The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: Identification and evaluation of the resident candidate tumor suppressor genes

Michael I. Lerman, John D. Minna, Yoshitaka Sekido, Scott Bader, David Burbee, Kwun Fong, Eva Forgacs, Boning Gao, Harold Garner, Adi F. Gazdar, Luc Girard, Craig Kamibayashi, Masashi Kondo, Ashwini Pande, Alex Persemlidis, Vivek Ramalingam, Dwight Randle, Yoshio Tomizawa, Arvind Virmani, Ivan WistubaGrace Zeng, Donia Macartney, Sofia Honorio, Eamonn Maher, Farida Latif, Vladimir Kashuba, Alexei Protopopov, Jingfeng Li, George Klein, Eugene Zabarovsky, Fuh Mei Duh, Ming Hui Wei, Laura Geil, Igor Kuzmin, Sergei Ivanov, Debora Angeloni, Alla Ivanova, Bert Zbar, Bruce E. Johnson

Research output: Contribution to journalArticle

493 Citations (Scopus)

Abstract

We used overlapping and nested homozygous deletions, contig building, genomic sequencing, and physical and transcript mapping to further define a ∼630-kb lung cancer homozygous deletion region harboring one or more tumor suppressor genes (TSGs) on chromosome 3p21.3. This location was identified through somatic genetic mapping in tumors, cancer cell lines, and premalignant lesions of the lung and breast, including the discovery of several homozygous deletions. The combination of molecular manual methods and computational predictions permitted us to detect, isolate, characterize, and annotate a set of 25 genes that likely constitute the complete set of protein-coding genes residing in this ∼630-kb sequence. A subset of 19 of these genes was found within the deleted overlap region of ∼370-kb. This region was further subdivided by a nesting 200-kb breast cancer homozygous deletion into two gene sets: 8 genes lying in the proximal ∼120-kb segment and 11 genes lying in the distal ∼250-kb segment. These 19 genes were analyzed extensively by computational methods and were tested by manual methods for loss of expression and mutations in lung cancers to identify candidate TSGs from within this group. Four genes showed loss-of-expression or reduced mRNA levels in non-small cell lung cancer (CACNA2D2/α2δ-2, SEMA3B [formerly SEMA(V), BLU, and HYAL1] or small cell lung cancer (SEMA3B, BLU, and HYAL1) cell lines. We found six of the genes to have two or more amino acid sequence-altering mutations including BLU, NPRL2/Gene21, FUS1, HYAL1, FUS2, and SEMA3B. However, none of the 19 genes tested for mutation showed a frequent (>10%) mutation rate in lung cancer samples. This led us to exclude several of the genes in the region as classical tumor suppressors for sporadic lung cancer. On the other hand, the putative lung cancer TSG in this location may either be inactivated by tumor-acquired promoter hypermethylation or belong to the novel class of haploinsufficient genes that predispose to cancer in a hemizygous (1/2) state but do not show a second mutation in the remaining wild-type allele in the tumor. We discuss the data in the context of novel and classic cancer gene models as applied to lung carcinogenesis. Further functional testing of the critical genes by gene transfer and gene disruption strategies should permit the identification of the putative lung cancer TSG(s), LUCA. Analysis of the ∼630-kb sequence also provides an opportunity to probe and understand the genomic structure, evolution, and functional organization of this relatively gene-rich region.

Original languageEnglish
Pages (from-to)6116-6133
Number of pages18
JournalCancer Research
Volume60
Issue number21
Publication statusPublished - 01-11-2000

