Poster Presentation Australasian Melanoma Conference 2026

Comparing genetic risk profiles between in situ and invasive melanoma (#311)

Marloes Helder 1 2 , Daniel Dochtermann 3 , Saiju Pyarajan 3 , Huanwei Wang 1 2 , David C Whiteman 1 2 4 , Kevin Brown 5 , Rebecca Hartman 6 , Lee Wheless 6 , Nathan Ingold 7 , Matthew H Law 1 2 4
  1. Population health, QIMR Berghofer, Brisbane, QLD, Australia
  2. Faculty of health, Queensland University of Technology, Brisbane, QLD, Australia
  3. Center for Data and Computational Sciences , VA Boston Healthcare System, Boston, MA, USA
  4. School of public health, University of Queensland, Brisbane, QLD, Australia
  5. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  6. VA Boston Healthcare System, Boston, MA, USA
  7. Cancer Research, QIMR Berghofer, Brisbane, QLD, Australia

Over the past five decades, melanoma incidence has risen steadily in fair-skinned populations. In situ melanoma is confined to the epidermis, whereas invasive melanoma penetrates into the dermis and can metastasise. For invasive melanoma, survival is strongly inversely related to tumour depth. Although in situ melanoma can act as a precursor, many lesions remain indolent and may never progress, potentially influenced by germline genetic factors. With increased screening, the incidence of in situ melanoma has risen more rapidly than invasive disease, with over two-thirds of melanomas in Queensland, Australia, now classified as in situ. This underscores the importance of accurately distinguishing between the two, as identifying the more harmful invasive tumours is critical. Genome-wide association studies (GWAS) can help differentiate their genetic profiles. In this study, we compare the genetic profile of in situ and invasive melanoma by extending our existing meta-analysis from Ingold et al. (2024) to include new data from the Million Veterans Program (in situ=3,998, invasive=4,572, controls=414,252) and All of Us (in situ=578, invasive=2,400, controls=414,252), an increase of 56% and 40% of in situ and invasive cases respectively.

GWAS were performed within each cohort and combined with the prior individual studies to improve statistical power. This approach enables more precise estimates of heritability for both phenotypes and their genetic correlation. The proportion of trait variance captured by simple nucleotide polymorphisms (SNP heritability) included in the GWAS was 0.38% [95% confidence interval 0.0022, 0.0054, p < 0.0001] for in situ melanoma and 0.80% [95% C.I. 0.0047, 0.011, p < 0.0001] for invasive melanoma. Genetic correlation refers to the extent to which two traits share common genetic influences, indicating whether the same genetic factors affect both traits. The genetic correlation between the two traits was strongly non-zero (p < 0.0001) and had confidence intervals that spanned 1 (0.91, 95% C.I. 0.80-1.03). This suggests that the majority, and potentially all, genetic variation are in common. Future work will include assessment of an individual’s cumulative genetic risk to develop in situ and invasive melanoma, which has potential to improve risk stratification for invasive melanoma.