An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients.
OBJECTIVE
We examined the pattern of single-nucleotide polymorphisms (SNPs) of gemcitabine metabolism-related and target genes in breast cancer patients and evaluated their association with drug response or toxicity.


METHODS
SNPs in deoxycytidine kinase (dCK), deoxycytidine monophosphate deaminase (DCTD), and ribonucleotide reductase M1 polypeptide (RRM1) were analyzed with genomic DNA of 10 breast cancer cell lines, 74 peripheral blood mononuclear cell (PBMC) samples from advanced breast cancer patients treated with gemcitabine, and 56 PBMC samples from healthy volunteers.


RESULTS
The incidences of SNPs of breast cancer patients were 1.4% in dCK (626 A>G), 10.8% in DCTD (315 T>C), 40.5% in the first RRM1 (1082 C>A), 44.6% in the second RRM1 (2455 A>G), 44.6% in the third RRM1 (2464 G>A), and 23% in two RRM1 sites (2455 A>G and 2464 G>A) that were similar to those of the normal control group. We found a double SNP of RRM1 (2455 A>G and 2464 G>A) to be the novel haplotype that was associated with a lower frequency of chemotherapy-induced toxicity, such as neutropenia (p < .01) and G-CSF requirement (p < .005).


CONCLUSIONS
RRM1 haplotype showed an association with susceptibility to gemcitabine monotherapy in breast cancer patients.
Rha
Sun Young
SY
Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seodaemun-gyu, Shinchon-dong 134, Seoul, Korea, 120-752.
Jeung
Hei Cheul
HC
Choi
Yeon Ho
YH
Yang
Woo Ick
WI
Yoo
Jin Ho
JH
Kim
Byung Soo
BS
Roh
Jae Kyung
JK
Chung
Hyun Cheol
HC
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003844:DCMP Deaminase / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012262:Ribonucleoside Diphosphate Reductase; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D003842:Deoxycytidine Kinase; D003844:DCMP Deaminase; D000093542:Gemcitabine