P-045: Immunoglobulin V(D) J Recombination, Protein Ubiquitination, Cell Adhesion and Sonic Hedgehog Gene Variants are detected among familial Multiple Myeloma subjects following whole exome sequencing

Abstract

<h3>Background</h3> Familial multiple myeloma(MM) cases have been associated with some rare, germline variants, mostly among epigenetic modification genes and needs to be validated in other populations. The aim of this study is to investigate formerly reported rare variants in our population and to search for additional ones. <h3>Methods</h3> Following the ethical committee approval, hematology centers in Turkey were informed for collaboration in this familial MM genetic association study. Inclusion criteria was defined as having one or more first, second or third degree relatives who have plasma cell diseases. After obtaining informed consents, patients' peripheral blood samples or DNAs from pathological samples were collected. NGS analysis have been performed on 33 samples from 23 families, targeting 14 variants in 6 genes, previously reported to be associated with familial presentation (EP300, CDKN2A, USP45, ARID1A, KDM1A, DIS314)(Pertesi et al., Leukemia, 2020). To widen the range of analysis, whole exome sequencing (WES) within 3 families (6 patients) of first degree relatives were carried out. The detected variants were checked against NCBI's dbSNP. Mutation Taster was utilized for probable disease associations. <h3>Results</h3> 30 MM families(63 patients) were included. Of the patients 69% were first, 4% were second and 27% were third degree relatives. Neither of the previously reported rare variants were detected among the subjects in the targeted sequencing. However, an heterozygote variant (rs3731249) close to the targeted region in CDKN2A was detected in 3 patients. WES detected new variants which were not observed earlier. Family 1:Missense variants in BRIP1 (function: DNA double strand break repair)(rs886053214, rs886053215) and ACD (function: maintain telomere length)(rs1306270247). All of which were predicted as polymorphism, in silico. Family 2:Missense variant in RAG2 (function:V(D)J recombination of Ig and T cell receptor) (rs765298019) predicted as disease causing. Family 3:Missense variant in RET (function: receptor tyrosine kinase)(rs1366681125) predicted as polymorphism. Missense variants in CBL (function: protein ubiquitination)(rs754194646), APC (function: cell adhesion)(rs760591046) and PTCH1 (function: sonic hedgehog) (rs772574714) were predicted as disease causing. All of the variants from the patients were detected as one-copy-alleles. The variant in RAG2 was reported to cause severe combined immunodeficiency and histiocytic medullary reticulosis in homozygous state. The PTCH1 variant is known to give rise to nevoid basal cell carcinoma syndrome. Germline mutations of CBL and APC are related to the juvenile myelomonocytic leukemia, familial AML and familial adenomatous polyposis respectively. <h3>Conclusion</h3> MM development is a multistep process. As of actual literature, MM susceptibility in familial cases involve various gene variants. Here we suggest the consideration of RAG2, CBL, APC, PTCH1 as additional loci for the progression to familial MM.