Monitoring tumour burden and therapeutic response through analysis of circulating tumour DNA and extracellular RNA in multiple myeloma patients

Mithraprabhu, Sridurga; Morley, Rachel; Khong, Tiffany; Kalff, Anna; Bergin, Krystal; Hocking, Jennifer Jane; Savvidou, Ioanna; Bowen, Kathryn M.; Ramachandran, Malarmathy; Choi, Kawa; Wong, Boris Ka Leong; Reynolds, John; Spencer, Andrew

doi:10.1038/s41375-019-0469-x

Cited by 55 publications

(65 citation statements)

References 40 publications

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“…Patients with more than two mutations, or a fractional abundance of a mutation greater than 1%, had significantly shorter overall survival. These findings were validated by another study, where a higher absolute number of mutations, as well as a higher fractional abundance of these mutations, was also associated with worse overall survival [38] .…”

Section: Cfdna In MMsupporting

confidence: 53%

“…MM is the archetypal haematological disease for studying the utility of cfDNA and liquid biopsies. The marked spatial and temporal genetic heterogeneity of MM is well established, and the gold standard bone marrow biopsy is now recognised as not being genomically representative of the disease as a whole [36][37][38] . cfDNA, representing DNA from the tumour in its entirety, better captures the genetic diversity of MM compared with bone marrow (BM) samples alone [35][36][37][38] .…”

Section: Cfdna In MMmentioning

confidence: 99%

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The role of cell free DNA and liquid biopsies in haematological conditions

Bingham¹,

Spencer²

2020

CDR

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Cell free nucleic acids (CFNAs) are nucleic acids released from cells that circulate within bodily fluids. Recent advances in molecular techniques have led to the ability to interrogate CFNAs in a clinically meaningful way, for example the identification and assessment of foetal CFNAs in maternal blood, allowing minimally invasive testing for foetal genetic abnormalities. The majority of CFNAs arise from haemopoietic cells, making it a particularly rich source of genetic information in haematological conditions. Furthermore, the innate genetic heterogeneity of haematological malignancies, as epitomised by multiple myeloma, lend itself well to "liquid biopsies". This approach promises to provide a more wholistic assessment of whole disease genetics, especially when contrasted against the current gold-standard of single site tissue biopsies. This review briefly summarises the definitions and physiology of CFNAs, both cell free DNA (cfDNA) and extracellular RNA (exRNA), before exploring the literature surrounding the current and future roles of cfDNA in the haematological malignancies and patient care.

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Section: Cfdna In MMsupporting

confidence: 53%

Section: Cfdna In MMmentioning

confidence: 99%

The role of cell free DNA and liquid biopsies in haematological conditions

Bingham¹,

Spencer²

2020

CDR

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“…Subsequently, we used CRBN expression to adjust the levels of the 3 genes determined as per previous reports . Ratios of IKZF1 , IKZF3 , and KPNA2 to CRBN were calculated and analyzed for determining patient response to Ld therapy.…”

Section: Resultsmentioning

confidence: 99%

Expression, mutation, and methylation of cereblon‐pathway genes at pre‐ and post‐lenalidomide treatment in multiple myeloma

Tachita

Kinoshita

et al. 2020

Cancer Science

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Cereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN-pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN-binding proteins and mutations in these genes after Len treatment. Forty-eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post-Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN-pathway genes.Following normalization with CRBN levels, there was a significantly reduced IKZF1/ CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression-free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post-Ld samples.In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy. K E Y W O R D SCRBN, IKZF1, KPNA2, lenalidomide, multiple myeloma

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“…These exRNA biomarkers were identified and validated with credible clinical performance for non-invasive detection of gastric cancer. Another recent study reported analysis of ctDNA and exRNA for monitoring tumour burden and therapeutic response in patients with multiple myeloma [52] . This exploratory analysis has provided evidence of ctDNA for predicting disease outcome and the utility of exRNA as a biomarker of therapeutic response in multiple myeloma.…”

Section: Exrna As Cancer Biomarkermentioning

confidence: 99%

Extracellular RNAs as potential biomarkers for cancer

Happel

Ganguly

Tagle

2020

JCMT

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The discovery that all cells secrete extracellular vesicles (EVs) to shuttle proteins and nucleic acids to recipient cells suggested they play an important role in intercellular communication. EVs are widely distributed in many body fluids, including blood, cerebrospinal fluid, urine and saliva. Exosomes are nano-sized EVs of endosomal origin that regulate many pathophysiological processes including immune responses, inflammation, tumour growth, and infection. Healthy individuals release exosomes with a cargo of different RNA, DNA, and protein contents into the circulation, which can be measured non-invasively as biomarkers of healthy and diseased states. Cancer-derived exosomes carry a unique set of DNA, RNA, protein and lipid reflecting the stage of tumour progression, and may serve as diagnostic and prognostic biomarkers for various cancers. However, many gaps in knowledge and technical challenges in EVs and extracellular RNA (exRNA) biology, such as mechanisms of EV biogenesis and uptake, exRNA cargo selection, and exRNA detection remain. The NIH Common Fund-supported exRNA Communication Consortium was launched in 2013 to address major scientific challenges in this field. This review focuses on scientific highlights in biomarker discovery of exosome-based exRNA in cancer and its possible clinical application as cancer biomarkers.

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Monitoring tumour burden and therapeutic response through analysis of circulating tumour DNA and extracellular RNA in multiple myeloma patients

Cited by 55 publications

References 40 publications

The role of cell free DNA and liquid biopsies in haematological conditions

The role of cell free DNA and liquid biopsies in haematological conditions

Expression, mutation, and methylation of cereblon‐pathway genes at pre‐ and post‐lenalidomide treatment in multiple myeloma

Extracellular RNAs as potential biomarkers for cancer

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