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Laboratory science
Prognostic significance of melanogenesis pathway and its association with the ultrastructural characterisation of melanosomes in uveal melanoma
  1. Jayanti Jha1,
  2. Mithalesh Kumar Singh2,
  3. Lata Singh3,
  4. Neelam Pushker4,
  5. Rachna Meel4,
  6. Neiwete Lomi4,
  7. Sameer Bakhshi5,
  8. Tapas Chandra Nag6,
  9. Kunzang Chosdol7,
  10. Seema Sen8,
  11. Seema Kashyap1
  1. 1Ocular Pathology, All India Institute of Medical Sciences, New Delhi, Delhi, India
  2. 2Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, USA
  3. 3Pediatrics, All India Institute of Medical Sciences, New Delhi, India
  4. 4Ophthalmology, All India Institute of Medical Sciences, New Delhi, Delhi, India
  5. 5Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
  6. 6Department of Anatomy, All India Institute of Medical Sciences, New Delhi, Delhi, India
  7. 7Biochemistry, All India Institute of Medical Sciences, New Delhi, Delhi, India
  8. 8Ocular Pathology, Dr.R.P. Centre, All India Institute of Medical Sciences, New Delhi, Delhi, India
  1. Correspondence to Professor Seema Kashyap, Ocular Pathology, All India Institute of Medical Sciences, New Delhi, India; seemakashyap65{at}gmail.com

Abstract

Background Pigmentation could be a relevant prognostic factor in uveal melanoma (UM) development. Microphthalmia-associated transcription factor (MITF) regulates melanin synthesis by activating tyrosinase-related protein 2 (TYRP2) and silver protein (SILV) that induce the melanogenesis pathway. Although their oncogenic potential has been observed in various malignancies but has not been investigated in UM Asian population. Our aim is to study the ultrastructure of melanosomes and the prognostic significance of pigmentation markers such as TYRP2, MITF and SILV in UM.

Methods Transmission electron microscopy was performed to compare the ultrastructure of melanosomes in the normal choroid and UM cases. Immunoexpression of TYRP2, SILV and MITF was analysed in 82 UM samples. The mRNA expression level of all genes was measured in 70 UM cases. A statistical correlation was performed to determine the prognostic significance of all markers.

Results Premelanosomes and mature melanosomes undergoing dedifferentiation were observed in high-pigmented UM cases as compared with low-pigmented UM cases. Seventy per cent of UM cases showed high SILV expression while TYRP2 and MITF expression was present in 58% and 56% of cases, respectively. At the mRNA level, upregulation of TYRP2, SILV and MITF markers was seen in around 50% of UM cases, which was statistically significant with high pigmentation. Reduced metastatic-free survival was statistically significant with the MITF protein expression.

Conclusion Our results demonstrated that ultrastructural changes in melanosomes and high expression of TYRP2, MITF and SILV could dysregulate the melanogenesis pathway and might be responsible for the aggressive behaviour of UM.

  • Choroid
  • Pathology

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.

http://dx.doi.org/10.1136/bjo-2023-323181

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.

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    Footnotes

    • Contributors JJ executed the study and data analysis in association with SK. SK is responsible for the overall content as guarantor.The guarantor accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. MKS and LS contributed to the design and draft of the manuscript. TCN and KC helped in the experiments and coordination of the manuscript. NP, NL and RM provided the enucleated specimens. SS and SK were responsible for histopathological examination. SB provided the follow-up of the patients. All authors read and approved the final manuscript.

    • Funding Indian Council of Medical Research (ICMR), New Delhi. Senior Research Fellowship (Grant no. 3/1/2(7)/OPH/2019-NCD-11). The funding organisation participated in conducting the study of the manuscript.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.