Genomic Landscape of Immunoglobulin Light Chain (AL) Amyloidosis and Comparative Analyses with Related Malignant Plasma Cell Disorder- Multiple Myeloma

Abstract Abstract 809 Immunoglobulin light chain amlyloidosis (AL) is a rare plasma cell disorder characterized by deposition of misfolded light chains in various organ systems with an average survival of 1–2 years. AL is also the most common form of systemic amyloidosis with 1200–3200 newly diagnosed cases reported annually in the United States. Very little is known regarding specific genomic aberrations associated with AL-amyloidosis. Aside from the light chain selection, no phenotypic or genetic features have been identified that distinguish AL amyloidosis from other plasma cell dyscrasias. Understanding the genetics of AL and the molecular mechanisms involved in amyloid formation may lead to early diagnosis and the identification of novel drug targets and therapies. We therefore have attempted to study the genomic landscape of AL patients and MM for comparison. Genomic copy number and loss of heterozygosity (LOH) analyses were performed on DNA derived from tumor (CD138 sorted cells) and matched germline (skin) from biopsy proven AL patients using Affymetrix single nucleotide polymorphism (SNP) 6.0 arrays. Numerous genomic changes with gains in chromosome 1q, 6, 9, 11q, 15, 19 and 21 and loss on chromosome 1p, 2q, 8, 10, 12, 13, 14, 16, 18, 20 and 22 were observed in more than 10% of the patients. Recurrent genomic changes in about 249 segments involving 457 genes were present in about 1/3 of AL patients. In particular, deletion of IGK, IGH, PIK3CA, FLT3, RB1, PCDH9, GPC6, RASA3, ADAM6 genes and amplification of CFHR1, JAK2, GCNT1, TSC1, PGR genes were observed. Gene network analysis showed five distinct major modules consisting of 51 distinct elements and involving PDGF, TP53, interleukin signaling, TRKA signaling, cell cycle and mitotic pathways were enriched. Allele specific copy number analysis in tumor (ASCAT) profile showed increased ploidy status of the AL genome in 47% of the assessed patients. LOH was observed in chromosomes 4, 5, 6, 8, 9, 12, 13, 18 and 22 in 30% of patients, ranging from 5Mb to entire chromosome. Furthermore, genomic comparisons of AL with multiple myeloma (MM) showed the typical archetype of myeloma’s signature with exception of gain of chromosomes 3, 5, 7 and loss of chromosome 6q and 8p. Interestingly deletion of IGH, IGK locus and PIK3CA gene were observed at a higher frequency in AL patients. Categorical analysis using isotype specific classification in AL showed a significantly higher frequency of deletion in chromosome 14, 13, 8 and amplification of chromosome 9q in the kappa type than lambda isotype. To the best of our knowledge, this is the first ultra-high resolution study of the genomic landscape of AL amyloidosis. In this study, we have found several novel genes and pathways associated with this rare disease. The numerous copy number alterations of AL thus reflect the genomic complexity and the heterogeneity of this disease. Additional genome-wide analysis in a larger panel with target organ stratified patients is under way and may further our understanding of genetic changes specifically associated with AL. Disclosures: No relevant conflicts of interest to declare.