High-resolution profiling of an 11 Mb segment of human chromosome 22 in sporadic schwannoma using array-CGH.
Previous low-resolution schwannoma studies have reported diverse frequencies (30-80%) of 22q deletions, involving the neurofibromatosis-2 tumor suppressor (NF2) gene. We constructed an array spanning 11 million base pairs of 22q encompassing the NF2 gene, with 100% coverage and an average resolution of 58 kb. Moreover, the 220 kb genomic sequence encompassing the NF2 gene was covered by 13 cosmids to further enhance the resolution of analysis. The rationale of this array-CGH study was to map and size 22q deletions around the NF2 gene in sporadic schwannoma using a reliable method with maximal resolution. We studied tumor and constitutional DNA from 47 patients and detected heterozygous deletions in 21 (45%) tumors, which could be classified into three profiles. The predominant profile (12/21) was a continuous deletion of the 11 Mb segment, consistent with monosomy 22. The second profile, comprising five schwannomas, was also in agreement with a continuous 11 Mb heterozygous deletion. However, these displayed a distinctly different level of deletion when compared to the first profile, suggesting a considerable amount of normal tissue in the tumor samples. This is the first report demonstrating the sensitivity of array-CGH to discriminate such samples. The third profile was composed of four cases displaying interstitial deletions of various sizes. Two of these did not encompass the NF2 locus, which further emphasize the importance of other loci in schwannoma development. This is the first high-resolution study performed on a large series of tumors, using an array continuously covering 1/3 of a human chromosome. Our findings warrant further studies of an extended tumor series on a full 22q genomic array, to better define additional, putative 22q-located loci important for schwannoma development. Our array also provides a new diagnostic tool for analysis of NF2 gene deletions in patients affected with neurofibromatosis-2.
Mantripragada
Kiran K
KK
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
Buckley
Patrick G
PG
Benetkiewicz
Magdalena
M
De Bustos
Cecilia
C
Hirvelä
Carina
C
Jarbo
Caroline
C
Bruder
Carl E G
CE
Wensman
Helena
H
Mathiesen
Tiit
T
Nyberg
Gunnar
G
Papi
Laura
L
Collins
V Peter
VP
Ichimura
Koichi
K
Evans
Gareth
G
Dumanski
Jan P
JP
D000328:Adult; D000368:Aged; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003390:Cranial Nerve Neoplasms / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009006:Monosomy; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009442:Neurilemmoma / Q000235:genetics* / Q000378:metabolism; D009464:Neuroma, Acoustic / Q000235:genetics / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010524:Peripheral Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D013127:Spinal Nerves
D009363:Neoplasm Proteins