Nucleotide Substitution in the Ectodomain of TRAIL Receptor DR4 Is Associated with Lung Cancer and Head and Neck Cancer

• Published in: Clinical cancer research Vol. 7; no. 6; pp. 1688 - 1697
• Main Authors: FISHER, Michael J, VIRMANI, Arvind K, LI WU, APLENC, Richard, HARPER, Jeffrey C, POWELL, Steven M, REBBECK, Timothy R, SIDRANSKY, David, GAZDAR, Adi F, EL-DEIRY, Wafik S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-06-2001
• Subjects: Adenine - chemistry; Adenocarcinoma - ethnology; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adult; African Continental Ancestry Group; Age Factors; Aged; Aged, 80 and over; Alleles; Amino Acid Sequence; Apoptosis Regulatory Proteins; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - ethnology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Case-Control Studies; Chromosomes, Human, Pair 8; European Continental Ancestry Group; Exons; Female; Guanine - chemistry; Head and Neck Neoplasms - ethnology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Heterozygote; Homozygote; Humans; Introns; Ligands; Lung Neoplasms - ethnology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Male; Medical sciences; Membrane Glycoproteins - chemistry; Middle Aged; Models, Genetic; Molecular Sequence Data; Mutation, Missense; Pneumology; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Protein Structure, Tertiary; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - chemistry; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Sequence Homology, Amino Acid; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - chemistry; Tumors of the respiratory system and mediastinum; Tumoral tissue; Biological marker; Bronchopulmonary; Specificity; Substitution; Predisposition; Head and neck; Bronchus disease; ENT disease; Tumor suppressor gene; Biological receptor; Human; Lung disease; Squamous cell carcinoma; Nucleotide sequence; Respiratory disease; Gene organization; Malignant tumor; In vitro; Allele; Tumor necrosis factor-related apoptosis-inducing ligand; Risk factor; Loss of heterozygosity; Nucleotide; Mutation; Molecular domain
• ISSN: 1078-0432; 1557-3265

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 (χ 2 = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (χ 2 = 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 (χ 2 = 8.6, P = 0.003 and χ 2 = 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.