Frequency of germline genomic homozygosity associated with cancer cases.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


METHODS
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.
Assié
Guillaume
G
Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
LaFramboise
Thomas
T
Platzer
Petra
P
Eng
Charis
C
D001943:Breast Neoplasms / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000235:genetics; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics