Low Mutational Burden of Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue in Patients with Primary Sjogren's Syndrome

Simple Summary Patients with primary Sjogren's syndrome (pSS) are at risk of developing extranodal marginal zone lymphoma (ENMZL) of the mucosa-associated lymphoid tissue (MALT) in the parotid glands. The genetic mechanism underlying development of MALT lymphoma in the context of pSS is unknown. The aim of our study was to define the genomic landscape of pSS-associated MALT lymphoma. For 17 localized pSS-associated MALT lymphomas, we analyzed the presence of nonsynonymous mutations, copy number alterations (CNAs) and MALT1 translocations. pSS-associated MALT lymphomas were characterized by a low mutational load (median number of nonsynonymous somatic variants per case was 7, range 2-78) and a limited number of CNAs. Unlike the recurrent genomic aberrations observed in MALT lymphoma, which were not associated with pSS, pSS-associated MALT lacked a clear lymphoma-related profile. The data suggest that localized pSS-associated MALT lymphomas are a distinct type of ENMZL, which are genomically stable and most likely depend on a stimulatory micro-environment. Patients with primary Sjogren's syndrome (pSS) are at risk of developing extranodal marginal zone lymphoma (ENMZL) of the mucosa-associated lymphoid tissue (MALT) in the parotid glands. Unlike recurrent genomic aberrations observed in MALT lymphoma, which were not associated with pSS (non-pSS), it is unknown which somatic aberrations underlie the development of pSS-associated MALT lymphomas. Whole-exome sequencing was performed on 17 pSS-associated MALT lymphomas. In total, 222 nonsynonymous somatic variants affecting 182 genes were identified across the 17 cases. The median number of variants was seven (range 2-78), including three cases with a relatively high mutational load (>= 24/case). Out of 16 recurrently mutated genes, ID3, TBL1XR1, PAX5, IGLL5 and APC are known to be associated with lymphomagenesis. A total of 18 copy number alterations were detected in eight cases. MALT1 translocations were not detected. With respect to outcome, only two cases relapsed outside of the salivary glands. Both had a high mutational load, suggesting a more advanced stage of lymphoma. The low mutational load and lack of a clear lymphoma-related mutation profile suggests that localized pSS-associated MALT lymphomas are genomically more stable than non-pSS MALT lymphomas and most likely depend on a stimulatory micro-environment.