Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients.
OBJECTIVE
Pharmacogenetics suggests variants of genes involved in gemcitabine pharmacology could be useful markers for predicting inter-ethnic and inter-patient outcomes from treatment with the agent. Here, we have characterized the distribution of variants of genes involved in gemcitabine pharmacology in ethnic Asian populations and their association with non-small cell lung cancer (NSCLC) patient outcome.


METHODS
All genes involved in gemcitabine transport, metabolism and activity were screened for suitable variants for analysis using publications and public databases. By pyrosequencing, the frequency of qualifying variants was characterized from germline DNA of 94 healthy Asian donors and 53 NSCLC patients receiving gemcitabine-based chemotherapy.


RESULTS
Significant differences in genotype distribution between Caucasians and Asians were seen at 10/25 (45%) variant loci. In NSCLC patients, CDA+435 C>T variants were associated with response (p=0.026) and time to progression (p=0.016) and SLC28A1+1561 G>A variants were associated with neutropenia (p=0.030) and thrombocytopenia nadir (p=0.037).


CONCLUSIONS
Many genotypes in gemcitabine pharmacology vary in their frequency between Caucasians and Asians. CDA+435, and SLC28A1+1561 are worthy of further investigation as potential indicators of patient outcome after gemcitabine treatment.
Department of Haematology-Oncology, National University of Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore. ross_soo@nuh.com.sg
Ross A
RA
Soo
Ling Zhi
LZ
Wang
Swee Siang
SS
Ng
Pei Yi
PY
Chong
Wei Peng
WP
Yong
Soo Chin
SC
Lee
Jian Jun
JJ
Liu
Tai Bee
TB
Choo
Lai San
LS
Tham
How Sung
HS
Lee
Boon Cher
BC
Goh
Richie
R
Soong
D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D003564:Cytidine Deaminase / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D012189:Retrospective Studies; D012846:Singapore; D016896:Treatment Outcome; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine