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

Abstract

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 Röwert‐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 Röwert‐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.

Increased Expression of KNSTRN in Lung Adenocarcinoma Predicts Poor Prognosis: A Bioinformatics Analysis Based on TCGA Data

“…Thus, a mutated KNSTRN gene, especially the p.Ser24Phe mutation, might functionally lead to disrupted chromatid cohesion in normal cells and correlated with increased aneuploidy in primary tumors and enhanced SCC development in vivo (5). Additionally, Schmitz et al recently reported that another recurrent somatic mutation "p.Ala40Glu" in the KNSTRN gene was associated with basal proliferative AK lesions and invasive carcinoma (6). Recent studies also found that altered KNSTRN expression resulted in the loss of chromatid cohesion in the noncutaneous tumor cell line HeLa cells (4,7).…”

Development and Validation of a Unique Gignature of Cancer Stemness-related Genes for Predicting the Overall survival of Colorectal Cancer Patients

“…KNSTRN, an important component of the mitotic spindle, was found to regulate chromosome segregation and anaphase onset during mitosis in cancer cells [72]. Furthermore, recent studies demonstrated that accumulation of KNSTRN mutations may be an early event in cancer development that accelerates tumor growth in cutaneous squamous cell carcinoma and melanoma [73,74]. KIF2C is an important regulator of chromosome segregation, bipolar spindle formation and microtubule depolymerization during mitosis, and it may be related with poor prognosis in non-small cell lung cancer [75].…”

Aktinische Keratosen

“…Apoptose UV-geschädigter Zellen und im Weiteren, durch die Aktivierung von Pro-Onkogenen, zu einem unkontrollierten Wachstum atypischer Keratinozyten [17]. Zusätzlich finden sich UV-induzierte Amplifikationen und aktivierende Mutationen in den Onkogenen HRAS und KNSTRN [18,19].…”