Genomic Expression Discovery Predicts Pathways and Opposing Functions behind Phenotypes

Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19,200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192,000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes. Meningiomas appear to acquire aberrant phenotypes by disturbing the balanced expression of molecules that promote opposing functions. The findings expose interconnected genes and propose a role of genomic expression discovery in functional genomics of living systems. Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19,200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192,000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes. Meningiomas appear to acquire aberrant phenotypes by disturbing the balanced expression of molecules that promote opposing functions. The findings expose interconnected genes and propose a role of genomic expression discovery in functional genomics of living systems. The completion of the Human Genome Project combined with the development of microarray technology and recent advances in mathematical biology have set the stage for the genome-wide discovery of differential gene expression between any biological samples from any living system. The term discovery implies the extrapolation of data without the confound of pre-existing biases. This laboratory has developed a mathematical solution for discovering highly specific states of genetic expression between genetic samples (up- or down-regulated). The false discovery rate of the algorithm for microarrays that contain 19,200 CDNAs is < 0.001%. 1H. M. Fathallah-Shaykh, B. He, L.-J. Zhao, and A. Badruddin, submitted for publication. 1H. M. Fathallah-Shaykh, B. He, L.-J. Zhao, and A. Badruddin, submitted for publication. To explore the idea that genomic expression discovery predicts pathways and functions behind the biological phenotypes of living systems, we compare a tumor to its normal host organ. The expression data accurately predict activation of signaling pathways and propose that unbalanced opposing genetic functions create “aberrant” phenotypes. In addition, known molecular interactions reveal a rich network of stimulatory and inhibitory genetic interconnections.We use microarrays containing 19,200 cDNAs to profile gene expression in 10 meningiomas versus normal brain. Meningiomas are compared with normal brain, its host organ, because both tissue types contain non-tumor cells such as blood vessels and cells of lymphocytic lineage. Meningiomas comprise 15–20% of all primary intracranial tumors. They are abundantly vascular, tend to bleed during surgery, and often show ectopic calcification on computed tomagraphic (CT) scanning. Multiple meningiomas occur in association with a mutated neurofibromatosis type II tumor suppressor gene, known as merlin or schwannomin. Merlin protein appears to stabilize F-actin (2Ayerbe J. Lobato R.D. de la Cruz J. Alday R. Rivas J.J. Gomez P.A. Cabrera A. Acta Neurochir. 1999; 141: 921-932Google Scholar, 3James M.F. Manchanda N. Gonzalez-Agosti C. Hartwig J.H. Ramesh V. Biochem. J. 2002; 356: 377-386Google Scholar, 4Antinheimo J. Sankila R. Carpen O. Pukkala E. Sainio M. Jaaskelainen J. Neurology. 2002; 54: 71-76Google Scholar). Normal brain RNA was pooled from the occipital lobes of four individuals with no known neurological disease whose brains were frozen less than 3 h postmortem.EXPERIMENTAL PROCEDURESReagents—Information on the antibodies used may be obtained from the corresponding web sites: anti-β-catenin, www.upstatebiotech.com; anti-glyceraldehydes-3-phosphate dehydrogenase (G3PDH), www.trevigen.com.; anti-Akt, 2The abbreviations used are: Akt, protein kinase B; ERK, extracellular signal-regulated kinase; MAP, mitogen-activated protein; PI3K, phosphoinositide 3-kinase; EST, expressed sequence tag. anti-phospho-Akt (Ser-473), anti-p44/42 MAP kinase (ERK), and anti-phospho-p44/p42 Map kinase (Thr-202/Tyr-204, ERK-P), www.cellsignal.com.Tumors—Patients signed informed consents, and the study is approved by the Institutional Review Boards of Rush University and Cook County Hospital. Tumor samples are frozen in liquid nitrogen in the operating room. The quality of RNA is assayed by gel electrophoresis; only high quality reference and sample RNAs are processed.Microarray Experiments—All total RNA samples are analyzed in reference to a single standard obtained by pooling RNA from human occipital lobes. The latter are harvested and pooled from four individuals with no known neurological disease whose brains were