Association of cytochrome P450 2C9 polymorphism with locally advanced head and neck squamous cell carcinoma and response to concurrent cisplatin-based radical chemoradiation

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Abstract

Aims:

The aim of the present study is to investigate the association between polymorphism of cytochrome P450 2C9 ( CYP2C9) enzyme with head and neck squamous cell carcinoma (HNSCC) and response in patients receiving cisplatin-based radical chemoradiation (CT-RT).

Materials and Methods:

Four hundred and sixty patients suffering from locally advanced HNSCC and an equal number of healthy controls were genotyped for CYP2C9*2 and CYP2C9*013, leading to poor metabolizers (PMs) by polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP). Each case was assessed thoroughly for treatment response as per the World Health Organization (WHO) criteria.

Results and Analysis:

The frequency of heterozygous genotypes of both CYP2C9*2 (27.8%) and CYP2C9*3 (25%) were found to be significantly higher in the HNSCC cases as compared to the healthy controls. Tobacco intake in the form of chewing or smoking and alcohol intake resulted in several folds increase in the risk to HNSCC in the cases carrying variant genotypes of CYP2C9*2 or CYP2C9*013. Further, majority of the cases assessed for response ( n = 436) carrying variant alleles of CYP2C9*2 (69.6%) or CYP2C9*3 (65.2%) were found to respond poorly to cisplatin-based radical CT-RT.

Conclusion:

The data suggests a significant association of the CYP2C9 polymorphism with HNSCC and treatment outcome underlining the importance of pretherapeutic genotyping in determining the treatment protocol.

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Most cited references 21

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Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

Mitchell Higashi (2002)

Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established. To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy. Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash. Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included. Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events. Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, chi(2)(5) = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P =.004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86). The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.

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Profiling early head and neck cancer.

E. Kenneth Parkinson, P. Harrison, Keith Hunter (2005)

Head and neck squamous-cell carcinoma (HNSCC) is the sixth most common cancer worldwide and, disappointingly, survival rates are not improving. Moreover, HNSCC has a severe impact on the quality of life of patients and survivors, and the significant morbidity subsequent to treatment often mandates long-term multidisciplinary care, which places significant financial pressures on the treating institution. Therefore, prevention and early diagnosis of high-risk pre-malignant lesions are high priorities for reducing deaths due to head and neck cancer. Recent advances have begun to elucidate the different aetiologies of HNSCCs in relation to previous pre-malignancies and to identify which pre-malignant lesions are likely to progress to malignancy.

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CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population.

Nathalie Gérard, Elvis A. Peter, Adithan Chandrasekaran … (2005)

The aim of the study was to establish the frequencies of CYP2C9*1, *2, *3 and CYP2C19*1, *2 and *3 in the south Indian population and to compare them with the inter-racial distribution of the CYP2C9 and CYP2C19 genetic polymorphisms. Genotyping analyses of CYP2C9 and CYP2C19 were conducted in unrelated, healthy volunteers from the three south Indian states of Andhra Pradesh, Karnataka and Kerala, by the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). The allele frequencies of the populations of these three states were then pooled with our previous genotyping data of Tamilians (also in south India), to arrive at the distribution of CYP2C9 and CYP2C19 alleles in the south Indian population. Frequencies of CYP2C9 and CYP2C19 alleles and genotypes among various populations were compared using the two-tailed Fisher's exact test. The frequencies of CYP2C9*1, *2 and *3 in the south Indian population were 0.88 (95% CI 0.85-0.91), 0.04 (95% CI 0.02-0.06) and 0.08 (95% CI 0.06-0.11), respectively. The frequencies of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 0.78 (95% CI 0.74-0.82), 0.05 (95% CI 0.03-0.07), 0.15 (95% CI 0.12-0.18), 0.01 (95% CI 0.0-0.02), 0.01 (95% CI 0.0-0.02) and 0.0, respectively. CYP2C19*1, *2 and *3 frequencies were 0.64 (95% CI 0.60-0.68), 0.35 (95% CI 0.31-0.39) and 0.01 (95% CI 0.0-0.03), respectively. As a result of a significant heterogeneity, the data on CYP2C19 genotype frequencies were not pooled. The frequency of CYP2C9*2 mutant alleles in south Indians was higher than in Chinese and Caucasians, while CYP2C9*3 was similar to Caucasians. CYP2C19*2 was higher than in other major populations reported so far. The relatively high CYP2C19 poor-metabolizer genotype frequency of 12.6% indicates that over 28 million south Indians are poor metabolizers of CYP2C19 substrates.

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Author and article information

Journal

Journal ID (nlm-ta): South Asian J Cancer

Journal ID (iso-abbrev): South Asian J Cancer

Journal ID (publisher-id): SAJC

Title: South Asian Journal of Cancer

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 2278-330X

ISSN (Electronic): 2278-4306

Publication date (Print): Jul-Sep 2014

Volume: 3

Issue: 3

Pages: 154-158

Affiliations

[1]Department of Radiotherapy, Chhatrapati Shahuji Maharaj Medical University, Formerly, King George's Medical University, Lucknow, India

[1 ]Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

[2 ]Department of Developmental Toxicology and Environmental Epidemiology, Indian Institute of Toxicology and Research, Lucknow, Uttar Pradesh, India

Author notes

Correspondence to: Dr. Tamojit Chaudhuri, E-mail: tamojit.cnmc@ 123456gmail.com

Article

Publisher ID: SAJC-3-154

DOI: 10.4103/2278-330X.136771

PMC ID: 4134605

SO-VID: 767047fa-24ea-4a98-8c92-17eb5c8e9715

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Association of cytochrome P450 2C9 polymorphism with locally advanced head and neck squamous cell carcinoma and response to concurrent cisplatin-based radical chemoradiation

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Abstract

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Materials and Methods:

Results and Analysis:

Conclusion:

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Special issue: Radical periodicals

Most cited references 21

Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

Profiling early head and neck cancer.

CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population.

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