Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors

Giuseppe Zardo, Maarit I. Tiirikainen, Chibo Hong, Anjan Misra, Burt G.F. Feuerstein, Stanislav Volik, Colin C. Collins, Kathleen R. Lamborn, Andrew Bollen, Daniel Pinkel, Donna G. Albertson, Joseph F. Costello

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments2 and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.

Original languageEnglish (US)
Pages (from-to)453-458
Number of pages6
JournalNature Genetics
Volume32
Issue number3
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

Fingerprint

Gene Silencing
Epigenomics
Methylation
CpG Islands
Neoplasms
Genome
Comparative Genomic Hybridization
Neoplasm Genes
Human Genome
Tumor Suppressor Genes
Brain Neoplasms
Computer Simulation
Genes
Organism Cloning
Digestion
Carcinogenesis
Chromosomes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Zardo, G., Tiirikainen, M. I., Hong, C., Misra, A., Feuerstein, B. G. F., Volik, S., ... Costello, J. F. (2002). Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nature Genetics, 32(3), 453-458. https://doi.org/10.1038/ng1007

Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. / Zardo, Giuseppe; Tiirikainen, Maarit I.; Hong, Chibo; Misra, Anjan; Feuerstein, Burt G.F.; Volik, Stanislav; Collins, Colin C.; Lamborn, Kathleen R.; Bollen, Andrew; Pinkel, Daniel; Albertson, Donna G.; Costello, Joseph F.

In: Nature Genetics, Vol. 32, No. 3, 01.11.2002, p. 453-458.

Research output: Contribution to journalArticle

Zardo, G, Tiirikainen, MI, Hong, C, Misra, A, Feuerstein, BGF, Volik, S, Collins, CC, Lamborn, KR, Bollen, A, Pinkel, D, Albertson, DG & Costello, JF 2002, 'Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors', Nature Genetics, vol. 32, no. 3, pp. 453-458. https://doi.org/10.1038/ng1007
Zardo, Giuseppe ; Tiirikainen, Maarit I. ; Hong, Chibo ; Misra, Anjan ; Feuerstein, Burt G.F. ; Volik, Stanislav ; Collins, Colin C. ; Lamborn, Kathleen R. ; Bollen, Andrew ; Pinkel, Daniel ; Albertson, Donna G. ; Costello, Joseph F. / Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. In: Nature Genetics. 2002 ; Vol. 32, No. 3. pp. 453-458.
@article{6a54c8a80c8d49d5a1acb75880b59cec,
title = "Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors",
abstract = "Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments2 and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.",
author = "Giuseppe Zardo and Tiirikainen, {Maarit I.} and Chibo Hong and Anjan Misra and Feuerstein, {Burt G.F.} and Stanislav Volik and Collins, {Colin C.} and Lamborn, {Kathleen R.} and Andrew Bollen and Daniel Pinkel and Albertson, {Donna G.} and Costello, {Joseph F.}",
year = "2002",
month = "11",
day = "1",
doi = "10.1038/ng1007",
language = "English (US)",
volume = "32",
pages = "453--458",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors

AU - Zardo, Giuseppe

AU - Tiirikainen, Maarit I.

AU - Hong, Chibo

AU - Misra, Anjan

AU - Feuerstein, Burt G.F.

AU - Volik, Stanislav

AU - Collins, Colin C.

AU - Lamborn, Kathleen R.

AU - Bollen, Andrew

AU - Pinkel, Daniel

AU - Albertson, Donna G.

AU - Costello, Joseph F.

PY - 2002/11/1

Y1 - 2002/11/1

N2 - Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments2 and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.

AB - Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments2 and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.

UR - http://www.scopus.com/inward/record.url?scp=0036844322&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036844322&partnerID=8YFLogxK

U2 - 10.1038/ng1007

DO - 10.1038/ng1007

M3 - Article

C2 - 12355068

AN - SCOPUS:0036844322

VL - 32

SP - 453

EP - 458

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -