Single Nucleotide Polymorphisms and Incidence of Lymphoma Lucy Brining Abstract Lymphoma is the fifth most commonly diagnosed cancer in the United States and incidence levels are increasing with little new information on possible causes Several cancers are known to be associated with genetic aberrations This study investigates the relationship between developing lymphoma and genetic aberrations known as single nucleotide polymorphisms SNPs found in the MIF CY1PA APM1 and LEP genes SNPs are single nucleotide base changes within a gene whose presence is posited to interfere with the genes function The study tested whether the presence of one or more of the SNPs in question and the interactions between two SNPs increases the risk of developing lymphoma To investigate the hypothesis DNA was isolated from 1 236 controls and subjects with the subjects being cancer patients and analyzed for presence of the four SNPs using Real Time PCR analysis The data were tested for Hardy Weinburg equilibrium to determine normalcy of the data set and analyzed using chi squared analyses looking for associations between the presence of the SNPs and lymphoma Results are expected to show that the presence of two of the SNPs will have synergistic interactions and are associated with the development of lymphoma In addition the results might show the presence of at least one of the SNPs correlates with the development of lymphoma Findings from this study could serve as potential biomarkers for cancer in the future Introduction With only a five year survival rate of 52 in the US lymphomas are the fifth most common cancer affecting about 60 900 people a year Chang et al 2003 Despite diagnosis improvements and considerable efforts to identify possible risk factors the causes of most lymphoma cases are unknown and the incidence of lymphoma is increasing Chang et al 2003 Since 1970 the incidence of lymphoma has nearly doubled American Cancer Society 2002 With rates of lymphoma increasing and little understanding why there is a need for studies investigating possible factors Previous studies have looked at associations between lymphoma and environmental and occupational exposures to chemicals including pesticides Few of these studies however resulted in consistent conclusions and in fact many contradicted one another Zheeb and Blettner 1998 Medically applied radio and chemotherapy have been reported as high risk factors however again inconsistently Hereditary factors like chromosomal syndromes and genetically inherited diseases are proven to put an individual in a high risk category however they are extremely rare in the population Zheeb and Blettner 1998 Even though such studies correlate the development of the disease with certain factors few of these studies draw solid conclusions about the known risks for none of the risks are absolute Conclusions drawn from such studies are inconsistent with one another due to the fact that cancers are not caused by exposure to one chemical or radiation treatment but rather a combination of events In an attempt to investigate synergistic relationships between risk factors like smoking drinking or diet there have been case studies looking at whether the incidence of lymphomas is affected by such risk factors Zheeb and Blettner 1998 However there have been very few studies investigating synergistic relationships between genes Thus there have been few attempts at identifying groups of genes which could serve as potential biomarkers for lymphoma The few that have been determined are genes that lead to breast cancer pancreatic cancer and gastrointestinal cancer Mimori et al 02 Kawakam et al 99 Chang et al 03 The aim of this study is to identify possible new biomarkers so that in the future populations can be tested to evaluate the risk of developing lymphoma In order to develop such biomarkers we need to investigate possible genes and the synergistic relationships between genes For this study we are looking specifically at single nucleotide polymorphisms or SNPs SNPs are single nucleotide base changes in a genetic sequence which on their own do not result in a change of phenotype The SNP could in theory go unnoticed for an entire lifetime However it is posited that such base changes in combination with other factors could become the starting points for cancer development For instance if the SNP codes for a different amino acid within the protein and if there is some change in the gene environment the amino acid coded by the SNP might act differently changing the shape and thus the function of the protein Skibola et al 2002 The change in function could lead to over or under expression of the gene resulting in the development of cancer The presence of SNPs is not significant for all genes only genes whose over or under expression could result in cancerous growth In our case the specific genes in question for this study are MIF CYP1A LEP and AMP1 An interesting characteristic of the MIF gene is that it is thought to control cell proliferation cell survival angiogenesis cell differentiation T Lymphocytic activation and thus tumor progression Chesney et al 1998 Takahashi et al 1998 Wistow et al 1993 There are also reports that MIF is over expressed in many cancers including leukemia Chesney et al 1998 Huggins and Fukunishi 1964 CYP1A encodes an enzyme that converts environmental pro carcinogens to reactive intermediates with carcinogenic effects Additionally studies have shown that CYP1A catalyzes the oxidative metabolites of estrogens another possible starting point for cancer Chang et al 2003 Studies found that SNPs in the CYP1A gene are associated with increased cancer risks Chang et al 2003 LEP is ubiquitous in recent literature correlating the gene with obesity However in addition to obesity LEP also controls hematopoiesis angiogenesis and immune and inflammatory responses LEP is also found to be involved in certain cancers In their 2003 study Comings et al found that the LEP gene is related to breast cancer Finally AMP1 is the adipose tissue s most abundant gene transcript and is exclusively expressed in adipose tissue It is similar to the LEP gene in that it is thought to have some correlation with obesity Diez and Iglesias found in March 2003 that APM1 also decreases inflammatory responses All of the above genes serve as possible starting points for cancer and thus are good areas to study For the study we collected blood samples from San Francisco a population From the blood
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