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Human Chromosomes
Tumor Suppressor Genes
Lung Neoplasms
Genes
Mutation
Neoplasms
Lung
Neoplasm Genes
Small Cell Lung Carcinoma
Mutation Rate
Tumor Cell Line
Non-Small Cell Lung Carcinoma
Carcinogens
Amino Acid Sequence
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lerman, M. I., Minna, J. D., Sekido, Y., Bader, S., Burbee, D., Fong, K., ... Johnson, B. E. (2000). The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: Identification and evaluation of the resident candidate tumor suppressor genes. Cancer Research, 60(21), 6116-6133.
Lerman, Michael I. ; Minna, John D. ; Sekido, Yoshitaka ; Bader, Scott ; Burbee, David ; Fong, Kwun ; Forgacs, Eva ; Gao, Boning ; Garner, Harold ; Gazdar, Adi F. ; Girard, Luc ; Kamibayashi, Craig ; Kondo, Masashi ; Pande, Ashwini ; Persemlidis, Alex ; Ramalingam, Vivek ; Randle, Dwight ; Tomizawa, Yoshio ; Virmani, Arvind ; Wistuba, Ivan ; Zeng, Grace ; Macartney, Donia ; Honorio, Sofia ; Maher, Eamonn ; Latif, Farida ; Kashuba, Vladimir ; Protopopov, Alexei ; Li, Jingfeng ; Klein, George ; Zabarovsky, Eugene ; Duh, Fuh Mei ; Wei, Ming Hui ; Geil, Laura ; Kuzmin, Igor ; Ivanov, Sergei ; Angeloni, Debora ; Ivanova, Alla ; Zbar, Bert ; Johnson, Bruce E. / The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3 : Identification and evaluation of the resident candidate tumor suppressor genes. In: Cancer Research. 2000 ; Vol. 60, No. 21. pp. 6116-6133.
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abstract = "We used overlapping and nested homozygous deletions, contig building, genomic sequencing, and physical and transcript mapping to further define a ∼630-kb lung cancer homozygous deletion region harboring one or more tumor suppressor genes (TSGs) on chromosome 3p21.3. This location was identified through somatic genetic mapping in tumors, cancer cell lines, and premalignant lesions of the lung and breast, including the discovery of several homozygous deletions. The combination of molecular manual methods and computational predictions permitted us to detect, isolate, characterize, and annotate a set of 25 genes that likely constitute the complete set of protein-coding genes residing in this ∼630-kb sequence. A subset of 19 of these genes was found within the deleted overlap region of ∼370-kb. This region was further subdivided by a nesting 200-kb breast cancer homozygous deletion into two gene sets: 8 genes lying in the proximal ∼120-kb segment and 11 genes lying in the distal ∼250-kb segment. These 19 genes were analyzed extensively by computational methods and were tested by manual methods for loss of expression and mutations in lung cancers to identify candidate TSGs from within this group. Four genes showed loss-of-expression or reduced mRNA levels in non-small cell lung cancer (CACNA2D2/α2δ-2, SEMA3B [formerly SEMA(V), BLU, and HYAL1] or small cell lung cancer (SEMA3B, BLU, and HYAL1) cell lines. We found six of the genes to have two or more amino acid sequence-altering mutations including BLU, NPRL2/Gene21, FUS1, HYAL1, FUS2, and SEMA3B. However, none of the 19 genes tested for mutation showed a frequent (>10{\%}) mutation rate in lung cancer samples. This led us to exclude several of the genes in the region as classical tumor suppressors for sporadic lung cancer. On the other hand, the putative lung cancer TSG in this location may either be inactivated by tumor-acquired promoter hypermethylation or belong to the novel class of haploinsufficient genes that predispose to cancer in a hemizygous (1/2) state but do not show a second mutation in the remaining wild-type allele in the tumor. We discuss the data in the context of novel and classic cancer gene models as applied to lung carcinogenesis. Further functional testing of the critical genes by gene transfer and gene disruption strategies should permit the identification of the putative lung cancer TSG(s), LUCA. Analysis of the ∼630-kb sequence also provides an opportunity to probe and understand the genomic structure, evolution, and functional organization of this relatively gene-rich region.",
author = "Lerman, {Michael I.} and Minna, {John D.} and Yoshitaka Sekido and Scott Bader and David Burbee and Kwun Fong and Eva Forgacs and Boning Gao and Harold Garner and Gazdar, {Adi F.} and Luc Girard and Craig Kamibayashi and Masashi Kondo and Ashwini Pande and Alex Persemlidis and Vivek Ramalingam and Dwight Randle and Yoshio Tomizawa and Arvind Virmani and Ivan Wistuba and Grace Zeng and Donia Macartney and Sofia Honorio and Eamonn Maher and Farida Latif and Vladimir Kashuba and Alexei Protopopov and Jingfeng Li and George Klein and Eugene Zabarovsky and Duh, {Fuh Mei} and Wei, {Ming Hui} and Laura Geil and Igor Kuzmin and Sergei Ivanov and Debora Angeloni and Alla Ivanova and Bert Zbar and Johnson, {Bruce E.}",
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Lerman, MI, Minna, JD, Sekido, Y, Bader, S, Burbee, D, Fong, K, Forgacs, E, Gao, B, Garner, H, Gazdar, AF, Girard, L, Kamibayashi, C, Kondo, M, Pande, A, Persemlidis, A, Ramalingam, V, Randle, D, Tomizawa, Y, Virmani, A, Wistuba, I, Zeng, G, Macartney, D, Honorio, S, Maher, E, Latif, F, Kashuba, V, Protopopov, A, Li, J, Klein, G, Zabarovsky, E, Duh, FM, Wei, MH, Geil, L, Kuzmin, I, Ivanov, S, Angeloni, D, Ivanova, A, Zbar, B & Johnson, BE 2000, 'The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: Identification and evaluation of the resident candidate tumor suppressor genes', Cancer Research, vol. 60, no. 21, pp. 6116-6133.

