Nucleotide excision repair (NER) gene haplotypes and advanced non-small cell lung cancer (NSCLC) prognosis

S Gurubhagavatula; Wuding Zhou; S Park; D S Neuberg; T J Lynch; J C Wain; L Su; G Liu; D C Christiani

Nucleotide excision repair (NER) gene haplotypes and advanced non-small cell lung cancer (NSCLC) prognosis

S Gurubhagavatula, Wuding Zhou, S Park, D S Neuberg, T J Lynch, J C Wain, L Su, G Liu, D C Christiani

King's College London

Research output: Contribution to journal › Article › peer-review

Abstract

3040 Background: ERCC1 and ERCC2,two major components of the NER pathway, are critical to platinum chemotherapy function. We demonstrated previously that DNA repair gene single nucleotide polymorphisms (SNPs) are associated with overall survival (OS) in platinum-treated NSCLC patients. We hypothesized that NER gene haplotypes (i.e., combinations of polymorphic markers on a single chromosome segment) are associated with NSCLC OS.

METHODS: Four SNPs (ERCC1 C8092Aand C19007T; ERCC2 Asp312Asn and Lys751Gln) were genotyped in 124 stage III (61%) and IV (39%) NSCLC patients treated with platinum chemotherapy. Haplotypes were generated using Partition Ligation-Expectation Maximization algorithms.

RESULTS: Median age was 59 (32-77); 48% were female; median follow-up was 64.6 months. Median survival time (MST) was 15.7 months; by stage, MST was 29.6 (IIIA), 17.9 (IIIB), and 10.1 (IV) months. Stage was not associated with any haplotypes. Strong linkage disequilibrium was observed for the two ERCC1polymorphisms, and separately for the ERCC2polymorphisms. ERCC1 haplotype frequencies were: 25% (8092A-19007C), 15% (8092C-19007C), 59% (8092C-19007T), and 1% (8092A-19007T); ERCC2frequencies were: 7% (312Asp-751Gln), 27% (312Asn-751Gln), 62% (312Asp-751Lys), and 4% (312Asn-751Lys). The ERCC1 8092A-19007Cand ERCC2 312Asn-751Glnhaplotypes were associated with significantly decreased OS (p=0.014 and p=0.0004, respectively, logrank test, see table). The combination of high-risk haplotypes from both NER genes was also highly prognostic (p=0.002, logrank test).

CONCLUSIONS: Specific ERCC1and ERCC2haplotypes confer significantly decreased OS in platinum-treated advanced NSCLC patients. NER gene haplotypes provide prognostic information in NSCLC OS in addition to that previously reported with SNPs. Supported by NIH grants CA092824 and CA074386. [Figure: see text] No significant financial relationships to disclose.

Original language	English
Pages (from-to)	3040
Journal	Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume	22
Issue number	14_suppl
Publication status	Published - 15 Jul 2004

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@article{a64b78fa83da4f23b99105d93d08d1dd,

title = "Nucleotide excision repair (NER) gene haplotypes and advanced non-small cell lung cancer (NSCLC) prognosis",

abstract = "3040 Background: ERCC1 and ERCC2,two major components of the NER pathway, are critical to platinum chemotherapy function. We demonstrated previously that DNA repair gene single nucleotide polymorphisms (SNPs) are associated with overall survival (OS) in platinum-treated NSCLC patients. We hypothesized that NER gene haplotypes (i.e., combinations of polymorphic markers on a single chromosome segment) are associated with NSCLC OS.METHODS: Four SNPs (ERCC1 C8092Aand C19007T; ERCC2 Asp312Asn and Lys751Gln) were genotyped in 124 stage III (61%) and IV (39%) NSCLC patients treated with platinum chemotherapy. Haplotypes were generated using Partition Ligation-Expectation Maximization algorithms.RESULTS: Median age was 59 (32-77); 48% were female; median follow-up was 64.6 months. Median survival time (MST) was 15.7 months; by stage, MST was 29.6 (IIIA), 17.9 (IIIB), and 10.1 (IV) months. Stage was not associated with any haplotypes. Strong linkage disequilibrium was observed for the two ERCC1polymorphisms, and separately for the ERCC2polymorphisms. ERCC1 haplotype frequencies were: 25% (8092A-19007C), 15% (8092C-19007C), 59% (8092C-19007T), and 1% (8092A-19007T); ERCC2frequencies were: 7% (312Asp-751Gln), 27% (312Asn-751Gln), 62% (312Asp-751Lys), and 4% (312Asn-751Lys). The ERCC1 8092A-19007Cand ERCC2 312Asn-751Glnhaplotypes were associated with significantly decreased OS (p=0.014 and p=0.0004, respectively, logrank test, see table). The combination of high-risk haplotypes from both NER genes was also highly prognostic (p=0.002, logrank test).CONCLUSIONS: Specific ERCC1and ERCC2haplotypes confer significantly decreased OS in platinum-treated advanced NSCLC patients. NER gene haplotypes provide prognostic information in NSCLC OS in addition to that previously reported with SNPs. Supported by NIH grants CA092824 and CA074386. [Figure: see text] No significant financial relationships to disclose.",

author = "S Gurubhagavatula and Wuding Zhou and S Park and Neuberg, {D S} and Lynch, {T J} and Wain, {J C} and L Su and G Liu and Christiani, {D C}",

year = "2004",

month = jul,

day = "15",

language = "English",

volume = "22",

pages = "3040",

journal = "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "14_suppl",

}

TY - JOUR

T1 - Nucleotide excision repair (NER) gene haplotypes and advanced non-small cell lung cancer (NSCLC) prognosis

