Abstract
Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers capable of metastasizing. Proteomic analysis of cSCCs can provide insight into the biological processes responsible for metastasis, as well as future therapeutic targets and prognostic biomarkers. To identify proteins associated with development of metastasis in cSCC. A proteomic-based approach was employed on 105 completely excised, primary cSCCs, comprising 52 that had metastasized (P-M) and 53 that had not metastasized at 5years post-surgery (P-NM). Formalin-fixed, paraffin-embedded cSCCs were microdissected and subjected to proteomic profiling after one-dimensional (1D), and separately two-dimensional (2D), liquid chromatography fractionation. A discovery set of 24 P-Ms and 24 P-NMs showed 144 significantly differentially expressed proteins, including 33 proteins identified via both 1D and 2D separation, between P-Ms and P-NMs. Several differentially expressed proteins were also associated with survival in SCCs of other organs. The findings were verified by multiple reaction monitoring on six peptides from two proteins, annexin A5 (ANXA5) and dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), in the discovery group and validated on a separate cohort (n=57). Increased expression of ANXA5 and DDOST was associated with reduced time to metastasis in cSCC and decreased survival in cervical and oropharyngeal cancer. A prediction model using ANXA5 and DDOST had an area under the curve of 0·93 (confidence interval 0·83-1·00), an accuracy of 91·2% and higher sensitivity and specificity than cSCC staging systems currently in clinical use. This study highlights that increased expression of two proteins, ANXA5 and DDOST, is significantly associated with poorer clinical outcomes in cSCC.
Highlights
There is a need to undertake research into factors which contribute to more aggressive tumours11, to understand the mechanisms responsible for development of metastases in cutaneous squamous cell carcinoma (cSCC) and to identify more accurately those patients at risk of metastases
Samples were categorised as primary cSCCs that metastasised (P-M) or primary cSCCs that had not metastasised at 5 years postsurgery (P-NM), with the latter based on no evidence of metastasis during 5 years follow-up and/or patient review for another reason after 5 years in Dermatology UHS-NHSFT
This study investigated proteomic differences between P-M and P-NM cSCCs to identify proteins associated with metastasis in cSCC
Summary
The number of keratinocyte cancers in the United Kingdom is >211,120 annually, with cutaneous squamous cell carcinoma (cSCC) accounting for >44,672, constituting one of the most common types of cancer capable of metastasising. The risk of metastasis for cSCC depends on clinical and histological parameters, including site, depth of invasion, diameter, differentiation of the tumour, the presence of lymphovascular or perineural invasion, and host immunosuppression. Following surgical excision, cSCC metastasises in 16% of cases with tumour depth >6mm, and in 30% of tumours >2cm diameter. Whereas the 3-year disease specific survival rate for patients with cSCC is 85%,6 for patients with distant metastasis the median survival is 6mm, and in 30% of tumours >2cm diameter.. Staging systems assist identification of patients at greater risk of metastases after excision of primary cSCC. moderately” between patients who do and those who don’t develop cSCC metastases and onethird of patients are classified incorrectly using these staging systems.. There is a need to undertake research into factors which contribute to more aggressive tumours, to understand the mechanisms responsible for development of metastases in cSCC and to identify more accurately those patients at risk of metastases
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