Somatic mutations in kinetochore gene KNSTRN are associated with basal proliferating actinic keratoses and cutaneous squamous cell carcinoma

BACKGROUND: Mutations in kinetochore gene KNSTRN accelerate the development of cutaneous squamous cell carcinoma (SCC) and may correlate with different histological classifications of actinic keratosis (AKs). OBJECTIVE: To determine KNSTRN gene mutation frequency in healthy skin (HS), actinically damaged skin (ADS), in AKs with different histomorphological gradings and invasive SCCs. METHODS: All samples were histologically evaluated. AK lesions were additionally classified according to their upwards (AK I-III) and downwards (PRO I-III) directed growth pattern. Mutation analyses of all samples were performed using the Sanger method. RESULTS: With one exception, all detected mutations in KNSTRN gene showed an alanine-to-glutamate substitution at codon 40 (p.Ala40Glu). p.Ala40Glu mutation was found in 6.9% (2/29) of HS, in 16.1% (5/31) of ADS, in 18.3% (20/109) of AKs and in 30.0% (9/30) of invasive SCCs. Further stratification of AKs using the common AK classification of Rowert-Huber revealed the p.Ala40Glu mutation in 14.7% (5/43), 13.3% (4/30) and 24.4% (11/45) (AK I, II and III). In contrast, the new PRO classification showed a distribution of 3.6% (1/28) in PRO I, 21.7% (13/60) in PRO II and 28.6% (6/21) in PRO III. Mutation frequency in HS showed significant differences compared to AKs classified as PRO III and invasive SCCs (P < 0.05). In contrast, there were no statistically significant differences between HS and AKs when classified according to Rowert-Huber. CONCLUSIONS: Recurrent somatic mutation p.Ala40Glu in KNSTRN gene is associated with basal proliferating AKs in accordance with invasive SCCs. This supports the impact of basal proliferative pattern in terms of progression.