The Clinical Significance of Thymidylate Synthase Expression in Human Papillomavirus-related Oropharyngeal Squamous Carcinoma

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  • Kato Hisayuki
    Department of Otolaryngology, School of Medicine, Fujita Health University
  • Yui Takehiro
    Department of Otolaryngology, School of Medicine, Fujita Health University
  • Yamamoto Naoki
    Laboratory of Molecular Biology and Histochemistory, Joint Research Laboratory, Fujita Health University
  • Okada Tatsuyoshi
    Department of Otolaryngology, School of Medicine, Fujita Health University
  • Urano Makoto
    Department of Diagnostic Pathology, School of Medicine, Fujita Health University
  • Sakurai Kazuo
    Department of Otolaryngology, School of Medicine, Fujita Health University
  • Naito Kensei
    Department of Otolaryngology, School of Medicine, Fujita Health University

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Other Title
  • ヒト乳頭腫ウイルス関連中咽頭扁平上皮癌におけるThymidylate synthase発現とその臨床像に関する検討
  • ヒト ニュウトウ シュ ウイルス カンレン チュウ イントウ ヘンペイ ジョウヒガン ニ オケル Thymidylate synthase ハツゲン ト ソノ リンショウゾウ ニ カンスル ケントウ

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Abstract

The focus of human papilloma virus (HPV), particulary HPV 16 is on the role of carcinogenic and prognostic factors on oropharyngeal squamous carcinoma (OSCC). However, it remains unclear why patients with HPV-positive tumors have better outcomes than those with HPV-negative tumors. Thymidylate synthase (TS) is one of the initial key enzymes in the 5-fluouracil (5-FU) metabolic pathway. Clinical studies showed that intratumoural TS level was related to the response to 5-FU-based chemotherapy in patients with several types of cancer such as gastroenterological and head and neck cancers.<br>We investigated the prevalence of HPV infection and TS expression in the patients with OSCC and evaluated the prognostic implications according to the HPV status and TS expression. We evaluated for high-risk HPV types (HPV 16, 18, 31, 33, 51, 52, 58) using a real-time polymerase chain reaction (RT-PCR) assay on archival biopsies from 54 patients with OSCC. Immunohistochemical assessments for TS were also performed. HPV was positive in 22 (40.7%) of 54 samples. Of these positive cases, 21 (95%) carried HPV 16 and only 1 (5%) HPV58 sequences. TS was overexpressed in 25 (46.3%) of 54 samples. Of these, 19 (76.0%) had an HPV-negative status and 21 (84.0%) were heavy smokers. TS overexpression was associated with the patients with HPV-negative tumors (P=0.02) and heavy smokers (p=0.012). Univariate analysis revealed that HPV positive status (77.3% vs. 29.0%; p=0.006) significantly improved overall survival. Conversely, no remarkable prognostic difference was observed on immunohistochemical analysis of TS expression. A multivariate analysis using Cox's proportional hazard model showed that early T stage (T1-2), early N stage (N0-1), and positive HPV status were significantly independent predictors for superior overall survival.<br>Our studies suggested that positive HPV status was most strongly associated with a favorable prognosis in the patients with OSCC. TS expression has an unusual aspect as a biomarker for OSCC, though it was not related to prognosis.

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