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Oncol Res. 17(6):273-82. 2008.

Deletion at Dickkopf (dkk)-3 locus (11p15.2) is related with lower lymph node metastasis and better prognosis in head and neck squamous cell carcinomas.

Katase NGunduz MBeder LGunduz ELefeuvre MHatipoglu OFBorkosky SSTamamura RTominaga S
Yamanaka NShimizu KNagai NNagatsuka H.


Head and neck squamous cell carcinoma (HNSCC) is a frequently occurring cancer, and despite improvement of its treatment methods, including chemotherapy, radiotherapy, and surgery, the improvement of survival remains poor. Recent advances in molecular biology of human cancer indicated various molecular abnormalities in HNSCC, including activation of oncogenes and inactivation of tumor suppressor genes (TSGs). Dickkopf (Dkk)-3 gene is known as a negative regulator of Wnt signaling and is suggested to function as TSG in several kinds of malignancies. We hypothesized that Dkk-3 might play an important role in HNSCC, too. Thus, in the current study, we analyzed allelic alteration of Dkk-3 locus (chromosome 11p15.2) by means of loss of heterozygosity (LOH) analysis. The study population consisted of 50 patients with HNSCC (mean age of 65 years old). Furthermore, we also examined the correlation between LOH findings of Dkk-3 locus with clinicopathological parameters to investigate its use as a biomarker in HNSCC. A remarkable LOH ratio (57%) was detected in the cases studied, implying that Dkk-3 is likely to be involved in HNSCC carcinogenesis. However, interestingly and in contrast to the expectations, we found that the group with LOH of Dkk-3 locus had less lymph node metastasis, and showed a favorable overall survival compared to the patients with retention of Dkk-3 area in survival analysis. These results indicate that Dkk-3 can play a role in HNSCC carcinogenesis with unknown mechanism. Moreover, allelic loss at Dkk-3 locus may also be used as a novel prognostic biomarker in HNSCC.



結果:DKK familyが存在する染色体上の領域にLOHが生じており、特にDKK3を含む領域でLOHが高頻度に認められた。

   DKK3のLOHの状態はリンパ節転移の有無やoverall survivalと相関があり、治療のターゲットとなりうる可能性が示唆された。

HNSCCの発生と進展に関わる癌関連遺伝子については不明な点が多い。細胞の癌化は、癌遺伝子の活性化、癌抑制遺伝子の機能低下などが蓄積した結果として生じると考えられる。我々は、HNSCCにおいて特異的に欠失する染色体上の領域を検索するため、LOH解析を行い、染色体の1p, 2q, 4q, 7q, 9p, 10q, 11p, 19pなどで高頻度にLOHが存在することを報告してきた。


(1) 頭頸部扁平上皮癌の発生と癌関連遺伝子―LOH解析



 DKK1: 10q11.2


 DKK3: 11p15.3

 DKK4: 8p11.2









(2) DKK3領域のLOHと臨床データとの相関

DKK3領域にLOHを有する患者は有意にリンパ節転移が少なかった。また、overall survivalが有意に短かった。





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