Prognostic value of ALDH2 polymorphism for patients with oropharyngeal cancer in a Japanese population

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Abstract

Background

Half of Japanese possess a polymorphism of aldehyde dehydrogenase 2(ALDH2), while few white individuals possess this mutation. The purpose of this study was to investigate the possibility of ALDH2 polymorphism as a prognostic factor for oropharyngeal cancer (OPC) among Japanese population.

Methods

We analyzed 82 Japanese patients with OPC treated between 2006 and 2011. The median observation period was 50 months. P16-staining and ALDH2 polymorphisms were investigated. To examine the frequencies of second primary pharyngeal and esophageal cancers (SPPEC),37 Japanese patients with OPC treated at Tokyo University Hospital were included for statistical analysis.

Results

Statistically significant differences were noted in OS among sex, age, N classification, and p16 (p = 0.045, 0.024, 0.020, 0.007, respectively). In addition, OS and DSS rates of the patients with heterozygous ALDH2 tended to be worse than those of the patients with homozygous ALDH2 (p = 0.21, 0.086, respectively). Of note, OS and DSS of the patients with p16-negative OPC and heterozygous ALDH2 was significant poorer than those of the patients with p16-positive OPC (p = 0.002, 0.006, respectively), while there was no significant difference in OS and DSS between patients with p16-positive OPC and patients with p16-negative OPC and homozygous ALDH2.

Conclusions

ALDH2 polymorphism might be a promising prognostic factor for Japanese patients with p16-negative OPC.

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Most cited references 14

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Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.

M. L. Gillison, W Koch, R B Capone … (2000)

High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis. HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0. 36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4- 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88). These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.

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EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer.

Douglas B. Chepeha, C. Bradford, H. Tran … (2008)

To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer. Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status. EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002). Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.

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Genetic polymorphisms of alcohol and aldehyde dehydrogenases, and drinking, smoking and diet in Japanese men with oral and pharyngeal squamous cell carcinoma.

Tetsuji Yokoyama, Manabu Muto, Takahiro Asakage … (2007)

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-1B (ADH1B, previously called ADH2), and ADH1C (previously called ADH3) affect the metabolism of alcohol. The inactive ALDH2 encoded by ALDH2*1/*2 and the less-active ADH1B encoded by ADH1B*1/*1 increase the risk of esophageal squamous cell carcinoma in East Asian drinkers. This case-control study involved 96 Japanese men with oral and pharyngeal squamous cell carcinoma (hypopharyngeal cancer in 43 patients and oral/oropharyngeal cancer in 53) and 642 cancer-free Japanese men. The risk of the cancers overall and of hypopharyngeal cancer was increased 3.61- and 10.08-fold, respectively, by ALDH2*1/*2 among moderate-to-heavy drinkers (9+ units/week; one unit = 22 g of ethanol), but the risk of oral/oropharyngeal cancer was not significantly affected by the ALDH2 genotype. The results obtained with a simple alcohol flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping. Among moderate-to-heavy drinkers, men with the less-active ADH1B*1/*1 had a significantly higher risk of the cancers overall, of hypopharyngeal cancer, and of oral/oropharyngeal cancer (OR = 5.56, 7.21 and 4.24, respectively). In view of the linkage disequilibrium between ADH1B and ADH1C, the ADH1C genotype does not significantly affect cancer risk. The significant independent risk factors for oral and pharyngeal cancer overall among moderate-to-heavy drinkers were inactive ALDH2*1/*2, less-active ADH1B*1/*1, frequent drinking of strong alcohol beverages straight, smoking, and lower intake of green-yellow vegetables. Educating these risks for cancer of the upper aerodigestive tract could be a useful new strategic approach to the prevention of these cancers in Japanese.

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Author and article information

Contributors

Hirotaka Shinomiya: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: Writing – original draft

Hitomi Shinomiya: Role: Data curationRole: InvestigationRole: Methodology

Mie Kubo: Role: InvestigationRole: Methodology

Yuki Saito: Role: Data curation

Masafumi Yoshida: Role: Data curation

Mizuo Ando: Role: Data curation

Masanori Teshima: Role: Data curation

Naoki Otsuki: Role: ResourcesRole: Supervision

Naomi Kiyota: Role: Supervision

Ryohei Sasaki: Role: Supervision

Ken-ichi Nibu:

ORCID: http://orcid.org/0000-0002-5461-4871

Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: Writing – review & editing

Qingyi Wei: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 5 December 2017

Publication date Collection: 2017

Volume: 12

Issue: 12

Electronic Location Identifier: e0187992

Affiliations

[1 ] Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan

[2 ] Department of Head and Neck Surgery-Otolaryngology, University of Tokyo, Tokyo, Japan

[3 ] Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan

[4 ] Department of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe, Japan

Duke Cancer Institute, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: hshino@ 123456med.kobe-u.ac.jp (HS); nibu@ 123456med.kobe-u.ac.jp (KIN)

Author information

Ken-ichi Nibu http://orcid.org/0000-0002-5461-4871

Article

Publisher ID: PONE-D-17-25575

DOI: 10.1371/journal.pone.0187992

PMC ID: 5716598

PubMed ID: 29206831

SO-VID: b37f4134-f679-4d49-9b81-d00afc311005

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 July 2017

Date accepted : 30 October 2017

Page count

Figures: 5, Tables: 6, Pages: 12

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;

Award ID: 16ck0106223h0001

Award Recipient :

ORCID: http://orcid.org/0000-0002-5461-4871

Ken-ichi Nibu

Funded by: funder-id http://dx.doi.org/10.13039/501100003478, Ministry of Health, Labour and Welfare;

Award ID: 26861379

Award Recipient : Hirotaka Shinomiya

Funded by: funder-id http://dx.doi.org/10.13039/501100003478, Ministry of Health, Labour and Welfare;

Award ID: 16H05481

Award Recipient :

ORCID: http://orcid.org/0000-0002-5461-4871

Ken-ichi Nibu

This work is partly supported by Grant-in-Aid for Scientific Research (26861379, H. S. & 16H0548, 16H05481 K.N) and Japan Agency for Medical Research and Development (16ck0106223h001, K.N.).

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Prognostic value of ALDH2 polymorphism for patients with oropharyngeal cancer in a Japanese population

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 14

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.

EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer.

Genetic polymorphisms of alcohol and aldehyde dehydrogenases, and drinking, smoking and diet in Japanese men with oral and pharyngeal squamous cell carcinoma.

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