

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Journal: Scientific Reports	Publication Date: Jul 22, 2020
Citations: 4	License type: open-access

Affiliation: Arizona State University, Mayo Clinic

Abstract

Lynch syndrome (LS) arises in patients with pathogenic germline variants in DNA mismatch repair genes. LS is the most common inherited cancer predisposition condition and confers an elevated lifetime risk of multiple cancers notably colorectal and endometrial carcinomas. A distinguishing feature of LS associated tumors is accumulation of variants targeting microsatellite repeats and the potential for high tumor specific neoepitope levels. Recurrent somatic variants targeting a small subset of genes have been identified in tumors with microsatellite instability. Notably these include frameshifts that can activate immune responses and provide vaccine targets to affect the lifetime cancer risk associated with LS. However the presence and persistence of targeted neoepitopes across multiple tumors in single LS patients has not been rigorously studied. Here we profiled the genomic landscapes of five distinct treatment naïve tumors, a papillary transitional cell renal cell carcinoma, a duodenal carcinoma, two metachronous colorectal carcinomas, and multi-regional sampling in a triple-negative breast tumor, arising in a LS patient over 10 years. Our analyses suggest each tumor evolves a unique complement of variants and that vaccines based on potential neoepitopes from one tissue may not be effective across all tumors that can arise during the lifetime of LS patients.

Highlights

Lynch syndrome (LS) arises in patients with pathogenic germline variants in DNA mismatch repair genes
Given previous IHC results we focused on variants in mutS homologue 2 (MSH2) and mutS homologue 6 (MSH6) as candidates
We identified the pathogenic variant NM_000251.2 (MSH2):c.942 + 3A > T that was heterozygous in the germ line but had converted to homozygosity in each tumor profiled (Fig. 2)

Summary

Introduction

Lynch syndrome (LS) arises in patients with pathogenic germline variants in DNA mismatch repair genes. In each case we flow sorted tumor fractions from archived formalin fixed paraffin embedded (FFPE) tissue and profiled the tumor genomes with whole genome copy number variant (CNV) arrays and whole exome sequencing These data were used to identify the pathogenic variant underlying the diagnosis of LS, and to compare and contrast the CNV, mutational and neoepitope patterns across these divergent tumors that arose over a 10 year period. These results provide a unique analysis of distinct MSI + tumors arising in a single LS patient (Fig. 1)

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Conclusion