Genetic alterations of protein-o-mannosyltransferase-1 in glioneuronal and glial brain tumors with subarachnoid spread

• Published in: Neuropathology 2009-04, Vol.29 (2), p.116-124
• Main Authors: Snoei, Julia, Urbach, Horst, Engels, Gudrun, Fassunke, Jana, Von Lehe, Marec, Becker, Albert J., Majores, Michael
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Brain Neoplasms - enzymology; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Child; Child, Preschool; Female; glioma; Glioma - enzymology; Glioma - genetics; Glioma - pathology; Humans; laser capture microdissection; Male; Mannosyltransferases - genetics; Microdissection; Middle Aged; mutation analysis; Mutation, Missense; Polymerase Chain Reaction; Polymorphism, Genetic; protein-o-mannosyltransferase-1; Sequence Analysis, DNA; Subarachnoid Space; subarachnoid spread; Young Adult
• ISSN: 0919-6544; 1440-1789
• DOI: 10.1111/j.1440-1789.2008.00954.x

Leptomeningeal spread is a casual but conspicuous finding in both low‐ and high‐grade gliomas. We hypothesized a compromised integrity of the glia limitans‐basal lamina complex due to glycosylation defects by loss of protein‐o‐mannosyltransferase‐1 (POMT1) activity, also a well‐known feature in developmental brain disorders with leptomeningeal heterotopia. Hypothesizing it as analogous in gliomas, we have performed a comprehensive polymerase chain reaction‐single strand conformation polymorphism (PCR‐SSCP) analysis of the POMT1 gene in 41 brain tumor specimens. Each specimen was subjected to laser capture microdissection analyses to dissect: (i) subarachnoid tumor components; (ii) deeply localized tumor areas; and (iii) histologically unaffected CNS fragments. In addition, leukocyte DNA of healthy Caucasians served as controls (n = 100). Sequence alterations were found in exons 7, 9, 15 and 18. Exon 7 bore two sequence alterations, one 751C > T transition with amino acid exchange of arginine by tryptophane (Arg251Trp) (n = 12/41 in Tu vs n = 7/82 in Co) and a 752G > A transition with replacement of arginine by glutamine (Arg251Gln) (n = 3/41 in Tu vs n = 0/82 in Co) that were significantly increased in the tumor specimens compared to controls (P  A transition in exon 9 resulted in a valine to isoleucine switch (Val327Ile) (n = 6/40 in Tu vs n = 4/84 in Co). Individual specimens revealed a 1565G > A (Arg522Lys) transition in exon 15 and a 1922C > T (Ala641Val) transition in exon 18. Two gangliogliomas only revealed sequence alterations in the superficial area but not in intraparenchymal and adjacent control specimens. We conclude that a significant increase of POMT1 missense mutations may indicate a functional role in neoplastic conditions in individual tumors. Future studies will be important to evaluate a functional impact of POMT1 alterations in human brain tumors.