Heritability and linkage analysis of sensitivity to cisplatin-induced cytotoxicity.
Little is known about the genetic determinants explaining variation in sensitivity to chemotherapeutic cytotoxicity. We characterized the degree of cisplatin sensitivity, using lymphoblastoid cell lines derived from 10 Centre d'Etude du Polymorphisme Humain pedigrees. We estimated the heritability for susceptibility to cisplatin-induced cytotoxicity to be approximately 0.47; therefore, sensitivity to the cytotoxic effects of cisplatin is under appreciable genetic influence. Linkage analysis was performed, and the strongest signal (lod score, 2.16; empirical P = 0.0005) was found on chromosome 1 at 44 cM. Susceptibility to cisplatin-induced cytotoxicity is likely due to multiple loci, with low locus-specific heritability contributing to the trait. These data show the power of using large pedigrees that have been extensively genotyped for evaluating the genetic contribution to sensitivity to cell growth inhibition by anticancer agents.
Dolan
M Eileen
ME
Department of Medicine, and Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Illinois 60637, USA. edolan@medicine.bsd.uchicago.edu
Newbold
Karla G
KG
Nagasubramanian
Ramamoorthy
R
Wu
Xiaolin
X
Ratain
Mark J
MJ
Cook
Edwin H
EH
Badner
Judith A
JA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D011110:Polymorphism, Genetic
D000970:Antineoplastic Agents; D002945:Cisplatin