Yonsei Med J.  2013 Sep;54(5):1158-1167. 10.3349/ymj.2013.54.5.1158.

NAD(P)H: Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 Polymorphisms in Papillary Thyroid Microcarcinoma: Correlation with Phenotype

• Lee J
• Kim KS
• Lee MH
• Kim YS
• Lee MH
• Lee SE
• Kim YK
• Ryu MJ
• Kim SJ
• Choi MJ
• Jo YS

• KMID: 1793163
• DOI: http://doi.org/10.3349/ymj.2013.54.5.1158

Abstract

PURPOSE
NAD(P)H:Quinone Oxidoreductase 1 (NQO1) C609T missense variant (NQO1*2) and 29 basepair (bp)-insertion/deletion (I29/D) polymorphism of the NRH:Quinone Oxidoreductase 2 (NQO2) gene promoter have been proposed as predictive and prognostic factors for cancer development and progression. The purpose of this study is to investigate the relationship between NQO1/NQO2 genotype and clinico-pathological features of papillary thyroid microcarcinoma (PTMC).
MATERIALS AND METHODS
Genomic DNA was isolated from 243 patients; and clinical data were retrospectively analyzed. NQO1*2 and tri-allelic polymorphism of NQO2 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.
RESULTS
PTMC with NQO1*2 frequently exhibited extra-thyroidal extension as compared to PTMC with wild-type NQO1 (p=0.039). There was a significant relationship between I29/I29 homozygosity of NQO2 and lymph node metastasis (p=0.042). Multivariate analysis showed that the I29/I29 genotype was associated with an increased risk of lymph node metastasis (OR, 2.24; 95% CI, 1.10-4.56; p=0.026).
CONCLUSION
NQO1*2 and I29 allele of the NQO2 are associated with aggressive clinical phenotypes of PTMC, and the I29 allele represents a putative prognostic marker for PTMC.

Keyword

NAD(P)H:Quinone Oxidoreductase 1; NRH:Quinone Oxidoreductase 2; thyroid neoplasm

MeSH Terms

Adult
Carcinoma, Papillary/*genetics/pathology
DNA Mutational Analysis
Female
Genetic Predisposition to Disease
Humans
Immunohistochemistry
Male
Middle Aged
Multivariate Analysis
Mutagenesis, Insertional
Mutation, Missense
NAD(P)H Dehydrogenase (Quinone)/chemistry/*genetics
Phenotype
Polymorphism, Genetic
Prognosis
Promoter Regions, Genetic
Retrospective Studies
Sequence Analysis, Protein
Sequence Deletion
Thyroid Neoplasms/*genetics/pathology
NAD(P)H Dehydrogenase (Quinone)

Figure

• 

  Fig. 1 Immunohistochemical staining of NQO1 in the normal thyroid and PTMC. (A) NQO1 was rarely detected in normal thyroid follicles. (B and C) Focal expression of NQO1 was observed in the apical areas of normal follicular cells (boxed area and arrows). (D and E) Diffuse intense cytoplasmic staining was observed in papillary thyroid cancer cells from same patient with wild-type NQO1. (F) NQO1 expression was barely detectable in a patient with heterozygous NQO1*2 polymorphism. All results are representative images. NQO1, NAD(P)H:Quinone Oxidoreductase 1; PTMC, papillary thyroid microcarcinoma.

• 

  Fig. 2 Representative immunohistochemical staining of Nrf2. (A) Nrf2 was rarely detected in PTMC with wild type NQO1 and NQO2. (B and C) Moderate expression of Nrf2 was observed in PTMC with NQO1*2 (B) or NQO2 I29/I29 (C). (D) Strong and diffuse intense staining was observed in PTMC with NQO1*2 and NQO2 I29/I29. PTMC, papillary thyroid microcarcinoma; NQO1, NAD(P)H:Quinone Oxidoreductase 1; NQO2, NRH:Quinone Oxidoreductase 2.

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