A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Stacey, Simon; Sulem, Patrick; Jónasdóttir, Áslaug; Másson, Gísli; Guðmundsson, Jūlı́us; Guðbjartsson, Daníel F.; Magnússon, Ólafur Þ.; Gudjonsson, Sigurjon A.; Sigurgeirsson, Bárður; Thorisdottir, Kristin; Ragnarsson, Rafn; Benediktsdóttir, Kristrún R.; Nexø, Bjørn A.; Tjønneland, Anne; Overvad, Kim; Rudnai, Péter; Gurzău, Eugen; Koppová, Kvetoslava; Hemminki, Kari; Corredera, Cristina; Fuentelsaz, Victoria; Grasa, Pilar; Navarrete, Sebastián; Fuertes, Fernando; García-Prats, María Dolores; Sanambrosio, Enrique; Panadero, Angeles; Juan, Ana De; Garcia, Almudena; Rivera, Fernando; Planelles, Dolores; Soriano, Vincent; Requena, Celia; Aben, Katja K.H.; Rossum, Michelle M. van; Cremers, R.G.H.M.; Oort, Inge M. van; Spronsen, Dick Johan van; Schalken, Jack A.; Peters, Wilbert H.M.; Helfand, Brian T.; Donovan, Jenny; Hamdy, Freddie C.; Badescu, D.; Codreanu, O.; Jinga, Mariana; Csiki, Irma Eva; Constantinescu, Vali; Badea, P; Mateș, Ioan Nicolae; Dinu, Daniela; Constantin, Adrian; Mateș, Dana; Kristjansdottir, Sjofn; Agnarsson, Bjarni A.; Jónsson, Eiríkur; Barkardóttir, Rósa B.; Einarsson, Guðmundur; Sigurdsson, Fridbjörn; Möller, Páll Helgi; Stefánsson, Tryggvi; Valdimarsson, Trausti; Jóhannsson, Óskar T.; Sigurðsson, Helgi; Jónsson, Þorvaldur; Jonasson, Jón G.; Tryggvadóttír, Laufey; Rice, Terri; Hansen, Helen M.; Xiao, Yuanyuan; Lachance, Daniel H.; O’Neill, Brian Patrick; Kosel, Matthew L.; Decker, Paul A.; Þorleifsson, Guðmar; Johannsdottir, Hrefna; Helgadottir, Hafdís T.; Sigurðsson, Ásgeir; Steinthórsdóttir, Valgerður; Lindblom, Annika; Sandler, Robert S.; Keku, Temitope O.; Banasik, Karina; Jørgensen, Torben; Witte, Daniel R.; Hansen, Torben; Pedersen, Oluf; Jinga, Viorel; Neal, David E.; Catàlona, William J.; Wrensch, Margaret; Wiencke, John K.; Jenkins, Robert B.; Nagore, Eduardo; Vogel, Ulla; Kiemeney, Lambertus A.; Kumar, Rajiv; Mayordomo, J. I.; Ólafsson, Jón; Kong, Augustine; Þorsteinsdóttir, Unnur; Rafnar, Thorunn; Stefánsson, Kāri

doi:10.1038/ng.926

Cited by 269 publications

(281 citation statements)

References 24 publications

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“…The proline variant is effective in the repair of DNA damage, while the arginine variant leads to a strong induction of apoptosis (13). To date, studies have been performed on the P53 codon 72 polymorphism in breast, colorectal, skin and stomach cancers; however, no comprehensive result has been obtained (13)(14)(15)(16). Considering the controversial results regarding the role of P53 gene polymorphism in gastric cancer, dependence of variants on geographical conditions, racial differences and genetic differences probably exists in different communities.…”

Section: Introductionmentioning

confidence: 99%

Association of P53 gene polymorphism with gastric cancer in Northern Iran as a high‑risk region