frozen less than 3 h postmortem. Total RNA (5–10 μg) is reverse-transcribed and the cDNA products labeled by the amino-allyl method with switching of probes between sample and reference and hybridized to 19K gene microarrays purchased from the Ontario Cancer Institute (www.microarrays.ca). Each 19K microarray consists of two slides containing a total of 38,400 spots representing 19,200 genes laid in duplicates (19,200 spots/slide). The 19K microarray slides are scanned at 10 μmby a confocal scanner (Packard 4000XL, lifesciences.perkinelmer.com). Images are analyzed by Imagene software (www.biodiscovery.com).RESULTS AND DISCUSSIONThe results reveal that 364 genes are consistently up- or down-regulated in at least 5/10 meningiomas as compared with normal brain (Fig. 1). The genes and their differential expression are presented in Tables I-XI in supplementary information; 256 genes are either known or are ESTs homologous to known genes (Tables I-X S (supplement)). The remaining are uncharacterized ESTs (Table XI S). Tables I-VII S classify the genes based on how they may influence the biological chemistry of the cell. However, this grouping is not exclusive, because multifunctional genes belong to several classes.The findings propose several hypotheses; elevated expression of dyskerin contributes to the in meningiomas R. Scholar). of and expression of are with genomic (Table S). compared with normal brain, is in meningiomas as of a of a and of the and (Table S). activation is with expression of genes that RNA and and genes homologous to and to is with as by elevated expression of in meningiomas (Table pathways by specific at specific that expression not in protein microarrays to genes that are either by the tumor or the signaling the and II S show the expressed genes to the MAP PI3K, and signaling and how they the known molecular interactions of The expression data reveal of and in meningiomas (Table II S). of the is to to of of the protein and its to the the expression of and by the gene expression data (Fig. the activation of signaling as by of the protein in and in meningiomas as compared with normal brain (Fig. of molecules that with protein kinase and and of the and predict signaling the MAP kinase and the expression of and in meningiomas implies activation of the MAP kinase (Table II S). as by the gene expression protein the activation of the MAP kinase and pathways as by of and kinase in and meningiomas not in normal brain, (Fig. of both the MAP kinase and pathways signaling the the elevated expression of and in meningiomas (Table II S). signaling is to the in human and appear to in signaling and the molecules in II S that signaling by the rate at and between and In addition, (Table II by 2The expressed genes predict activation of signaling a how of the expressed genes the PI3K, and signaling that are or down-regulated in meningiomas as compared with normal brain are in and and stimulatory are as and in the of between the and kinase; ERK, MAP kinase; protein; PI3K, phosphoinositide 3-kinase; kinase Akt, protein kinase B. the activation of the MAP and signaling pathways in of from normal brain 1 and and meningiomas and with antibodies dehydrogenase MAP kinase and Map kinase (Thr-202/Tyr-204, is by the of and their and (Table the expression of the and and the of molecules that signaling from (Table II and (Table is in and are by the for and to the is of genes that the and (Table II S). is for and a that all are to the and belong to the of that the at is by expression of the and (Table of genes (Table II and of the tumor suppressor genes and (Table and of the genes (Table II (Table and (Table S). In addition, molecules that with and the of and tumor suppressor genes are of (Table is for the of to and of the protein and with merlin (Tables II and S). (Table and (Table with and gene, expression of may be in to a of the tumor cells (Table S). that and and that and are in meningiomas (Table S). The findings link to the biology and phenotypes of The expression of molecules in and interactions and and and and are in meningiomas than of meningiomas is likely to contain of and of than brain (Table S). In addition, the expression of the (Table and (Table II are the expression of molecules that and are in meningiomas than brain (Table S). the to is and of the that and with and are often and ectopic the show expression of the types of in S than brain. of the and and of of The extracellular of meningiomas to be as by expression of and expression of 3 than brain (Table S). and the extracellular the latter