Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia.
² Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia.
³ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Department of Medicine, Blacktown Hospital, Blacktown, New South Wales, Australia; Department of Medicine, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia.
⁶ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁷ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
⁸ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia. Electronic address: richard.scolyer@health.nsw.gov.au.

PMID: 36788083
DOI: 10.1016/j.modpat.2023.100099

Free article

Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets

Ismael A Vergara et al. Mod Pathol. 2023 Apr.

Free article

. 2023 Apr;36(4):100099.

doi: 10.1016/j.modpat.2023.100099. Epub 2023 Jan 10.

Authors

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia.
² Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia.
³ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Department of Medicine, Blacktown Hospital, Blacktown, New South Wales, Australia; Department of Medicine, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia.
⁶ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁷ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
⁸ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia. Electronic address: richard.scolyer@health.nsw.gov.au.

PMID: 36788083
DOI: 10.1016/j.modpat.2023.100099

Abstract

Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up.

Keywords: basal cell carcinoma; diagnosis; drivers; genomics; metastasis; pathology; therapeutic targets; treatment.

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Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets

Affiliations

Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets

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Abstract

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Medical