Abstract 4158: Dissecting the role of zygosity and lineage in Lynch Syndrome-associated microsatellite Instability
Authors: Srinivasan Preethi , Bandlamudi Chaitanya , Shia Jinru , Latham Alicia S. , Jonsson Philip , Penson Alexander , Middha Sumit , Hechtman Jackie , Zehir Ahmet , Richards Allison , Chawan Shweta , Kemel Yelena , Mandelker Diana , Zhang Liying , Hyman David , Ladanyi Marc , Robson Mark , Offit Kenneth , Solit David , Taylor Barry , Berger Michael , Stadler Zsofia 
Published: August 2019

Abstract
Lynch syndrome (LS) is an inherited condition leading to an increased risk of developing colorectal cancer and other select malignancies. LS patients have germline alterations in mismatch repair (MMR) genes and their tumors often demonstrate microsatellite instability (MSI). With the advent of immune checkpoint blockade, this is of both prognostic and therapeutic significance. Nevertheless, the factors that dictate the presence of the MSI phenotype in tumors diagnosed in LS patients are poorly understood. We integrated germline pathogenicity with somatic alterations in 17,152 prospectively sequenced advanced cancer patients to determine how zygosity and lineage shape the presence and intensity of the somatic MSI phenotype in LS patients. Overall, we identified 117 LS patients (0.68%) with one of 46 distinct cancer types, 111 of which had sufficient purity for somatic assessment. The tumors of 72% (80/111) of these patients had biallelic inactivation of the germline allele as assessed by integrating high-precision mutant allele fractions with allele-specific DNA copy number analysis or, in select low purity tumors, confirmatory immunohistochemistry. Among patients with biallelic inactivation, 73% (58/80) had MSI positive tumors whereas, only 1/31 (3%) of heterozygous tumors were MSI positive, indicating that biallelic inactivation of the germline allele was obligate to drive the somatic MSI phenotype (p-value=5.4e-12). Lineage appears, however, to condition this dependence of MSI status on biallelic inactivation. Leveraging the prevalence of germline MMR mutations in our cohort, zygosity enrichment, and literature curation of MMR penetrance, we classified cancer types as either conventionally Lynch-associated or not. Notably, despite the presence of biallelic inactivation, MSI was not seen in LS patients whose cancers were not conventionally Lynch-associated such as breast, lung, and thyroid cancers among others. The nature and degree of the MSI phenotype also varied as a function of underlying genotype in these patients. Despite comparable mutational burdens, MSH6 germline carriers that were somatic biallelic had lower MSI scores, lower rates of frameshift indels and higher rates of missense mutations than patients with biallelic mutations in other MMR genes. Collectively, these data suggest that the presence of MSI is dictated by lineage-dependent selection for biallelic inactivation in LS tumors, and emerges to differing degrees driven by the underlying genotype, which together has implications for the immunogenicity of resulting tumors and the biomarker of greatest response to immune checkpoint blockade. By expanding our prospective cohort to &gt;30,000 patients with advanced cancer and integrating clinical response to immunotherapy, we will further explore gene-specific variability in MSI patterns observed in LS patients and its effects on outcome and therapeutic response.
Citation Format: Preethi Srinivasan, Chaitanya Bandlamudi, Jinru Shia, Alicia S. Latham, Philip Jonsson, Alexander Penson, Sumit Middha, Jackie Hechtman, Ahmet Zehir, Allison Richards, Shweta Chawan, Yelena Kemel, Diana Mandelker, Liying Zhang, David Hyman, Marc Ladanyi, Mark Robson, Kenneth Offit, David Solit, Barry Taylor, Michael Berger, Zsofia Stadler. Dissecting the role of zygosity and lineage in Lynch Syndrome-associated microsatellite Instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4158.