type 3 the activation of and the of is by expression of genes that and ectopic and (Table of a that by and of an of genes are in types and (Table tissue (Table (Table and (Table S). a of is the findings the idea of J. M. M. M. J. that is by of a between and meningiomas appear to a blood by molecules that blood The latter the protein S and genes that the (Table a the tumor from the (Table S). Meningiomas appear to by the and to from and the to the and the to the blood brain and the expression of to the blood brain In addition, may an the genes in Tables I-VII the genes and ESTs of Tables S are likely to in the phenotypes of meningiomas have expression states in meningiomas that are with data A. J. 2002; Scholar). of the expression states in Tables I-XI the have in by this laboratory M. L.-J. B. R. R. E. 2002; Scholar). ESTs are down-regulated in both and meningiomas and four ESTs are in both as compared with ESTs to and their genetic is an in their results the of genomic expression discovery to functional genomic expression discovery predicts activation of signaling pathways and unbalanced opposing functions behind specific phenotypes. The findings the of and balanced genetic is because of the of single genes and because a is not by a single by several genes that promote a “aberrant” function and by a of genes that a biological to be and by a of opposing molecular functions. Meningiomas this balanced expression to promote their phenotypes. genetic functions and interactions stimulatory and inhibitory (Fig. and the functions of the genes the ESTs for a of genetic may not be for an of how the genes to the mathematical of the may to the as a and to how 364 genes create the biological phenotypes 2002; Scholar, A. C. V. C. O. R. 2002; Scholar). The findings the and of discovering highly specific states of genetic The completion of the Human Genome Project combined with the development of microarray technology and recent advances in mathematical biology have set the stage for the genome-wide discovery of differential gene expression between any biological samples from any living system. The term discovery implies the extrapolation of data without the confound of pre-existing biases. This laboratory has developed a mathematical solution for discovering highly specific states of genetic expression between genetic samples (up- or down-regulated). The false discovery rate of the algorithm for microarrays that contain 19,200 CDNAs is < 0.001%. 1H. M. Fathallah-Shaykh, B. He, L.-J. Zhao, and A. Badruddin, submitted for publication. 1H. M. Fathallah-Shaykh, B. He, L.-J. Zhao, and A. Badruddin, submitted for publication. To explore the idea that genomic expression discovery predicts pathways and functions behind the biological phenotypes of living systems, we compare a tumor to its normal host organ. The expression data accurately predict activation of signaling pathways and propose that unbalanced opposing genetic functions create “aberrant” phenotypes. In addition, known molecular interactions reveal a rich network of stimulatory and inhibitory genetic use microarrays containing 19,200 cDNAs to profile gene expression in 10 meningiomas versus normal brain. Meningiomas are compared with normal brain, its host organ, because both tissue types contain non-tumor cells such as blood vessels and cells of lymphocytic lineage. Meningiomas comprise 15–20% of all primary intracranial tumors. They are abundantly vascular, tend to bleed during surgery, and often show ectopic calcification on computed tomagraphic (CT) scanning. Multiple meningiomas occur in association with a mutated neurofibromatosis type II tumor suppressor gene, known as merlin or schwannomin. Merlin protein appears to stabilize F-actin (2Ayerbe J. Lobato R.D. de la Cruz J. Alday R. Rivas J.J. Gomez P.A. Cabrera A. Acta Neurochir. 1999; 141: 921-932Google Scholar, 3James M.F. Manchanda N. Gonzalez-Agosti C. Hartwig J.H. Ramesh V. Biochem. J. 2002; 356: 377-386Google Scholar, 4Antinheimo J. Sankila R. Carpen O. Pukkala E. Sainio M. Jaaskelainen J. Neurology. 