Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

  1. Blake Ferguson
  2. Herlina Y Handoko
  3. Pamela Mukhopadhyay
  4. Arash Chitsazan
  5. Lois Balmer
  6. Grant Morahan
  7. Graeme J Walker  Is a corresponding author
  1. QIMR Berghofer Medical Research Institute, Australia
  2. Harry Perkins Institute of Medical Research, Australia

Abstract

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the 'usual suspects' by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.

Data availability

All data generated in this manuscript are provided in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Blake Ferguson

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Herlina Y Handoko

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Pamela Mukhopadhyay

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Arash Chitsazan

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Lois Balmer

    Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Grant Morahan

    Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Graeme J Walker

    QIMR Berghofer Medical Research Institute, Herston, Australia
    For correspondence
    Graeme.Walker@qimr.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9392-8769

Funding

Melanoma Research Alliance (Investigator Grant Award Number: 346859 2015-2018)

  • Graeme J Walker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations Australian code of Practice for the care and use of animals for scientific purposes.. All of the animals were handled according to approved institutional animal care and use committee of the Queensland Institute of Medical research. The protocol was approved by the Committee (A98004M). No surgery was performed. Animals were sacrificed when tumours reached 10mm in diameter, or animals were otherwise distressed.

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: October 2, 2018
  2. Accepted: January 25, 2019
  3. Accepted Manuscript published: January 25, 2019 (version 1)
  4. Version of Record published: March 21, 2019 (version 2)

Copyright

© 2019, Ferguson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Blake Ferguson
  2. Herlina Y Handoko
  3. Pamela Mukhopadhyay
  4. Arash Chitsazan
  5. Lois Balmer
  6. Grant Morahan
  7. Graeme J Walker
(2019)
Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma
eLife 8:e42424.
https://doi.org/10.7554/eLife.42424

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    Background:

    Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways.

    Methods:

    We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS).

    Results:

    Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common.

    Conclusions:

    Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful.

    Funding:

    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).