A novel MECA3 region in human 3p21.3 harboring putative tumor suppressor genes and oncogenes

Braga E., Loginov W., Khodyrev D., Pronina I., Kazubskaya T., Bogatyrova O., Kashuba V.I., Senchenko V.N., Klein G., Lerman M.I., Kisselev L.L., Zabarovsky E.R.

Background: Human chromosome arm 3p is often affected in various epithelial tumors, and several tumor suppressor genes were recently identified in this region. The most affected is 3p21 region that is 50–100% rearranged in more than 30 types of malignancies, mostly in epithelial cancers: lung, breast, ovarian, cervical, kidney, head and neck, nasopharyngeal, colon etc. These cancers are responsible for 90% of cancer deaths. Aim: To perform the detailed analysis of 3p (especially 3p21 region) to discover novel potential oncogenes and/or tumor suppressors. Methods: To find novel “hot spots” and genes involved in major cancers, dense 3p microsatellite markers (altogether 24 ) were allelotyped in four epithelial carcinomas (272 patients in total): breast (BC), renal cell (RCC), non-small cell lung (NSCLC) and epithelial ovarian (EOC) cancers. Results: As a main result, a novel region, frequently affected in BC, RCC, NSCLC and EOC was localized between markers D3S2409 and D3S3667 in the 3p21.3. This region (MECA3, major epithelial cancers affected region No. 3) covers numerous UniGene clusters, including genes involved in vital cell functions and carcinogenesis (e.g. MST1, MSTR1/RON, GPX1 and RHOA). The homozygous deletions were detected in the GPX1 in RCC (12%, 6 of 50 cases) and BC (1 of 37 cases). At the same time, amplifications and multiplications within the RHOA putative oncogene were identified in BC and RCC. Conclusions: The data suggest that genes with potential oncogenic features are located in the close proximity to putative tumor suppressor gene(s) (TSG(s)) in the MECA3. Multiplication of the RHOA was not reported before. Significant correlation of allelic alterations in the, AP20, MECA3 and LUCA regions with tumor progression was found for some common histological tumor subtypes (e.g. clear cell RCC, and serous EOC).

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