2002; 54: 71-76Google Scholar). Normal brain RNA was pooled from the occipital lobes of four individuals with no known neurological disease whose brains were frozen less than 3 h postmortem. PROCEDURESReagents—Information on the antibodies used may be obtained from the corresponding web sites: anti-β-catenin, www.upstatebiotech.com; anti-glyceraldehydes-3-phosphate dehydrogenase (G3PDH), www.trevigen.com.; anti-Akt, 2The abbreviations used are: Akt, protein kinase B; ERK, extracellular signal-regulated kinase; MAP, mitogen-activated protein; PI3K, phosphoinositide 3-kinase; EST, expressed sequence tag. anti-phospho-Akt (Ser-473), anti-p44/42 MAP kinase (ERK), and anti-phospho-p44/p42 Map kinase (Thr-202/Tyr-204, ERK-P), www.cellsignal.com.Tumors—Patients signed informed consents, and the study is approved by the Institutional Review Boards of Rush University and Cook County Hospital. Tumor samples are frozen in liquid nitrogen in the operating room. The quality of RNA is assayed by gel electrophoresis; only high quality reference and sample RNAs are processed.Microarray Experiments—All total RNA samples are analyzed in reference to a single standard obtained by pooling RNA from human occipital lobes. The latter are harvested and pooled from four individuals with no known neurological disease whose brains were frozen less than 3 h postmortem. Total RNA (5–10 μg) is reverse-transcribed and the cDNA products labeled by the amino-allyl method with switching of probes between sample and reference and hybridized to 19K gene microarrays purchased from the Ontario Cancer Institute (www.microarrays.ca). Each 19K microarray consists of two slides containing a total of 38,400 spots representing 19,200 genes laid in duplicates (19,200 spots/slide). The 19K microarray slides are scanned at 10 μmby a confocal scanner (Packard 4000XL, lifesciences.perkinelmer.com). Images are analyzed by Imagene software on the antibodies used may be obtained from the corresponding web sites: anti-β-catenin, www.upstatebiotech.com; anti-glyceraldehydes-3-phosphate dehydrogenase (G3PDH), www.trevigen.com.; anti-Akt, 2The abbreviations used are: Akt, protein kinase B; ERK, extracellular signal-regulated kinase; MAP, mitogen-activated protein; PI3K, phosphoinositide 3-kinase; EST, expressed sequence tag. anti-phospho-Akt (Ser-473), anti-p44/42 MAP kinase (ERK), and anti-phospho-p44/p42 Map kinase (Thr-202/Tyr-204, ERK-P), signed informed consents, and the study is approved by the Institutional Review Boards of Rush University and Cook County Hospital. Tumor samples are frozen in liquid nitrogen in the operating room. The quality of RNA is assayed by gel electrophoresis; only high quality reference and sample RNAs are Experiments—All total RNA samples are analyzed in reference to a single standard obtained by pooling RNA from human occipital lobes. The latter are harvested and pooled from four individuals with no known neurological disease whose brains were frozen less than 3 h postmortem. Total RNA (5–10 μg) is reverse-transcribed and the cDNA products labeled by the amino-allyl method with switching of probes between sample and reference and hybridized to 19K gene microarrays purchased from the Ontario Cancer Institute (www.microarrays.ca). Each 19K microarray consists of two slides containing a total of 38,400 spots representing 19,200 genes laid in duplicates (19,200 spots/slide). The 19K microarray slides are scanned at 10 μmby a confocal scanner (Packard 4000XL, lifesciences.perkinelmer.com). Images are analyzed by Imagene software AND DISCUSSIONThe results reveal that 364 genes are consistently up- or down-regulated in at least 5/10 meningiomas as compared with normal brain (Fig. 1). The genes and their differential expression are presented in Tables I-XI in supplementary information; 256 genes are either known or are ESTs homologous to known genes (Tables I-X S (supplement)). The remaining are uncharacterized ESTs (Table XI S). Tables I-VII S classify the genes based on how they may influence the biological chemistry of the cell. However, this grouping is not exclusive, because multifunctional genes belong to several classes.The findings propose several hypotheses; elevated expression of dyskerin contributes to the in meningiomas R. Scholar). of and expression of are with genomic (Table S). compared with normal brain, is in meningiomas as of a of a and of the and (Table S). activation is with expression of genes that RNA and and genes homologous to and to is with as by elevated expression of in meningiomas (Table pathways by specific at specific that expression not in protein microarrays to genes that are either by the tumor or the signaling the and II S show the expressed genes to the MAP PI3K, and signaling and how they the known molecular interactions of The expression data reveal of and in meningiomas (Table II S). of the is to to of of the protein and its to the the expression of and by the gene expression data (Fig. the activation of signaling as by of the protein in and in meningiomas as compared with normal