ERCC1 (excision repair complementing defective repair in Chinese hamster.)

2006-12-01   Ulla Vogel 

National Research Centre for the Working Environment, Lersø Parkalle 105, DK-2100 Copenhagen O, Denmark

Identity

HGNC
LOCATION
19q13.32
LOCUSID
ALIAS
COFS4,RAD10,UV20
FUSION GENES

DNA/RNA

Description

14 305 bp and 10 exons

Transcription

1,101 bps

Proteins

Description

297 amino acids

Expression

ERCC1 is expressed at higher levels in tumor tissue compared to normal tissue and the expression shows more inter-individual variation among cancer patients than among healthy individuals. ERCC1 expression and ERCC1 protein levels in tumor tissue may predict response to chemotherapy. Thus, non-small cell lung cancer patients with undetectable ERCC1 protein levels in tumor tissue had a longer survival after cisplatin-based adjuvant chemotherapy than patients with detectable ERCC1 protein levels. However, high ERCC1 protein levels were associated with increased survival among patients who were not treated with chemotherapy).

Function

ERCC1 was originally identified as a gene that complemented a certain DNA repair defective Chinese Hamster Ovary cells (CHO) UV20. ERCC1 forms a heterodimer with XPF (also called ERCC4) to form the endonuclease which makes the 5 incision during nucleotide excision repair.

ERCC1 mRNA levels in lymphocytes correlate positively with DNA repair capacity measured by host cell reactivation. ERCC1 mRNA levels correlate closely with XPD, OGG1 and RAI mRNA levels in lymphocytes.

In case-control studies of lung cancer patients, lung cancer patients were shown to have lower mRNA levels and lower DNA repair capacity than healthy controls. This was also found in a case-control study of head and neck cancer. However, in a prospective study of lung cancer, persons, who were later diagnosed with lung cancer did not have a lower ERCC1 mRNA level than those who did not get lung cancer, indicating that the low ERCC1 expression level observed in cancer patients may be a result of the disease rather than a cause.

ERCC1 expression seems to be inducible at least at the mRNA level. Thus, the expression of ERCC1 in human lymphocytes correlated with increased solar influx indicating that UV irradiation may induce ERCC1 expression. In mice, X-ray irradiation lead to increased ERCC1 expression in lung tissue, and ingestion of diesel exhaust particles increased ERCC1 expression in liver. This indicates that ERCC1 expression is inducible, and thus that ERCC1 expression levels may rather be a biomarker of the internal dose of DNA damage than a biomarker of DNA repair capacity or a mix of the two.

Mutations

Note

One of the most frequently studied polymorphisms in ERCC1 is ERCC1 Asn118Asn (rs11615). Homozygous carriers of the haplotype ERCC1 Asn118AsnA, ASE-1 G-21AG, PPP1R13L IVS1 A4364GA have been shown to be at increased risk of breast cancer and lung cancer.
The ERCC1 Asn118Asn polymorphism was found not to correlate with mRNA levels.
ERCC1 C8092A (rs3212986) was found to interact with smoking in relation to risk of lung cancer in a large case-control study. ERCC1 C8092A was found not to correlate with mRNA levels in peripheral blood cells.

Implicated in

Entity name
Breast cancer
Prognosis
Thus, women who were homozygous carriers of the haplotype had a 9.5-fold higher risk of breast cancer before 55 years of age than women who were not homozygous carriers. Older women and heterozygous carriers were not at an increased risk of breast cancer.
Entity name
Lung cancer
Disease
Homozygous carriers of the haplotype were found to be at 4.9-fold increased risk of lung cancer in the age interval 50-55 years. The association was stronger among women than among men, although the difference was not statistically significant. In subsequent study including more cases and a larger comparison group, a statistically significant difference between genders was found. Furthermore, it was found that the haplotype interacts with smoking intensity. Thus, among women, who were carriers of the haplotype, additional smoking at high smoking intensity (>20 cigarettes/day) was associated with increased lung cancer risk. This was not seen among women who were not homozygous carriers of the haplotype or among men.

The haplotype was not associated with risk of testis cancer or with risk of colorectal adenomas or colorectal cancer. Furthermore, the haplotype was not associated with risk of basal cell carcinoma among older persons (>60 years).These results indicate that the haplotype may be associated with risk of cancer primarily among young and middle aged persons and that it may be specific for women.

Entity name
Leukemia and bladder cancer
Disease
The variant allele of ERCC1 Asn118Asn has also been combined with the polymorphisms XPD Asp312Asn and XPD Lys752Gln in haplotype analysis. Here, the haplotype GAT was associated with increased risk of leukemia and bladder cancer among non-smokers and the ACC haplotype was associated with lowered risk of bladder cancer.
Entity name
Colorectal cancer, small cell lung cancer, and non small cell lung cancer
Disease
Carriers of the variant allele of ERCC1 Asn118Asn were found to have a worse prognosis of colorectal cancer, small cell lung cancer and non-small cell lung cancer, whereas no association with risk of colorectal cancer has been found.