AU - Gurubhagavatula, S

AU - Zhou, Wuding

AU - Park, S

AU - Neuberg, D S

AU - Lynch, T J

AU - Wain, J C

AU - Su, L

AU - Liu, G

AU - Christiani, D C

PY - 2004/7/15

Y1 - 2004/7/15

N2 - 3040 Background: ERCC1 and ERCC2,two major components of the NER pathway, are critical to platinum chemotherapy function. We demonstrated previously that DNA repair gene single nucleotide polymorphisms (SNPs) are associated with overall survival (OS) in platinum-treated NSCLC patients. We hypothesized that NER gene haplotypes (i.e., combinations of polymorphic markers on a single chromosome segment) are associated with NSCLC OS.METHODS: Four SNPs (ERCC1 C8092Aand C19007T; ERCC2 Asp312Asn and Lys751Gln) were genotyped in 124 stage III (61%) and IV (39%) NSCLC patients treated with platinum chemotherapy. Haplotypes were generated using Partition Ligation-Expectation Maximization algorithms.RESULTS: Median age was 59 (32-77); 48% were female; median follow-up was 64.6 months. Median survival time (MST) was 15.7 months; by stage, MST was 29.6 (IIIA), 17.9 (IIIB), and 10.1 (IV) months. Stage was not associated with any haplotypes. Strong linkage disequilibrium was observed for the two ERCC1polymorphisms, and separately for the ERCC2polymorphisms. ERCC1 haplotype frequencies were: 25% (8092A-19007C), 15% (8092C-19007C), 59% (8092C-19007T), and 1% (8092A-19007T); ERCC2frequencies were: 7% (312Asp-751Gln), 27% (312Asn-751Gln), 62% (312Asp-751Lys), and 4% (312Asn-751Lys). The ERCC1 8092A-19007Cand ERCC2 312Asn-751Glnhaplotypes were associated with significantly decreased OS (p=0.014 and p=0.0004, respectively, logrank test, see table). The combination of high-risk haplotypes from both NER genes was also highly prognostic (p=0.002, logrank test).CONCLUSIONS: Specific ERCC1and ERCC2haplotypes confer significantly decreased OS in platinum-treated advanced NSCLC patients. NER gene haplotypes provide prognostic information in NSCLC OS in addition to that previously reported with SNPs. Supported by NIH grants CA092824 and CA074386. [Figure: see text] No significant financial relationships to disclose.

AB - 3040 Background: ERCC1 and ERCC2,two major components of the NER pathway, are critical to platinum chemotherapy function. We demonstrated previously that DNA repair gene single nucleotide polymorphisms (SNPs) are associated with overall survival (OS) in platinum-treated NSCLC patients. We hypothesized that NER gene haplotypes (i.e., combinations of polymorphic markers on a single chromosome segment) are associated with NSCLC OS.METHODS: Four SNPs (ERCC1 C8092Aand C19007T; ERCC2 Asp312Asn and Lys751Gln) were genotyped in 124 stage III (61%) and IV (39%) NSCLC patients treated with platinum chemotherapy. Haplotypes were generated using Partition Ligation-Expectation Maximization algorithms.RESULTS: Median age was 59 (32-77); 48% were female; median follow-up was 64.6 months. Median survival time (MST) was 15.7 months; by stage, MST was 29.6 (IIIA), 17.9 (IIIB), and 10.1 (IV) months. Stage was not associated with any haplotypes. Strong linkage disequilibrium was observed for the two ERCC1polymorphisms, and separately for the ERCC2polymorphisms. ERCC1 haplotype frequencies were: 25% (8092A-19007C), 15% (8092C-19007C), 59% (8092C-19007T), and 1% (8092A-19007T); ERCC2frequencies were: 7% (312Asp-751Gln), 27% (312Asn-751Gln), 62% (312Asp-751Lys), and 4% (312Asn-751Lys). The ERCC1 8092A-19007Cand ERCC2 312Asn-751Glnhaplotypes were associated with significantly decreased OS (p=0.014 and p=0.0004, respectively, logrank test, see table). The combination of high-risk haplotypes from both NER genes was also highly prognostic (p=0.002, logrank test).CONCLUSIONS: Specific ERCC1and ERCC2haplotypes confer significantly decreased OS in platinum-treated advanced NSCLC patients. NER gene haplotypes provide prognostic information in NSCLC OS in addition to that previously reported with SNPs. Supported by NIH grants CA092824 and CA074386. [Figure: see text] No significant financial relationships to disclose.

M3 - Article

C2 - 28015219

SN - 0732-183X

VL - 22

SP - 3040

JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

IS - 14_suppl

ER -

Nucleotide excision repair (NER) gene haplotypes and advanced non-small cell lung cancer (NSCLC) prognosis

Abstract

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