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A systematic review of inter-individual differences in the DNA repair processes involved in melphalan monoadduct repair in relation to treatment outcomes

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Abstract

Purpose

Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response.

Methods

A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria.

Results

Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study.

Conclusion

It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.

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Data availability

Data collection spreadsheets can be provided by corresponding author upon request.

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  1. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Maia van Kan, Kathryn E. Burns & Nuala A. Helsby

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  1. Maia van Kan
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  2. Kathryn E. Burns
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Contributions

MVK carried out the literature search. MVK and NAH independently assessed relevance of articles using pre-determined inclusion/exclusion criteria. MVK and KEB undertook the data collection and critique. MVK, KEB and NAH all contributed in writing the manuscript.

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Correspondence to Maia van Kan.

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van Kan, M., Burns, K.E. & Helsby, N.A. A systematic review of inter-individual differences in the DNA repair processes involved in melphalan monoadduct repair in relation to treatment outcomes. Cancer Chemother Pharmacol 88, 755–769 (2021). https://doi.org/10.1007/s00280-021-04340-z

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