CyclinD1 and interleukin-1 receptor antagonist polymorphisms are associated with prognosis in neoadjuvant-treated gastric carcinoma.
OBJECTIVE
We evaluated DNA polymorphisms in genes related to DNA repair, cell-cycle control and tumour microenvironment to determine possible associations with response and survival in neoadjuvant-treated gastric cancer patients.


METHODS
One hundred and seventy eight patients who received platinum/5FU-based chemotherapy were genotyped for 10 polymorphisms in nine genes (ERCC1: Asn118Asn, C > T; ERCC1: 8092C > A; TP53: Arg72Pro, G < C; cyclinD1: Pro241Pro, G > A; STK15: Phe31Ile, A > T; VEGF: 936C > T; TNF-alpha: -308G > A; interleukin-1b (IL-1B): -511C >T; IL-1 receptor antagonist (IL-1RN): variable tandem repeat; IL-8: -251T>A). Genotypes were correlated with histopathological and clinical response and overall (OS) and progression-free survival (PFS).


RESULTS
Only the cyclinD1 genotypes were associated with clinical response (P(x)(2)=0.044). Significantly worse survival rates were noted in patients homozygous for the G-allele as compared to patients with the AG or AA genotypes of the cyclinD1 polymorphism (OS: P(log-rank) = 0.024; PFS: P(log-rank)=0.007) and in patients homozygous for the short allele compared to all other genotypes at the IL-1RN polymorphic locus (OS: P(log-rank) = 0.026; PFS: P(log-rank) = 0.013). The combination of both unfavourable genotypes demonstrated strong prognostic relevance (OS: P(log-rank) = 0.006; PFS: P(log-rank) = 0.001). Multivariate analysis for OS in the group of completely resected patients (n = 139) revealed statistical significance for ypM (P < 0.001), histopathological response (P < 0.001) and the combined cyclinD1/IL-1RN genotypes (P = 0.043).


CONCLUSIONS
The cyclinD1 and IL-1RN polymorphisms were associated with survival. The combination of specific cyclinD1 and IL-1RN genotypes showed a particular prognostic relevance and should be considered an independent prognostic marker for neoadjuvant-treated gastric cancer patients.
Stocker
Gertraud
G
Institute of Pathology, Technische Universität München, Trogerstr. 18, 81675 München, Germany.
Ott
Katja
K
Henningsen
Nils
N
Becker
Karen
K
Hapfelmeier
Alexander
A
Lordick
Florian
F
Hois
Stefan
S
Plaschke
Susanne
S
Höfler
Heinz
H
Keller
Gisela
G
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002453:Cell Cycle / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D019938:Cyclin D1 / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D055815:Young Adult
D000970:Antineoplastic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D019938:Cyclin D1; D002945:Cisplatin; D005472:Fluorouracil