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Tuesday, 25 February 2014

Endometrial Cancer - the Genes Mutation

Kyle J. Norton

The incidence of endometrial cancer among white women are higher in comparison to black. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as  BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.

Endometrium is the inner lining of the mammalian uterus and very susceptible hormone change, particular to menstrual cycle. Endometrial cancer is a late adulthood cancer defined as a condition of which the cells of the endometrial lining of uterus have growth uncontrollable or become cancerous as a result of the alternation of cells DNA. It's the fourth most common cancer among women overall, after breast cancer, lung cancer, and bowel cancer.

The genes mutation
1. BRCA1 or the BRCA2 gene 
Women who carry the genes BRCA1 or the BRCA2, according to Familial Breast Cancer Research study are associated to risk of endometrial cancer, specialty for  the gene BRCA, but the excessive risk is largely attributable to a history of Tamoxifen use.(1) and in aged group between 45 to 70(2).

2. Mutations in DNA mismatch repair (MMR) genes
Mutations in DNA mismatch repair (MMR) genes affects the DNA repair prowess, elevating endometrial cancer risk, due to the loss of proofreading activity of Polε (3). The University of Oxford study, indicated that mutation of germline exonuclease domain ((EDMs) of POLE and POLD1 are associated to predispose to endometrial cancer (EC) risk(4), Other study showed that defection in either DNA proofreading or MMR may relate to genomic instability and tumourigenesis(5).

3. Phosphatase and tensin homolog (PTEN)
Mation of Mutations of this gene are associated to the development of many types of cancer, specially in altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors(6)

4. K-ras mutations
K-ras gene, protein product plays an essential function in normal tissue signaling. Mutation of KRAS gene is associated to  the development of many cancers. According to the study by Haukel and University Hospital, KRAS mutations over amplification and expression were presented in 14.7% of primary lesions with no increase in metastatic lesions but in 18% of metastatic lesions, and high KRAS mRNA levels are associated with aggressive phenotype due to activation of ERK1/2 , (in regulating the malignant potential of cancer cells)(7). According to the study by Kanazawa University, 23% of patients with endometrial cancer carry  a mutation in exon 1 of KRAS(7) and 70% of Mutation in codon 12 of the K-ras gene in Serbian patients(8)

5.  β-catenin mutation
β-catenin plays an important role in dual function protein by regulating the coordination of cell–cell adhesion and gene transcription, Mutation and over expression are associated to increased risk of endometrial cancer(9). The Sapporo Medical University study insisted that alternation of the beta-catenin gene occurs in atypical hyperplasia or cancer, rather than in simple or complex hyperplasia without atypia(structural abnormality in a cell), during endometrial carcinogenesis(10).
In an immunohistochemically analyzed 80 endometrial samples (30 of normal endometrium, 20 of endometrial hyperplasia, and 30 of endometrial cancer), beta-catenin was observed in 30% of endometrial cancer samples(11).

6. Lynch syndrome
Lynch syndrome is an inherited condition with increased  risk of colon and other cancers, caused by a germ line mutation in a mismatch repair gene(12). The risk of Lynch syndrome among endometrial cancer patients is 4.6%(13). In a molecular screening for LS in patients with endometrial cancer  ≤ 70 years of age, the risk of  LS is 6% of cases(14), Inactivation of the mismatch repair genes MSH2 and MSH6 are associated to hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome)(15).

Taking altogether, genetic mutation of certain genes is associated with increased risk of endometrial cancer. Fortunately, certain foods and herbs have found to be effective in suppressing the expression and blocking the preoperative mechanism and pathways. Please note that all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.
 


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References
(1) The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study by Segev Y, Iqbal J, Lubinski J, Gronwald J, Lynch HT, Moller P, Ghadirian P, Rosen B, Tung N, Kim-Sing C, Foulkes WD, Neuhausen SL, Senter L, Singer CF, Karlan B, Ping S, Narod SA; Hereditary Breast Cancer Study Group.(PubMed)
(2) The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study by Beiner ME, Finch A, Rosen B, Lubinski J, Moller P, Ghadirian P, Lynch HT, Friedman E, Sun P, Narod SA; Hereditary Ovarian Cancer Clinical Study Group(PubMed)
(3) A common cancer-associated DNA polymerase {varepsilon} mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading by Kane DP, Shcherbakova PV(PubMed)
(4) [Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas].

[Article in French by Olschwang S, Bonaïti C, Feingold J, Frébourg T, Grandjouan S, Lasset C, Laurent-Puig P, Lecuru F, Millat B, Sobol H, Thomas G, Eisinger F.(PubMed)
(5) DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer by Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, Gorman M, Martin L, Howarth KM, Hodgson SV; NSECG Collaborators, Kaur K, Taylor J, Tomlinson IP(PubMed)
(6) Genetics of Endometrial Cancers by Tsuyoshi Okuda,1,* Akihiko Sekizawa,1 Yuditiya Purwosunu,1, 2 Masaaki Nagatsuka,1 Miki Morioka,1 Masaki Hayashi,1 and Takashi Okai(PubMed)
(7) KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer by Birkeland E, Wik E, Mjøs S, Hoivik EA, Trovik J, Werner HM, Kusonmano K, Petersen K, Raeder MB, Holst F, Øyan AM, Kalland KH, Akslen LA, Simon R, Krakstad C, Salvesen HB.(PubMed)
(8) Genetic alterations in SMAD4 and K-ras in Serbian patients with endometrial carcinoma by Nikolic A, Ristanovic M, Perovic V, Trifunovic J, Perovic M, Radojkovic D.(PubMed)
(9) Frequent β-catenin gene mutations in atypical polypoid adenomyoma of the uterus by Takahashi H, Yoshida T, Matsumoto T, Kameda Y, Takano Y, Tazo Y, Inoue H, Saegusa M(PubMed)
(10) Mutation of beta-catenin gene in endometrial cancer but not in associated hyperplasia by Ashihara K, Saito T, Mizumoto H, Nishimura M, Tanaka R, Kudo R.(PubMed)
(11) Nuclear localization of beta-catenin in normal and carcinogenic endometrium by Nei H, Saito T, Yamasaki H, Mizumoto H, Ito E, Kudo R.(PubMed)
(12) Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome by Win AK, Lindor NM, Winship I, Tucker KM, Buchanan DD, Young JP, Rosty C, Leggett B, Giles GG, Goldblatt J, Macrae FA, Parry S, Kalady MF, Baron JA, Ahnen DJ, Marchand LL, Gallinger S, Haile RW, Newcomb PA, Hopper JL, Jenkins MA(PubMed)
(13) Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers by Egoavil C, Alenda C, Castillejo A, Paya A, Peiro G, Sánchez-Heras AB, Castillejo MI, Rojas E, Barberá VM, Cigüenza S, Lopez JA, Piñero O, Román MJ, Martínez-Escoriza JC, Guarinos C, Perez-Carbonell L, Aranda FI, Soto JL.(PubMed)
(14) Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years by Leenen CH, van Lier MG, van Doorn HC, van Leerdam ME, Kooi SG, de Waard J, Hoedemaeker RF, van den Ouweland AM, Hulspas SM, Dubbink HJ, Kuipers EJ, Wagner A, Dinjens WN, Steyerberg EW.(PubMed)
(15) Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities Michael A. Edelbrocka,, Saravanan Kaliyaperumalb, , Kandace J. Williams(Science direct)