The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3 : Identification and evaluation of the resident candidate tumor suppressor genes. / Lerman, Michael I.; Minna, John D.; Sekido, Yoshitaka; Bader, Scott; Burbee, David; Fong, Kwun; Forgacs, Eva; Gao, Boning; Garner, Harold; Gazdar, Adi F.; Girard, Luc; Kamibayashi, Craig; Kondo, Masashi; Pande, Ashwini; Persemlidis, Alex; Ramalingam, Vivek; Randle, Dwight; Tomizawa, Yoshio; Virmani, Arvind; Wistuba, Ivan; Zeng, Grace; Macartney, Donia; Honorio, Sofia; Maher, Eamonn; Latif, Farida; Kashuba, Vladimir; Protopopov, Alexei; Li, Jingfeng; Klein, George; Zabarovsky, Eugene; Duh, Fuh Mei; Wei, Ming Hui; Geil, Laura; Kuzmin, Igor; Ivanov, Sergei; Angeloni, Debora; Ivanova, Alla; Zbar, Bert; Johnson, Bruce E.

In: Cancer Research, Vol. 60, No. 21, 01.11.2000, p. 6116-6133.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3

T2 - Identification and evaluation of the resident candidate tumor suppressor genes

AU - Lerman, Michael I.

AU - Minna, John D.

AU - Sekido, Yoshitaka

AU - Bader, Scott

AU - Burbee, David

AU - Fong, Kwun

AU - Forgacs, Eva

AU - Gao, Boning

AU - Garner, Harold

AU - Gazdar, Adi F.

AU - Girard, Luc

AU - Kamibayashi, Craig

AU - Kondo, Masashi

AU - Pande, Ashwini

AU - Persemlidis, Alex

AU - Ramalingam, Vivek

AU - Randle, Dwight

AU - Tomizawa, Yoshio

AU - Virmani, Arvind

AU - Wistuba, Ivan

AU - Zeng, Grace

AU - Macartney, Donia

AU - Honorio, Sofia

AU - Maher, Eamonn

AU - Latif, Farida

AU - Kashuba, Vladimir

AU - Protopopov, Alexei

AU - Li, Jingfeng

AU - Klein, George

AU - Zabarovsky, Eugene

AU - Duh, Fuh Mei

AU - Wei, Ming Hui

AU - Geil, Laura

AU - Kuzmin, Igor

AU - Ivanov, Sergei

AU - Angeloni, Debora

AU - Ivanova, Alla

AU - Zbar, Bert

AU - Johnson, Bruce E.

