Myeloma accounts for almost 14% of all hematologic cancers and is essentially incurable. Recent studies have documented increasing evidence for an inherited genetic basis for multiple myeloma (MM). Genome-wide association studies have identified common variants in transcriptional regulators and tumor suppressors associated with risk of sporadic MM and we have recently identified presumed deleterious germline variants in a group of familial cases following sequencing. As described in this application, we have already performed exome sequencing of 934 probands and affected relatives. However, systematic analyses of germline genetic alterations in sporadic and familial MM have not been performed to validate the interesting candidate genes from these exome data. In this proposal, we will build on our prior work and pre-existing genomic data to prioritize, identify and validate novel candidate genes conferring susceptibility to MM. We also undertake a meta-analysis with an African American study to understand commonality and heterogeneity of risks. These studies represents the first systematic approach to understand the germline genetic variations in a large group of well characterized MM cases and controls towards identification of moderate and high risk genetic variants that predispose to MM, which will be of utility in prevention, diagnosis, and modification of treatment of MM. Together, these studies will provide critical new insights into the genetic basis of MM and lymphoid malignancies.
While analysis of common genetic variants have provided some insights into genomic locations of variants that increase risk to Multiple Myeloma, not a lot is known about inherited mutations that cause Multiple Myeloma in families. We have sequenced many large families with Multiple Myeloma and discovered interesting variants that could putatively be causal for this disease, but we need to sequence these interesting genes in many more individuals with myeloma and compare against normal disease free individuals to further understand the role these variants play in Multiple Myeloma. Using this strategy, this project aims to identify inherited risk genes that can pinpoint which patients will develop Multiple Myeloma which is anticipated in improving early detection, treatment, and increasing the changes of a good outcome.
