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author:("karlin, Eric")
1.  A Copy Number Variant at the KITLG Locus Likely Confers Risk for Canine Squamous Cell Carcinoma of the Digit 
PLoS Genetics  2013;9(3):e1003409.
The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs), who have increased risk for squamous cell carcinoma of the digit (SCCD), a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS) on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (Praw = 1.60×10−7; Pgenome = 0.0066). Additional mapping resolved the region to the KIT Ligand (KITLG) locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72×10−8). Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders.
Author Summary
Domesticated dogs offer a unique mechanism for disentangling complex genetic traits, such as cancer. Over 300 breeds exist worldwide, each selected for particular morphologic and behavioral traits. Unfortunately the breeding programs used to generate such diversity are associated with breed-specific increase in disease. Squamous cell carcinoma of the digit (SCCD) is a locally aggressive cancer that causes lytic bone lesions and, occasionally, death. Among the breeds with the highest risk is the Standard Poodle (STPO), where the disease is found only in dark-coated dogs. We show that the KITLG locus is highly associated with SCCD and that a 5.7-Kb copy number variant is likely causative for the disease when in an expanded form. Interestingly, light-colored STPO carry the putative causal variant at the same frequency as black STPOs, but are protected from SCCD. We show this is likely due to a compensatory mutation in the well-known coat color locus, MC1R. This work demonstrates the utility of dog breeds for understanding the genetic causes of complex diseases of interest to both human and animal health.
PMCID: PMC3610924  PMID: 23555311
2.  Fine scale mapping of the breast cancer 16q12 locus 
Human Molecular Genetics  2010;19(12):2507-2515.
Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5′ end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case–control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case–control studies exhibit a different pattern of association suggestive of an additional causative variant.
PMCID: PMC2876886  PMID: 20332101
3.  FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation 
Human Molecular Genetics  2009;18(9):1692-1703.
Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate-causal single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03–1.41, Ptrend = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European (n = 7196 cases, 7275 controls) and Asian (n = 3901 cases, 3205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of < 1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to highly accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.
PMCID: PMC2733817  PMID: 19223389
4.  Association of FGFR4 Genetic Polymorphisms with Prostate Cancer Risk and Prognosis 
The fibroblast growth factor receptor 4 (FGFR4) is thought to be involved in many critical cellular processes and has been associated with prostate cancer risk. Four single nucleotide polymorphisms within or near FGFR4 were analysed in a population-based study of 1458 prostate cancer patients and 1352 age-matched controls. We found no evidence to suggest that any of the FGFR4 SNP genotypes were associated with prostate cancer risk or with disease aggressiveness, Gleason score or stage. A weak association was seen between rs351855 and prostate cancer-specific mortality. Subset analysis of cases that had undergone radical prostatectomy revealed an association between rs351855 and prostate cancer risk. While our results confirm an association between FGFR4 and prostate cancer risk in radical prostatectomy cases, they suggest that the role of FGFR4 in disease risk and outcomes at a population-based level appears to be minor.
PMCID: PMC2790323  PMID: 18762813
prostate cancer; population based association analysis; FGFR4; radical prostatectomy
5.  A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs 
Science (New York, N.Y.)  2007;316(5821):112-115.
The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.
PMCID: PMC2789551  PMID: 17412960
6.  No evidence of BRCA2 mutations in chromosome 13q-linked Utah high-risk prostate cancer pedigrees 
BMC Research Notes  2009;2:94.
Germline mutations in the BRCA2 gene have been suggested to account for about 5% of familial prostate cancer; mutations have been reported in 2% of early onset (i.e., ≤ 55 years) prostate cancer cases and a segregating founder mutation has been identified in Iceland (999del5). However, the role of BRCA2 in high risk prostate cancer pedigrees remains unclear.
We examined the potential involvement of BRCA2 in a set offive high-risk prostate cancer pedigrees in which all prostate cases were no more distantly related than two meioses from another case, and the resulting cluster contained at least four prostate cancer cases. We selected these five pedigrees from a larger dataset of 59 high-risk prostate cancer pedigrees analyzed in a genome-wide linkage screen. Selected pedigrees showed at least nominal linkage evidence to the BRCA2 region on chromosome 13q. We mutation screened all coding regions and intron/exon boundaries of the BRCA2 gene in the youngest prostate cancer case who carried the linked 13q segregating haplotype, as well as in a distantly related haplotype carrier to confirm any segregation. We observed no known protein truncating BRCA2 deleterious mutations. We identified one non-segregating BRCA2 variant of uncertain significance, one non-segregating intronic variant not previously reported, and a number of polymorphisms.
In this set of high-risk prostate cancer pedigrees with at least nominal linkage evidence to BRCA2, we saw no evidence for segregating BRCA2 protein truncating mutations in heritable prostate cancer.
PMCID: PMC2694822  PMID: 19476645

Results 1-6 (6)