PY - 2000/11/1

Y1 - 2000/11/1

N2 - We used overlapping and nested homozygous deletions, contig building, genomic sequencing, and physical and transcript mapping to further define a ∼630-kb lung cancer homozygous deletion region harboring one or more tumor suppressor genes (TSGs) on chromosome 3p21.3. This location was identified through somatic genetic mapping in tumors, cancer cell lines, and premalignant lesions of the lung and breast, including the discovery of several homozygous deletions. The combination of molecular manual methods and computational predictions permitted us to detect, isolate, characterize, and annotate a set of 25 genes that likely constitute the complete set of protein-coding genes residing in this ∼630-kb sequence. A subset of 19 of these genes was found within the deleted overlap region of ∼370-kb. This region was further subdivided by a nesting 200-kb breast cancer homozygous deletion into two gene sets: 8 genes lying in the proximal ∼120-kb segment and 11 genes lying in the distal ∼250-kb segment. These 19 genes were analyzed extensively by computational methods and were tested by manual methods for loss of expression and mutations in lung cancers to identify candidate TSGs from within this group. Four genes showed loss-of-expression or reduced mRNA levels in non-small cell lung cancer (CACNA2D2/α2δ-2, SEMA3B [formerly SEMA(V), BLU, and HYAL1] or small cell lung cancer (SEMA3B, BLU, and HYAL1) cell lines. We found six of the genes to have two or more amino acid sequence-altering mutations including BLU, NPRL2/Gene21, FUS1, HYAL1, FUS2, and SEMA3B. However, none of the 19 genes tested for mutation showed a frequent (>10%) mutation rate in lung cancer samples. This led us to exclude several of the genes in the region as classical tumor suppressors for sporadic lung cancer. On the other hand, the putative lung cancer TSG in this location may either be inactivated by tumor-acquired promoter hypermethylation or belong to the novel class of haploinsufficient genes that predispose to cancer in a hemizygous (1/2) state but do not show a second mutation in the remaining wild-type allele in the tumor. We discuss the data in the context of novel and classic cancer gene models as applied to lung carcinogenesis. Further functional testing of the critical genes by gene transfer and gene disruption strategies should permit the identification of the putative lung cancer TSG(s), LUCA. Analysis of the ∼630-kb sequence also provides an opportunity to probe and understand the genomic structure, evolution, and functional organization of this relatively gene-rich region.

AB - We used overlapping and nested homozygous deletions, contig building, genomic sequencing, and physical and transcript mapping to further define a ∼630-kb lung cancer homozygous deletion region harboring one or more tumor suppressor genes (TSGs) on chromosome 3p21.3. This location was identified through somatic genetic mapping in tumors, cancer cell lines, and premalignant lesions of the lung and breast, including the discovery of several homozygous deletions. The combination of molecular manual methods and computational predictions permitted us to detect, isolate, characterize, and annotate a set of 25 genes that likely constitute the complete set of protein-coding genes residing in this ∼630-kb sequence. A subset of 19 of these genes was found within the deleted overlap region of ∼370-kb. This region was further subdivided by a nesting 200-kb breast cancer homozygous deletion into two gene sets: 8 genes lying in the proximal ∼120-kb segment and 11 genes lying in the distal ∼250-kb segment. These 19 genes were analyzed extensively by computational methods and were tested by manual methods for loss of expression and mutations in lung cancers to identify candidate TSGs from within this group. Four genes showed loss-of-expression or reduced mRNA levels in non-small cell lung cancer (CACNA2D2/α2δ-2, SEMA3B [formerly SEMA(V), BLU, and HYAL1] or small cell lung cancer (SEMA3B, BLU, and HYAL1) cell lines. We found six of the genes to have two or more amino acid sequence-altering mutations including BLU, NPRL2/Gene21, FUS1, HYAL1, FUS2, and SEMA3B. However, none of the 19 genes tested for mutation showed a frequent (>10%) mutation rate in lung cancer samples. This led us to exclude several of the genes in the region as classical tumor suppressors for sporadic lung cancer. On the other hand, the putative lung cancer TSG in this location may either be inactivated by tumor-acquired promoter hypermethylation or belong to the novel class of haploinsufficient genes that predispose to cancer in a hemizygous (1/2) state but do not show a second mutation in the remaining wild-type allele in the tumor. We discuss the data in the context of novel and classic cancer gene models as applied to lung carcinogenesis. Further functional testing of the critical genes by gene transfer and gene disruption strategies should permit the identification of the putative lung cancer TSG(s), LUCA. Analysis of the ∼630-kb sequence also provides an opportunity to probe and understand the genomic structure, evolution, and functional organization of this relatively gene-rich region.

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