Contrary to the recent hypothesis that S100A2 is a tumour suppressor, no somatic mutations have yet been identified. We therefore screened 90 non-small cell lung carcinoma (NSCLC) samples, initially for mutations in S100A2 and then also for mutations in P53 and K-RAS genes. Alterations were detected in 46.7% of squamous lung cancer (SCC) samples, but we detected only one novel tumour specific mutation, Q23X in squamous carcinoma. We detected four polymorphisms, two of them published for the first time (144+109 C/G and 297+75A/G) and two already published: S62N, in the coding region and related to squamous cell carcinoma (SCC), and 297+17T/C. Analysis of S100A2 expression revealed that expression in adenocarcinomas and squamous cell carcinomas is significantly different, but not related to any of the found alterations. In one tumour with S62N polymorphism, P53 and K-RAS genes were also mutated, while two tumours with the Q23X mutation have a P53 but no K-RAS mutation. To the best of our knowledge, this is the first report describing alterations in the S100A2 gene proving a relation between changes in predominantly squamous lung cancer.