Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

Evaluation of clonality in lentigo maligna (#258)

Peinan Zhao 1 2 , Sophie Lim 1 3 , Nicholas Wong 4 5 , Pacman Szeto 1 2 , Trevor Wilson 6 , Helen Mitchell 7 , Ismael Vergara Correa 8 9 , Christoffer Flensburg 10 , Ian Majewski 10 , Chris McCormack 11 , Michael Henderson 11 , Tony Papenfuss 8 9 , Catriona Mclean 12 , Victoria Mar 3 13 , Mark Shackleton 1 2 4
  1. Cancer Development and Treatment Group, Department of Medicine Research Laboratories, Alfred Hospital, Monash University, Melbourne, VIC, Australia
  2. Department of Oncology, Alfred Hospital, Melbourne, VIC, Australia
  3. Victorian Melanoma Service, Alfred Hospital, Melbourne, VIC, Australia
  4. Central Clinical School, Monash University, Clayton, VIC, Australia
  5. Monash Bioinformatics Platform, Monash University, Clayton, VIC, Australia
  6. Medical Genomics Facility, Monash Health Translational Precinct , Clayton, VIC, Australia
  7. Alfred Research Alliance Sequencing Platform, Alfred Hospital, Melbourne, VIC, Australia
  8. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  9. Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  10. Division of Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  11. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  12. Department of Anatomical Pathology, Alfred Hospital, Melbourne, VIC, Australia
  13. School of Public Health and Preventative Medicine, Monash University, Clayton, VIC, Australia

Background Lentigo maligna (LM), a type of in situ melanoma, has a high rate of local recurrence.  Such recurrences might be redevelopment of inadequately excised LMs, or new primary LMs developing from distinct melanocytic clones in the same UV-damaged anatomic region (field cancerisation). Although distinguishing these possibilities has implications for patient management, they have never been formally tested. The primary objective of this project was thus to understand clonal relationships between incident LMs and their post-operative local recurrences. We also aimed to describe the mutational landscape of LM and lentigo maligna melanomas (LMMs), and identify distinguishing features of incident LMs that recur as LMMs.

Methods Formalin-fixed paraffin-embedded (FFPE) sections for LM/LMMs were laser microdissected for DNA extraction. Tumour and matched germline DNA underwent whole exome sequencing. Data were analysed to identify mutational profiles, copy number alterations and clonal relationships (SuperFreq).

Results 7 cases of incident LM with recurrent LM and 4 cases of incident LM with recurrent LMM were sequenced. Positive and negative controls for clonal relationships were also sequenced. All incident LMs were clonally related to their post-operative local recurrences.  LM/LMMs had a high mutational burden, expressed the UVR signature and were best characterised by mutations associated with melanomas arising from chronically sun-damaged skin. In addition, mutational signature of defective DNA repair and copy number alterations were also found in LM/LMM samples. There were no distinguishing features of incident LMs that recur to invasive disease.  

Conclusion The mutational landscape of LM/LMMs is typical of melanomas arising from chronic sun exposure. Genetic features typically associated with late-stage melanoma were discovered in LM/LMMs, indicating that such features can also be characteristic of early melanomagenic transformation. The local recurrence of LM primarily arises from the residual disease.

Acknowledgement This research was funded by the Australasian College of Dermatologists Scientific Research Fund.