Bibliography

Pubmed IDLast YearTitleAuthors
109109542000Reduced expression levels of nucleotide excision repair genes in lung cancer: a case-control analysis.Cheng L et al
80403251994Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy.Dabholkar M et al
129199632003DNA adduct formation and oxidative stress in colon and liver of Big Blue rats after dietary exposure to diesel particles.Dybdahl M et al
152772582004Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer.Isla D et al
158858922005Polymorphisms in RAI and in genes of nucleotide and base excision repair are not associated with risk of testicular cancer.Laska MJ et al
76576721995Human DNA repair excision nuclease. Analysis of the roles of the subunits involved in dual incisions by using anti-XPG and anti-ERCC1 antibodies.Matsunaga T et al
163083132006DNA repair polymorphisms and cancer risk in non-smokers in a cohort study.Matullo G et al
162843802005Polymorphisms/haplotypes in DNA repair genes and smoking: a bladder cancer case-control study.Matullo G et al
166090222006Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer.Moreno V et al
127710342003A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of post-menopausal breast cancer before age 55.Nexø BA et al
169571452006DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.Olaussen KA et al
75593821995Purification and characterization of the XPF-ERCC1 complex of human DNA repair excision nuclease.Park CH et al
162243972003ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy.Park DJ et al
129199622003Oxidative DNA damage and defence gene expression in the mouse lung after short-term exposure to diesel exhaust particles by inhalation.Risom L et al
151405442004Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy.Ryu JS et al
169140272006Increased mRNA expression levels of ERCC1, OGG1 and RAI in colorectal adenomas and carcinomas.Saebø M et al
168179482006Effects of polymorphisms in ERCC1, ASE-1 and RAI on the risk of colorectal carcinomas and adenomas: a case control study.Skjelbred CF et al
39194541985Correction of a nucleotide-excision-repair mutation by human chromosome 19 in hamster-human hybrid cells.Thompson LH et al
110562912000DNA repair capacity: inconsistency between effect of over-expression of five NER genes and the correlation to mRNA levels in primary lymphocytes.Vogel U et al
147571942004Two regions in chromosome 19q13.2-3 are associated with risk of lung cancer.Vogel U et al
121891942002Inter-individual variation, seasonal variation and close correlation of OGG1 and ERCC1 mRNA levels in full blood from healthy volunteers.Vogel U et al
160546572006ERCC1, XPD and RAI mRNA levels in lymphocytes are not associated with lung cancer risk in a prospective study of Danes.Vogel U et al
159365902005Effect of polymorphisms in XPD, RAI, ASE-1 and ERCC1 on the risk of basal cell carcinoma among Caucasians after age 50.Vogel U et al
166902072007Gene-environment interactions between smoking and a haplotype of RAI, ASE-1 and ERCC1 polymorphisms among women in relation to risk of lung cancer in a population-based study.Vogel U et al
87975731996Reduced DNA repair capacity in lung cancer patients.Wei Q et al
166798722006Effects of ERCC1 expression in peripheral blood on the risk of head and neck cancer.Yang M et al
157349772005Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer.Zhou W et al

Other Information

Locus ID:

NCBI: 2067
MIM: 126380
HGNC: 3433
Ensembl: ENSG00000012061

Variants:

dbSNP: 2067
ClinVar: 2067
TCGA: ENSG00000012061
COSMIC: ERCC1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000012061ENST00000013807P07992
ENSG00000012061ENST00000300853P07992
ENSG00000012061ENST00000300853A0A024R0Q6
ENSG00000012061ENST00000340192P07992
ENSG00000012061ENST00000423698P07992
ENSG00000012061ENST00000587888K7EJL2
ENSG00000012061ENST00000589165P07992
ENSG00000012061ENST00000589165A0A024R0Q6
ENSG00000012061ENST00000589214K7EK97
ENSG00000012061ENST00000589381K7ES46
ENSG00000012061ENST00000590701K7EMT9
ENSG00000012061ENST00000591636K7ER60
ENSG00000012061ENST00000592023K7ER89
ENSG00000012061ENST00000592083K7EP14
ENSG00000012061ENST00000592444K7EJW9