brain (Fig. of molecules that with protein kinase and and of the and predict signaling the MAP kinase and the expression of and in meningiomas implies activation of the MAP kinase (Table II S). as by the gene expression protein the activation of the MAP kinase and pathways as by of and kinase in and meningiomas not in normal brain, (Fig. of both the MAP kinase and pathways signaling the the elevated expression of and in meningiomas (Table II S). signaling is to the in human and appear to in signaling and the molecules in II S that signaling by the rate at and between and In addition, (Table II by is by the of and their and (Table the expression of the and and the of molecules that signaling from (Table II and (Table is in and are by the for and to the is of genes that the and (Table II S). is for and a that all are to the and belong to the of that the at is by expression of the and (Table of genes (Table II and of the tumor suppressor genes and (Table and of the genes (Table II (Table and (Table S). In addition, molecules that with and the of and tumor suppressor genes are of (Table is for the of to and of the protein and with merlin (Tables II and S). (Table and (Table with and gene, expression of may be in to a of the tumor cells (Table S). that and and that and are in meningiomas (Table S). The findings link to the biology and phenotypes of The expression of molecules in and interactions and and and and are in meningiomas than of meningiomas is likely to contain of and of than brain (Table S). In addition, the expression of the (Table and (Table II are the expression of molecules that and are in meningiomas than brain (Table S). the to is and of the that and with and are often and ectopic the show expression of the types of in S than brain. of the and and of of The extracellular of meningiomas to be as by expression of and expression of 3 than brain (Table S). and the extracellular the latter type 3 the activation of and the of is by expression of genes that and ectopic and (Table of a that by and of an of genes are in types and (Table tissue (Table (Table and (Table S). a of is the findings the idea of J. M. M. M. J. that is by of a between and meningiomas appear to a blood by molecules that blood The latter the protein S and genes that the (Table a the tumor from the (Table S). Meningiomas appear to by the and to from and the to the and the to the blood brain and the expression of to the blood brain In addition, may an the genes in Tables I-VII the genes and ESTs of Tables S are likely to in the phenotypes of meningiomas have expression states in meningiomas that are with data A. J. 2002; Scholar). of the expression states in Tables I-XI the have in by this laboratory M. L.-J. B. R. R. E. 2002; Scholar). ESTs are down-regulated in both and meningiomas and four ESTs are in both as compared with ESTs to and their genetic is an in their results the of genomic expression discovery to functional genomic expression discovery predicts activation of signaling pathways and unbalanced opposing functions behind specific phenotypes. The findings the of and balanced genetic is because of the of single genes and because a is not by a single by several genes that promote a “aberrant” function and by a of genes that a biological to be and by a of opposing molecular functions. Meningiomas this balanced expression to promote their phenotypes. genetic functions and interactions stimulatory and inhibitory (Fig. and the functions of the genes the ESTs for a of genetic may not be for an of how the genes to the mathematical of the may to the as a and to how 364 genes create the biological phenotypes 2002; Scholar, A. C. V. C. O. R. 2002; Scholar). The findings the and of discovering highly specific states of genetic The results reveal that 364 genes are consistently up- or down-regulated in at least 5/10 meningiomas as compared with normal brain (Fig. 1). The genes and their differential expression are presented in Tables I-XI in supplementary information; 256 genes are either known or are ESTs homologous to known genes (Tables I-X S (supplement)). The remaining are uncharacterized ESTs (Table XI S). Tables I-VII S classify the genes based on how they may influence the biological chemistry of the cell. However, this grouping is not exclusive, because multifunctional genes belong to several The findings propose several hypotheses; elevated expression of dyskerin contributes to the in meningiomas R. Scholar). of and expression of are with genomic (Table S). compared with normal brain, is in meningiomas as of a of