Germline genetic variation, cancer outcome, and pharmacogenetics.
Studies of the role of germline or inherited genetic variation on cancer outcome can fall into three distinct categories. First, the impact of highly penetrant but lowly prevalent mutations of germline DNA on cancer prognosis has been studied extensively for BRCA1 and BRCA2 mutations as well as mutations related to hereditary nonpolyposis colorectal cancer syndrome. These mainly modest-sized analyses have produced conflicting results. Although some associations have been observed, they may not be independent of other known clinical or molecular prognostic factors. Second, the impact of germline polymorphisms on cancer prognosis is a burgeoning field of research. However, a deeper understanding of potentially confounding somatic changes and larger multi-institutional, multistage studies may be needed before consistent results are seen. Third, research examining the impact of germline genetic variation on differential treatment response or toxicity (pharmacogenetics) has produced some proof-of-principle results. Putative germline pharmacogenetic predictors of outcome include DPYD polymorphisms and fluorouracil toxicity, UGT1A1 variation and irinotecan toxicity, and CYP2D6 polymorphisms and tamoxifen efficacy, with emerging data on predictors of molecularly targeted or biologic drugs. Here we review data pertaining to these germline outcome and germline toxicity relationships.
Coate
Linda
L
Department of Medical Oncology, Princess Margaret Hospital, 610 University Ave, Room 7-124, Toronto, Ontario, M5G 2M9 Canada.
Cuffe
Sinead
S
Horgan
Anne
A
Hung
Rayjean J
RJ
Christiani
David
D
Liu
Geoffrey
G
D001943:Breast Neoplasms / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D010597:Pharmacogenetics; D011379:Prognosis
D019389:Cytochrome P-450 CYP2D6; D042943:Dihydrouracil Dehydrogenase (NADP)