Work

Serial exome analysis of disease progression in premalignant gammopathies

Year: 2014

Type: article

Abstract: Nearly all human cancers are preceded by precursor states far more prevalent than clinical malignancy itself. Understanding which premalignant lesions are truly biologically premalignant versus those with impending clinical progression (biologically malignant) is a central question in cancer biology. Tracking the progression of human premalignant states (or lack thereof) in vivo is not feasible in most tumors because precursor lesions are typically resected at diagnosis. Multiple myeloma (MM) is characterized by progressive growth of malignant plasma cells (PCs) in the bone marrow leading to organ dysfunction. 1 Nearly all cases of clinical MM are preceded by asymptomatic monoclonal gammopathies (AMGs) further classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic myeloma (AMM). 1 , 2 MM is a unique model to dissect genetic evolution of early cancer as the precursor state is well defined and not resectable. Several studies have characterized the genetic architecture of malignant PCs in both MM and its precursor states. 3 MM tumor cells carry several cytogenetic abnormalities (most notably, IgH translocations and hyperdiploid karyotypes), and copy number abnormalities leading to genomic gains/losses and loss of heterozygosity (LOH). Comparisons of PCs in cohorts of MM versus MGUS/AMM show greater proportion of cytogenetically abnormal PCs in MM, suggesting the expansion of pre-existing and more proliferative clones during transition to MM. 4 , 5 However, nearly all of the cytogenetic changes described in MM tumor cells have also been observed in MGUS/AMM, and it has proven difficult to define the malignant phenotype on the basis of genetic changes alone. 4 , 5 Whole-genome and whole-exome-based sequencing strategies have recently been applied to human MM and shown that there are about 20–40 non-synonymous variants per MM tumor cell, but no single unifying variant has been identified. 6 , 7 , 8 The most common targets of recurrent mutation were known cancer genes, such as KRAS and TP53 , with KRAS mutations in 27% of the cases. 6 Analysis of serial samples from MM patients undergoing therapy recently demonstrated the presence of subclones, with greater changes in patients with cytogenetically high-risk disease. 9 , 10 Similar findings were made via serial genome sequencing in a patient with t(4:14) myeloma evolving to PCs leukemia. 8 In this study, we serially analyzed the exomes of patients with AMGs who progressed to clinical MM and compared the findings with those AMGs that did not progress to clinical MM.

Source: Leukemia

DOI: 10.1038/leu.2014.59