Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2011, vol. 20, nr 5, September-October, p. 583–590

Publication type: original article

Language: English

The Role of Chosen Polymorphisms in Genes Coding Xenobiotic Metabolizing Enzymes and DNA Repair Proteins in Laryngeal Cancers

Znaczenie wybranych polimorfizmów w genach kodujących enzymy metabolizujące ksenobiotyki i białka naprawy DNA w raku krtani

Agnieszka Stembalska1,, Justyna Gil1,, Izabela Łaczmańska1,, David Ramsey2,, Przemysław Leszczyński1,, Dorota Kaczmarek1,, Alicja Trusewicz1,, Maria Jagas3,, Marcin Frączek4,

1 Department of Genetics, Wroclaw Medical University, Poland

2 Department of Mathematics and Statistics, University of Limerick, Ireland

3 Lower Silesian Oncology Centre, Wrocław, Poland

4 Department of Otolaryngology, Wroclaw Medical University, Poland

Abstract

Background. Laryngeal cancer (LSCC – larynx squamous cell carcinoma) is the most common head and neck cancer (HNSCC – head and neck squamous cell carcinoma). The etiology of laryngeal cancer is complex, influenced by inter alia genetic alterations (e.g. SNPs, single nucleotide polymorphisms).
Objectives. The authors investigated the association between laryngeal cancer and 22 polymorphisms of 8 chosen genes involved in: i) Phase I of xenobiotic metabolism, such as: 1) CYP1A1, 2) CYP2A6 and 3) CYP2D6 and ii) mechanisms of DNA repair, such as 1) XRCC1, OGG1 (BER, base excision repair), 2) XPC, XPD (NER, nucleotide excision repair) and 3) XRCC3 (HR, homologous recombination repair). The next step of our analysis was to look for possible associations between the clinical course of the disease and the polymorphisms mentioned above.
Material and Methods. The authors studied a group of 60 patients with primary LSCC and 100 cancer-free individuals formed the control group. The clinical course of 30 randomly-selected patients was observed. The laryngeal cancer patients and cancer-free controls were genotyped by PCR or PCR-RFLP, as appropriate. Fisher’s exact test for association and the Cochran-Armitage test were used to investigate the association between the chosen polymorphisms and cancer. The Benjamini-Hochberg procedure for multiple testing was adopted. The Mann-Whitney test and Kendall test for correlation were also used (using the R and SPSS statistical packages).
Results. The authors found nine associations between the polymorphisms of the studied genes (CYP1A1, CYP2A6 and XPC PAT, XRCC3, OGG1) and laryngeal cancer. The association of XPC PAT and several CYP1A1 polymorphisms with cancer was particularly clear, remaining significant after the use of the Benjamini-Hochberg procedure for multiple testing. In addition, the authors found a few statistically significant associations between the polymorphisms analyzed and the available clinical data. However, none of the associations was significant after the application of the Benjamini-Hochberg procedure.
Conclusion. The results indicate an important role of polymorphisms of CYP1A1 and XPC, XRCC3, OGG1 genes in determining the risk of LSCC. However to clarify possible associations between polymorphisms and clinical data, further large studies are needed.

Streszczenie

Wprowadzenie. Rak krtani (LSCC – płaskonabłonkowy rak krtani) należy do najczęstszych nowotworów głowy i szyi (HNSCC – płaskonabłonkowy rak głowy i szyi). Etiologia raka krtani jest złożona, obejmuje m.in. wpływ zmian genetycznych (np. SNP, polimorfizm pojedynczych nukleotydów).
Cel pracy. Badano związek między rakiem krtani a 22 polimorfizmami wybranych 8 genów zaangażowanych w i) metabolizm ksenobiotyków pierwszej fazy, jak: 1) CYP1A1, 2) CYP2A6, 3) CYP2D6, i ii) mechanizmy naprawy DNA, jak 1) XRCC1, OGG1 (BER – naprawa przez wycięcie zasady); 2) XPC, XPD (NER – naprawa przez wycięcie nukleotydu); 3) XRCC3 (HR – naprawa przez homologiczną rekombinację). Dodatkowo przeprowadzono analizę korelacji między przebiegiem klinicznym a wyżej wymienionymi polimorfizmami.
Materiał i metody. Grupą badaną było 60 pacjentów z pierwotnym LSCC, grupą kontrolną 100 zdrowych osób. Przebieg kliniczny analizowano u 30 wyselekcjonowanych pacjentów z LSCC. Genotypowanie przeprowadzono w grupie badanej i kontrolnej metodą PCR lub PCR-RFLP. Analizę statystyczną przeprowadzono w programach R i SPSS z użyciem testów Fischera, Manna-Whitneya, Kendalla, Cochran-Armitage oraz procedury Benjamini-Hochberg.
Wyniki. Znaleziono 9 pozytywnych korelacji między określonymi polimorfizmami badanych genów (CYP1A1, CYP2A6 i XPC PAT, XRCC3, OGG1) i rakiem krtani. Stwierdzono dodatkowo kilka statystycznie istotnych korelacji między analizowanymi polimorfizmami i dostępnymi danymi klinicznymi. Niemniej żadna z nich nie była statystycznie znacząca po zastosowaniu procedury Benjaminiego-Hochberga do testowania wielokrotnego.
Wnioski. Wyniki badań wskazują na znaczącą rolę zarówno polimorfizmów genu CYP1A1, jak i XPC, XRCC3, OGG1 w modyfikacji ryzyka LSCC. Aby wyjaśnić możliwe asocjacje między polimorfizmami a danymi klinicznymi, wskazane jest rozszerzenie badań.

Key words

DNA repair, xenobiotic metabolizing enzymes (XME), genetic polymorphisms, LSCC – laryngeal squamous cell carcinoma, SNP – single nucleotide polymorphism

Słowa kluczowe

naprawa DNA, enzymy metabolizujące ksenobiotyki (XME), polimorfizm genetyczny, LSCC – płaskonabłonkowy rak krtani, SNP – polimorfizm pojedynczych nukleotydów

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