Objective Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management.
Methods Genetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed.
Results High-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20–89) with the two patients <45 years of age showing highest intratumour heterogeneity. TP53 was altered at VAF >22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance (KIT S821F, KIT T670I, RAS mutations at codons 12 and 13).
Conclusion We demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.
- cutaneous squamous cell carcinoma
- genetic heterogeneity
- head and neck
- targeted therapy
Statistics from Altmetric.com
Handling editor Runjan Chetty.
Presented at This work has been presented in poster form in the Head and Neck section at the United States and Canadian Academy of Pathologists meeting in Vancouver, Canada in March 2018.
Contributors All authors contributed to writing the submitted version of the manuscript. BY, RG and JC conceived the study. SK isolated performed laboratory procedures for data generation.BY analysed the genetic data and created Figure 3. CZ created Table 1 and Figure 2.
Funding Philanthropic funding from the O’Sullivan Family, ICAP, Tag Family and David Paradice. This study would not have been possible without their generous donations and support.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval HREC Reference number: HREC/15/RPAH/266. Project title: 'Understanding the molecular and genetic changes that lead to metastasis in cutaneous SCC'. Protocol number: X15-0203.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.