CONTEXT: Cancer is a multigenic disease resulting from both germline susceptibility and somatic events. While studying loss of heterozygosity (LOH) in cancer tissues, we anecdotally observed a low frequency of heterozygosity in cancer patients compared with controls, raising the question whether homozygosity could play a role in cancer predisposition. OBJECTIVES: To determine the frequency of germline homozygosity in a large series of patients with 3 different types of solid tumors compared with population-based controls. DESIGN, SETTING, AND PATIENTS: Germline and corresponding tumor DNA isolated from 385 patients with carcinomas (147 breast, 116 prostate, and 122 head and neck carcinomas) were subjected to whole genome (345-microsatellite marker) LOH analysis. MAIN OUTCOME MEASURES: Frequency of homozygosity at microsatellite markers in cancer cases vs controls and frequency of somatic LOH in cancers at loci with the highest homozygosity. RESULTS: We identified 16 loci in common among the 3 cancer types, with significantly increased germline homozygosity frequencies in the cancer patients compared with controls (P < .001). In the cases who happened to be germline heterozygous at these 16 loci, we found a mean (SD) LOH frequency of 58% (4.2%) compared with 50% (7.5%) at 197 markers without increased germline homozygosity (P < .001). Across the genome, this relationship holds as well (r = 0.46; 95% confidence interval, 0.37-0.53; P < .001). We validated the association of specific loci with high germline homozygosity frequencies in an independent, single-nucleotide polymorphism-based, public data set of 205 lung carcinomas from white individuals (P < .05 to P < .001) as well as the correlation between genome-wide germline homozygosity and LOH frequencies (r = 0.21; 95% confidence interval, 0.18-0.24; P < .001). CONCLUSIONS: In our study of 4 different types of solid tumors (our data for 3 types validated in a fourth type), increased germline homozygosity occurred at specific loci. When the germline was heterozygous at these loci, high frequencies of LOH/allelic imbalance occurred at these loci in the corresponding carcinomas.
CONTEXT: Cancer is a multigenic disease resulting from both germline susceptibility and somatic events. While studying loss of heterozygosity (LOH) in cancer tissues, we anecdotally observed a low frequency of heterozygosity in cancerpatients compared with controls, raising the question whether homozygosity could play a role in cancer predisposition. OBJECTIVES: To determine the frequency of germline homozygosity in a large series of patients with 3 different types of solid tumors compared with population-based controls. DESIGN, SETTING, AND PATIENTS: Germline and corresponding tumor DNA isolated from 385 patients with carcinomas (147 breast, 116 prostate, and 122 head and neck carcinomas) were subjected to whole genome (345-microsatellite marker) LOH analysis. MAIN OUTCOME MEASURES: Frequency of homozygosity at microsatellite markers in cancer cases vs controls and frequency of somatic LOH in cancers at loci with the highest homozygosity. RESULTS: We identified 16 loci in common among the 3 cancer types, with significantly increased germline homozygosity frequencies in the cancerpatients compared with controls (P < .001). In the cases who happened to be germline heterozygous at these 16 loci, we found a mean (SD) LOH frequency of 58% (4.2%) compared with 50% (7.5%) at 197 markers without increased germline homozygosity (P < .001). Across the genome, this relationship holds as well (r = 0.46; 95% confidence interval, 0.37-0.53; P < .001). We validated the association of specific loci with high germline homozygosity frequencies in an independent, single-nucleotide polymorphism-based, public data set of 205 lung carcinomas from white individuals (P < .05 to P < .001) as well as the correlation between genome-wide germline homozygosity and LOH frequencies (r = 0.21; 95% confidence interval, 0.18-0.24; P < .001). CONCLUSIONS: In our study of 4 different types of solid tumors (our data for 3 types validated in a fourth type), increased germline homozygosity occurred at specific loci. When the germline was heterozygous at these loci, high frequencies of LOH/allelic imbalance occurred at these loci in the corresponding carcinomas.
Authors: Akio Tanaka; Sarah Weinel; Nikoletta Nagy; Mark O'Driscoll; Joey E Lai-Cheong; Carol L Kulp-Shorten; Alfred Knable; Gillian Carpenter; Sheila A Fisher; Makiko Hiragun; Yuhki Yanase; Michihiro Hide; Jeffrey Callen; John A McGrath Journal: Am J Hum Genet Date: 2012-02-16 Impact factor: 11.025
Authors: Manny D Bacolod; Gunter S Schemmann; Sarah F Giardina; Philip Paty; Daniel A Notterman; Francis Barany Journal: Cancer Res Date: 2009-01-20 Impact factor: 12.701