Distinct loci on chromosome 1q21 and 6q22 predispose to familial nonmedullary thyroid cancer: A SNP array-based linkage analysis of 38 families

Suh, Insoo; Filetti, Sebastiano; Vriens, Menno R.; Guerrero, Marlon A.; Tumino, Salvatore; Wong, Mariwil; Shen, Wen T.; Kebebew, Electron; Duh, Quan-Yang; Clark, Orlo H.

doi:10.1016/j.surg.2009.09.012

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Volume 146, Issue 6 , Pages 1073-1080, December 2009

Distinct loci on chromosome 1q21 and 6q22 predispose to familial nonmedullary thyroid cancer: A SNP array-based linkage analysis of 38 families

Insoo Suh, MD
- Department of Surgery, University of California, San Francisco, CA
Sebastiano Filetti, MD
- Department of Medicine, Sapienza University of Rome, Rome, Italy
Menno R. Vriens, MD, PhD
- Department of Surgery, University of California, San Francisco, CA
Marlon A. Guerrero, MD
- Department of Surgery, University of California, San Francisco, CA
Salvatore Tumino, MD
- Department of Biomedical Sciences, University of Catania, Catania, Italy
Mariwil Wong, BS
- Department of Surgery, University of California, San Francisco, CA
Wen T. Shen, MD
- Department of Surgery, University of California, San Francisco, CA
Electron Kebebew, MD
- Department of Surgery, University of California, San Francisco, CA
Quan-Yang Duh, MD
- Department of Surgery, University of California, San Francisco, CA
- Surgical Service, Veterans Affairs Medical Center, San Francisco, CA
Orlo H. Clark, MD
- Department of Surgery, University of California, San Francisco, CA
- Reprint requests: Orlo H. Clark, MD, Department of Surgery, UCSF-Mount Zion Medical Center. 1600 Divisadero Street, Box 1674, Hellman Building, Room C-347, San Francisco, CA 94143-1674.

Accepted 17 September 2009.

Background

Familial nonmedullary thyroid cancer (FNMTC) is associated with earlier onset and more aggressive behavior than its sporadic counterpart. Although candidate chromosomal loci have been proposed for isolated families with variants of FNMTC, the etiology of most cases is unknown. We aimed to identify loci linked to FNMTC susceptibility using single-nucleotide polymorphism (SNP) array-based linkage analysis in a broad sampling of affected families.

Methods

We enrolled and pedigreed 38 FNMTC families. Genomic DNA was extracted from the peripheral blood of 110 relatives, and hybridized to Affymetrix SNP arrays. We performed genotyping and linkage analysis, calculating exponential logarithm-of-the-odds (LOD) scores to identify chromosomal loci with a significant likelihood of linkage.

Results

Forty-nine affected and 61 unaffected members of FNMTC families were genotyped. In pooled linkage analysis of all families, 2 distinct loci with significant linkage were detected at 6q22 and 1q21 (LOD=3.3 and 3.04, respectively).

Conclusion

We have identified 2 loci on chromosomes 1 and 6 that demonstrate linkage in a broad sampling of FNMTC families. Our findings suggest the presence of germline mutations in heretofore-undiscovered genes at these loci, which may potentially lead to accurate genetic tests. Future studies will consist of technical validation and subset analyses of higher-risk pedigrees.