Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer

M. J. Fisher, A. K. Virmani, L. Wu, R. Aplenc, J. C. Harper, S. M. Powell, T. R. Rebbeck, David Sidransky, A. F. Gazdar, W. S. El-Deiry

Research output: Contribution to journalArticle

Abstract

Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96% of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35% in the lung cancer cell lines but only 13% in age- and race-matched controls, which was a significant increase (X2 = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (X2 = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven % of the former and 44% of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (X2 = 8.6, P = 0.003 and X2 = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies.

Original languageEnglish (US)
Pages (from-to)1688-1697
Number of pages10
JournalClinical Cancer Research
Volume7
Issue number6
StatePublished - 2001

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TNF-Related Apoptosis-Inducing Ligand Receptors
Head and Neck Neoplasms
Lung Neoplasms
Nucleotides
Alleles
Non-Small Cell Lung Carcinoma
Squamous Cell Neoplasms
Guanine
Arginine
Ligands
Chromosomes, Human, Pair 22
Cell Line
Neoplasms
Loss of Heterozygosity
Cytosine
Small Cell Lung Carcinoma
Adenine
Threonine
Tumor Suppressor Genes
DNA Sequence Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fisher, M. J., Virmani, A. K., Wu, L., Aplenc, R., Harper, J. C., Powell, S. M., ... El-Deiry, W. S. (2001). Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer. Clinical Cancer Research, 7(6), 1688-1697.

Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer. / Fisher, M. J.; Virmani, A. K.; Wu, L.; Aplenc, R.; Harper, J. C.; Powell, S. M.; Rebbeck, T. R.; Sidransky, David; Gazdar, A. F.; El-Deiry, W. S.

In: Clinical Cancer Research, Vol. 7, No. 6, 2001, p. 1688-1697.

Research output: Contribution to journalArticle

Fisher, MJ, Virmani, AK, Wu, L, Aplenc, R, Harper, JC, Powell, SM, Rebbeck, TR, Sidransky, D, Gazdar, AF & El-Deiry, WS 2001, 'Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer', Clinical Cancer Research, vol. 7, no. 6, pp. 1688-1697.
Fisher, M. J. ; Virmani, A. K. ; Wu, L. ; Aplenc, R. ; Harper, J. C. ; Powell, S. M. ; Rebbeck, T. R. ; Sidransky, David ; Gazdar, A. F. ; El-Deiry, W. S. / Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 6. pp. 1688-1697.
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abstract = "Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96{\%} of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35{\%} in the lung cancer cell lines but only 13{\%} in age- and race-matched controls, which was a significant increase (X2 = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (X2 = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven {\%} of the former and 44{\%} of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (X2 = 8.6, P = 0.003 and X2 = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies.",
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T1 - Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer

AU - Fisher, M. J.

AU - Virmani, A. K.

AU - Wu, L.

AU - Aplenc, R.

AU - Harper, J. C.

AU - Powell, S. M.

AU - Rebbeck, T. R.

AU - Sidransky, David

AU - Gazdar, A. F.

AU - El-Deiry, W. S.

PY - 2001

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N2 - Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96% of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35% in the lung cancer cell lines but only 13% in age- and race-matched controls, which was a significant increase (X2 = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (X2 = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven % of the former and 44% of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (X2 = 8.6, P = 0.003 and X2 = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies.

AB - Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96% of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35% in the lung cancer cell lines but only 13% in age- and race-matched controls, which was a significant increase (X2 = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (X2 = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven % of the former and 44% of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (X2 = 8.6, P = 0.003 and X2 = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies.

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