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Nucleotide excision repairKEGGko03420
Nucleotide excision repairKEGGhsa03420
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
DNA RepairREACTOMER-HSA-73894
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
Nucleotide Excision RepairREACTOMER-HSA-5696398
Global Genome Nucleotide Excision Repair (GG-NER)REACTOMER-HSA-5696399
Formation of Incision Complex in GG-NERREACTOMER-HSA-5696395
Dual Incision in GG-NERREACTOMER-HSA-5696400
Transcription-Coupled Nucleotide Excision Repair (TC-NER)REACTOMER-HSA-6781827
Dual incision in TC-NERREACTOMER-HSA-6782135
Fanconi Anemia PathwayREACTOMER-HSA-6783310
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10352palonosetronChemicalClinicalAnnotationassociatedPD29177570
PA128406956fluorouracilChemicalClinicalAnnotationassociatedPD21057378, 23314736, 28796378
PA131285527oxaliplatinChemicalClinicalAnnotationassociatedPD18347182, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 23314736, 25069034, 27498158, 29662106
PA150595617platinumChemicalClinicalAnnotationassociatedPD18347182, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 25069034, 27498158, 29662106
PA164713176Platinum compoundsChemicalClinicalAnnotationassociatedPD18347182, 19203783, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 23962907, 25069034, 27498158, 28796378, 29662106
PA166122986radiotherapyChemicalClinicalAnnotationassociatedPD25026457, 28796378
PA166170245febrile neutropeniaDiseaseClinicalAnnotationassociatedPD
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD25495407
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD18347182, 19203783, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 23962907, 25069034, 27498158, 29662106
PA443756Colonic NeoplasmsDiseaseClinicalAnnotationassociatedPD23314736
PA444101Esophageal NeoplasmsDiseaseClinicalAnnotationassociatedPD18347182, 19203783, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 23962907, 25069034, 27498158, 29662106
PA444937MesotheliomaDiseaseClinicalAnnotationassociatedPD18347182, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 25069034, 27498158, 29662106
PA444985Multiple MyelomaDiseaseClinicalAnnotationassociatedPD21435719
PA445048NauseaDiseaseClinicalAnnotationassociatedPD29177570
PA445062NeoplasmsDiseaseClinicalAnnotationassociatedPD18347182, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 25069034, 27498158, 29177570, 29662106
PA445204Ovarian NeoplasmsDiseaseClinicalAnnotationassociatedPD18347182, 19203783, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 25069034, 27498158, 29662106
PA445218Pancreatic NeoplasmsDiseaseClinicalAnnotationassociatedPD18347182, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 25069034, 27498158, 29662106
PA445503Rectal NeoplasmsDiseaseClinicalAnnotationassociatedPD25026457
PA445742Stomach NeoplasmsDiseaseClinicalAnnotationassociatedPD28796378
PA445828Testicular NeoplasmsDiseaseClinicalAnnotationassociatedPD
PA446051VomitingDiseaseClinicalAnnotationassociatedPD29177570
PA446108Colorectal NeoplasmsDiseaseClinicalAnnotationassociatedPD18347182, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 25069034, 27498158, 29662106
PA448645bleomycinChemicalClinicalAnnotationassociatedPD
PA448771capecitabineChemicalClinicalAnnotationassociatedPD25026457
PA448803carboplatinChemicalClinicalAnnotationassociatedPD18347182, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 25069034, 27498158, 29662106
PA449014cisplatinChemicalClinicalAnnotationassociatedPD18347182, 19203783, 19362955, 19786980, 21057378, 21262916, 21902499, 22026922, 22188361, 22329723, 23962907, 25069034, 27498158, 29662106
PA449165cyclophosphamideChemicalClinicalAnnotationassociatedPD19786980, 22188361
PA449383docetaxelChemicalClinicalAnnotationassociatedPD25495407
PA449412doxorubicinChemicalClinicalAnnotationassociatedPD
PA449552etoposideChemicalClinicalAnnotationassociatedPD
PA449748gemcitabineChemicalClinicalAnnotationassociatedPD
PA449809granisetronChemicalClinicalAnnotationassociatedPD29177570
PA450198leucovorinChemicalClinicalAnnotationassociatedPD21057378, 23314736
PA450761paclitaxelChemicalClinicalAnnotationassociatedPD25495407
PA451644thalidomideChemicalClinicalAnnotationassociatedPD21435719

References

Pubmed IDYearTitleCitations
146906022003ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes.139
161952372006Polymorphisms of DNA repair genes and risk of non-small cell lung cancer.112
185091812008Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial.96
172297762007Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.81
172739662007First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure.78
174010132007Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy.77
152137132004A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer.75
198055132009XPF-ERCC1 participates in the Fanconi anemia pathway of cross-link repair.72
166090222006Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer.71
218966582011Human SNM1A and XPF-ERCC1 collaborate to initiate DNA interstrand cross-link repair.71

Citation

Ulla Vogel

ERCC1 (excision repair complementing defective repair in Chinese hamster.)

Atlas Genet Cytogenet Oncol Haematol. 2006-12-01

Online version: http://atlasgeneticsoncology.org/gene/40481/ercc1