Alterations in the ATP2A2 gene in correlation with colon and lung cancer

Sarcoendoplasmic reticulum calcium transport ATPases (SERCA-type calcium pumps), proteins that accumulate calcium in the endoplasmic reticulum, play an important role in numerous signaling pathways controlling tumor growth, differentiation, and cell death. Reports that Atp2a2 (Serca2) haploinsufficient mice often developed cancer prompted us to study the involvement of the ATP2A2 gene in human cancer development. We found 13 different novel alterations of the ATP2A2 gene in 27 of 416 alleles of patients with two different types of cancer. Changes in ATP2A2 were significantly more common in patients with colon cancer (P < 0.0001, odds ratio OR = 25.3) or lung cancer (P = 0.046, OR = 8.05). The 13 alterations were missense mutations (2), intronic deletions (2), intronic insertions (1), and single-nucleotide alterations (8: two in the coding region, three in the intronic region, and three in the promoter region). We detected lost or reduced expression of ATP2A2 in all patients with alterations in the promoter region, as well as in patients with a combination of gene alterations. Our results suggest that germline alterations of ATP2A2 may predispose to lung and colon cancer and that an impaired ATP2A2 gene might be involved, directly or indirectly, as an early event in carcinogenesis.