Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M3P)

Abstract

Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3%of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

The landscape of somatic mutation in sporadic Chinese colorectal cancer

“…A few other genes with mutation frequency greater than 5% were reported in this study and their association with CRC is revealed previously, such as HMCN1 [35], SYNE1 [10], NEB [36], OBSCN [37], MUC16, RYR2 [38] and FAT4 [10]. A few genes with little study in CRC also show medium mutation prevalence, including ABCA13, ABCC10, CEP192, DCHS2, DNAH5, DYNC1H1, PTPRT, MYO16, LRRK2, DYNC2H1, FBN1, FCGBP, FLG, FREM2, PAPPA2, RP1L1, TTN, ZFHX4 and ZNF717.…”

Loss of FAM46C Promotes Cell Survival in Myeloma

“…We have previously suggested that FAM46C mutations are less frequent in newly diagnosed MM patients harboring deletion 17p(8), potentially inferring some overlap in function. Moreover, acquisition of mutations was observed in longitudinal analysis in MM patients(9), suggesting that FAM46C loss of function is a progression event in MM.…”

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

“…More recent longitudinal studies using next-generation sequencing have shown changes consistent with those seen with CNAs but did not address the impact of specific treatments. 5,6 In a "Darwinian model" of progression/relapse, treatment can be considered as a selective pressure. Therefore, to understand the molecular mechanisms underlying relapse, the analysis has to be done within the context of a standard treatment.…”