et al. 2018

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Abstract. Gastric cancer has the fourth highest morbidity rate of all cancers worldwide. Genetic factors including alterations in oncogenes and tumor suppressor genes serve an important role in gastric cancer development and progression. The P53 gene acts as a tumor suppressor gene by regulating the cell cycle, DNA transcription and repair, apoptosis, senescence and genome stability. In addition to somatic P53 mutations in cancer development, germline polymorphisms are also involved in different malignancies. The polymorphism of P53 at codon 72 (Arg72Pro) is established as a common variant that increases susceptibility to various cancers. The present case-control study was conducted to evaluate the possible association between this P53 polymorphism and gastric cancer in the Iranian population. A total of 59 patients with gastric cancer and 59 healthy controls were enrolled in the present study. Genomic DNA was extracted from peripheral blood mononuclear cells and genotype analysis was performed using a polymerase chain reaction-based restriction fragment length polymorphism assay. Genotype frequencies did not differ significantly between the patients and controls (P=0.4); the frequencies of the three genotypes Arg/Arg, Arg/Pro and Pro/Pro in gastric cancer patients were 28.8, 49.2 and 22.0%, and in controls were 37.3, 49.2 and 13.6%. Additionally, there were no differences in genotype frequencies based on tumor location, histological differentiation or tumor stage. Based on these findings, it may be concluded that the P53 codon 72 polymorphism does not contribute to gastric cancer susceptibility in Northern Iran. IntroductionGastric cancer has the third highest mortality and fourth highest morbidity rates of all cancers worldwide (1). In 2012, GloboCan statistics reported almost 1 million new cases of gastric cancer, and more than 700,000 mortalities caused by gastric cancer (1). Gastric cancer is a multifactorial disorder, in which genetic and environmental interactions serve an important role in development and progression (2). Increasing age, gender, lifestyle, dietary regime, environmental factors and Helicobacter pylori infections are among the known risk factors for stomach cancer (3,4). While dietary regime and lifestyle are the most recognized factors, more effective identification of the genetic risk factors is expected to improve understanding of the basic molecular events involved in tumorigenesis (5). Various genetic and epigenetic changes that have the potential to convert normal epithelial cells in the stomach into malignant neoplasms may be responsible for the development of both familial and sporadic gastric cancer (6,7). Studies performed recently have demonstrated that a high number of genes and various environmental factors are the causal agents of gastric cancer, and the presence of different forms of alleles in genes (polymorphisms) may promote the development of cancers; in this regard, the P53 gene has been a research focus due to its role as a major tumor suppressor gene (8,9). The P53 ge...

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Section: Introductionmentioning

confidence: 99%

Association of P53 gene polymorphism with gastric cancer in Northern Iran as a high‑risk region

et al. 2018

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“…These advances will largely facilitate the discovery of disease-causing variants. Of note, recent whole genome sequencing studies have discovered a number of novel abnormalities in cancer genomes [22][23][24][25][26][27][28] (Table 2). Furthermore, the characterization of unique mutational patterns of individual cancer genomes has shown great promise in personalized cancer therapy [29,30].…”

Section: Genome-wide Discovery Of Causal Variantsmentioning

confidence: 99%

Next-generation sequencing in the clinic: Promises and challenges

et al. 2013

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The advent of next generation sequencing (NGS) technologies has revolutionized the field of genomics, enabling fast and cost-effective generation of genome-scale sequence data with exquisite resolution and accuracy. Over the past years, rapid technological advances led by academic institutions and companies have continued to broaden NGS applications from research to the clinic. A recent crop of discoveries have highlighted the medical impact of NGS technologies on Mendelian and complex diseases, particularly cancer. However, the everincreasing pace of NGS adoption presents enormous challenges in terms of data processing, storage, management and interpretation as well as sequencing quality control, which hinder the translation from sequence data into clinical practice. In this review, we first summarize the technical characteristics and performance of current NGS platforms. We further highlight advances in the applications of NGS technologies towards the development of clinical diagnostics and therapeutics. Common issues in NGS workflows are also discussed to guide the selection of NGS platforms and pipelines for specific research purposes.

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“…It is believed that genetic variants are the main risk factors that contribute to prostate cancer. There is now substantial knowledge that many genes and chromosome segments are significantly associated with prostate cancer risks in a multiethnic population, such as PCA3 , CYP17 (Wang et al, 2011), TP53 (Stacey et al, 2011), 8q24 (Zeegers et al, 2011), and 9q22 (Wentzensen et al, 2011). However, no comprehensive knowledge on the precise mechanism of the interaction of these genetic factors, especially in the prognosis of prostate cancer, has been provided to date.…”

Section: Discussionmentioning

confidence: 99%

Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population

Liu¹,

Liu²,

Wei³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. has been implicated in a wide variety of cellular functions that affect the biological response to tumors. However, there is insufficient evidence to prove that IL-18 gene variants are associated with risk of prostate cancer. We examined a possible association between two promoter polymorphisms, -137G/C (rs187238) and -607C/A (rs1946518), in the IL-18 gene and prostate cancer occurrence and prognosis in Han Chinese. We used a high-resolution melting method to genotype these two polymorphisms in 375 Chinese Han patients with prostate cancer and in 400 age-matched healthy controls. A hundred and eighty-one prostate cancer patients who had been receiving androgen deprivation therapy, including operational and medical castration, were enrolled to follow-up in this study. Carriers of the GG genotype of the -137G/ C polymorphism had a 2.165-times higher risk of prostate cancer progression than carriers of GC [95% confidence interval (CI) = 1.270-3.687]. Patients with the GG genotype at clinical stages III and IV also had significantly lower rates of progression-free survival (relative risk = 2.174, 95%CI = 1.211-3.906). However, we found no significant association of genotype or allele distributions of these two polymorphisms with occurrence of prostate cancer. We conclude that there is evidence that the IL-18 gene promoter polymorphism -137G/ C influences the prognosis of prostate cancer patients in androgen deprivation therapy, although neither of the two SNPs contributes to prostate cancer development.

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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Cited by 269 publications

References 24 publications

Association of P53 gene polymorphism with gastric cancer in Northern Iran as a high‑risk region

Association of P53 gene polymorphism with gastric cancer in Northern Iran as a high‑risk region

Next-generation sequencing in the clinic: Promises and challenges

Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population

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