a and of the and (Table S). activation is with expression of genes that RNA and and genes homologous to and to is with as by elevated expression of in meningiomas (Table S). pathways by specific at specific that expression not in protein microarrays to genes that are either by the tumor or the signaling the and II S show the expressed genes to the MAP PI3K, and signaling and how they the known molecular interactions of The expression data reveal of and in meningiomas (Table II S). of the is to to of of the protein and its to the the expression of and by the gene expression data (Fig. the activation of signaling as by of the protein in and in meningiomas as compared with normal brain (Fig. of molecules that with protein kinase and and of the and predict signaling the MAP kinase and the expression of and in meningiomas implies activation of the MAP kinase (Table II S). as by the gene expression protein the activation of the MAP kinase and pathways as by of and kinase in and meningiomas not in normal brain, (Fig. of both the MAP kinase and pathways signaling the the elevated expression of and in meningiomas (Table II S). signaling is to the in human and appear to in signaling and the molecules in II S that signaling by the rate at and between and In addition, (Table II by is by the of and their and (Table the expression of the and and the of molecules that signaling from (Table II and (Table The is in and are by the for and to the is of genes that the and (Table II S). is for and a that all are to the and belong to the of that the at is by expression of the and (Table of genes (Table II and of the tumor suppressor genes and (Table and of the genes (Table II (Table and (Table S). In addition, molecules that with and the of and tumor suppressor genes are of (Table is for the of to and of the protein and with merlin (Tables II and S). (Table and (Table with and gene, The expression of may be in to a of the tumor cells (Table S). that and and that and are in meningiomas (Table S). The findings link to the biology and phenotypes of The expression of molecules in and interactions and and and and are in meningiomas than brain. The of meningiomas is likely to contain of and of than brain (Table S). In addition, the expression of the (Table and (Table II are the expression of molecules that and are in meningiomas than brain (Table S). the to is and of the that and with and are Meningiomas often and ectopic the show expression of the types of in S than brain. of the and and of of The extracellular of meningiomas to be as by expression of and expression of 3 than brain (Table S). and the extracellular the latter type 3 the activation of and the of is by expression of genes that and ectopic and (Table of a that by and of an of genes are in types and (Table tissue (Table (Table and (Table S). a of is the findings the idea of J. M. M. M. J. that is by of a between and meningiomas appear to a blood by molecules that blood The latter the protein S and genes that the (Table S). To a the tumor from the (Table S). Meningiomas appear to by the and to from and the to the and the to the blood brain and the expression of to the blood brain In addition, may an the genes in Tables I-VII the genes and ESTs of Tables S are likely to in the phenotypes of meningiomas have expression states in meningiomas that are with data A. J. 2002; Scholar). of the expression states in Tables I-XI the have in by this laboratory M. L.-J. B. R. R. E. 2002; Scholar). ESTs are down-regulated in both and meningiomas and four ESTs are in both as compared with ESTs to and their genetic is an in their functions. The results the of genomic expression discovery to functional genomic expression discovery predicts activation of signaling pathways and unbalanced opposing functions behind specific phenotypes. The findings the of and balanced genetic is because of the of single genes and because a is not by a single by several genes that promote a “aberrant” function and by a of genes that a biological to be and by a of opposing molecular functions. Meningiomas this balanced expression to promote their phenotypes. genetic functions and interactions stimulatory and inhibitory (Fig. and the functions of the genes the ESTs for a of genetic may not be for an of how the genes to the mathematical of the may to the as a and to how 364 genes create the biological phenotypes 2002; Scholar, A. C. V. C. O. R. 2002; Scholar). The findings the and of discovering highly specific states of genetic R. for a with with

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