Polymorphisms associated with the risk of lung cancer in a healthy Mexican Mestizo population: Application of the additive model for cancer.

Rebeca Pérez-Morales,Clementina Castro-Hernández,Ollin C Martínez-Ramírez,Julieta Rubio,María Eugenia Gonsebatt,Ignacio Méndez-Ramírez

doi:10.1590/s1415-47572011005000053

Rebeca Pérez-Morales, Clementina Castro-Hernández + Show 4 more

Open Access

https://doi.org/10.1590/s1415-47572011005000053

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Abstract

Lung cancer is the leading cause of cancer mortality in Mexico and worldwide. In the past decade, there has been an increase in the number of lung cancer cases in young people, which suggests an important role for genetic background in the etiology of this disease. In this study, we genetically characterized 16 polymorphisms in 12 low penetrance genes (AhR, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTPI, XRCC1, ERCC2, MGMT, CCND1 and TP53) in 382 healthy Mexican Mestizos as the first step in elucidating the genetic structure of this population and identifying high risk individuals. All of the genotypes analyzed were in Hardy-Weinberg equilibrium, but different degrees of linkage were observed for polymorphisms in the CYP1A1 and EPHX1 genes. The genetic variability of this population was distributed in six clusters that were defined based on their genetic characteristics. The use of a polygenic model to assess the additive effect of low penetrance risk alleles identified combinations of risk genotypes that could be useful in predicting a predisposition to lung cancer. Estimation of the level of genetic susceptibility showed that the individual calculated risk value (iCRV) ranged from 1 to 16, with a higher iCRV indicating a greater genetic susceptibility to lung cancer.

Highlights

Lung cancer (LC) is the major cause of mortality from neoplasias worldwide
Association studies have focused mainly on polymorphisms in genes coding for (1) enzymes involved in the bioactivation of carcinogens, such as cytochromes P450 CYP1A1 (Shah et al, 2008), CYP2E1 (Zhan et al, 2010) and CYP2D6 (Shaw et al, 1998), (2) enzymes involved in detoxification, e.g., glutathione transferases GSTM1, GSTT1 and GSTP1 (Sobti et al, 2008), N-acetyl transferase 2 (NAT2) and epoxide hydrolase (EPHX1) (Zhou et al, 2002), (3) proteins involved in DNA repair, such as XRCC1, XRCC3, ERCC2, ERCC4, MGMT and OGG1 (Zienolddiny et al, 2006; Hung et al, 2007) and (4) proteins implicated in the cell cycle and apoptosis, such as CCND1, CHEK2, MDM2, TP53 and EGF (Hosgood III et al, 2008)
The following polymorphisms were studied in candidate genes: AhR rs2066853, CYP1A1 rs4646903, CYP1A1 rs1048943, CYP1A1 rs1800031, CYP1A1 rs1799814, CYP2E1 rs2031920, EPHX1 rs1051740, EPHX1 rs2234922, GSTM1 null, GSTT1 null, GSTPI rs947894, XRCC1 rs25487, ERCC2 rs13181, MGMT rs12917, CCND1 rs603965 and TP53 rs1042522

Summary

Introduction

Lung cancer (LC) is the major cause of mortality from neoplasias worldwide. In Mexico, LC was responsible for 11.45% of deaths by malignant neoplasia from 1998-2002, and a prospective study indicated that mortality from LC will be even greater in the future (Ruíz-Godoy et al, 2007). The World Health Organization (WHO) estimates that in 2030 the number of deaths attributable to the consumption of tobacco will be 100 million, accompanied by an increased incidence of LC (Xie and Minna, 2008). Lung cancer is highly related to tobacco consumption, only 20% of smokers develop LC. The number of cases among people under 50 years old has increased (Gemignani et al, 2007), highlighting the importance of genetic background in the etiology of LC. In this context, efforts have been made to identify polymorphisms associated with the risk of developing LC. Association studies have focused mainly on polymorphisms in genes coding for (1) enzymes involved in the bioactivation of carcinogens, such as cytochromes P450 CYP1A1 (Shah et al, 2008), CYP2E1 (Zhan et al, 2010) and CYP2D6 (Shaw et al, 1998), (2) enzymes involved in detoxification, e.g., glutathione transferases GSTM1, GSTT1 and GSTP1 (Sobti et al, 2008), N-acetyl transferase 2 (NAT2) and epoxide hydrolase (EPHX1) (Zhou et al, 2002), (3) proteins involved in DNA repair, such as XRCC1, XRCC3, ERCC2, ERCC4, MGMT and OGG1 (Zienolddiny et al, 2006; Hung et al, 2007) and (4) proteins implicated in the cell cycle and apoptosis, such as CCND1, CHEK2, MDM2, TP53 and EGF (Hosgood III et al, 2008)

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