Analysis of polymorphisms / mutations of PTEN, CDKN2A, TP53 genes and of hMSH6 gene in endometrial hyperplasia and carcinoma

• Authors: Michał Bednarek , Maria Constantinou , Bogdan Kałużewski

Title variants

PL

Analiza polimorfizmów/mutacji genów PTEN, CDKN2A, TP53 oraz genu hMSH6 w rozrostach oraz rakach endometrium

• Languages of publication: EN

Abstracts

EN

Endometrial cancer belongs to the most frequent malignancies in the female genital organs with a growing incidence trend. The molecular changes, which are specific for particular stages of neoplastic transformation or the histopathological type of neoplasm, have not yet been described in any more uniform way. The goal of the undertaken studies was the evaluation of the polymorphisms / mutations of PTEN, CDKN2A, TP53 suppressor genes and of hMSH6 gene of incorrectly paired base-pairs in a group of female patients with endometrial hyperplasia and endometrial cancer. The studies involved forty-four (44) female patients: five (5) cases, despite the fact that clinical inclusion criteria had been met, no hyperplastic features were confirmed in a histopathological analysis. Twenty-six (26) patients with histopathologically confirmed endometrial hyperplasia and thirteen (13) patients with diagnosed carcinoma of uterine body mucosa were added into the study. The sequencing method was used for the identification of mutations / polymorphisms in MSH6, CDKN2A, PTEN and TP53 genes. Two changes were identified in TP53 gene: R175H G>A (CGC>CAC) polymorphism in exon 5 and R213R (CGA>CGG) synonimic change in exon 6 in 15% of the examined patients (2/13 cases of endometrial cancer). Regarding DNA sequence of exon 3 in MSH6 gene, the following polymorphism was found in 29% of the patients: D180D (GAT>GAC). None of the patients demonstrated any changes, either in DNA sequence of CDKN2A gene or in exons 2, 5, 7 and 8 of the PTEN gene.

PL

Rak endometrium należy do najczęstszych nowotworów złośliwych żeńskich narządów płciowych. Rejestruje się stały wzrost liczby zachorowań. Dotychczas nie zostały jednoznacznie opisane zmiany molekularne, specyficzne dla poszczególnych etapów transformacji nowotworowej lub typu histopatologicznego nowotworu. Celem podjętych badań była analiza polimorfizmów/ mutacji genów supresorowych PTEN, CDKN2A, TP53 oraz genu naprawy błędnie sparowanych zasad hMSH6 w grupie pacjentek z rozrostem endometrium oraz rakiem endometrium. Badaniami objęto 44 pacjentki: w 5 przypadkach, pomimo spełnienia klinicznych kryteriów włączenia, histopatologicznie nie potwierdzono cech rozrostu, do dalszych badań włączono 26 pacjentek z histopatologicznie potwierdzonym rozrostem endometrium oraz 13 pacjentek ze zdiagnozowanym rakiem błony śluzowej trzonu macicy. Do identyfikacji mutacji/polimorfizmów w genach MSH6, CDKN2A, PTEN i TP53 wykorzystano metodę sekwencjonowania. W genie TP53 wykryliśmy dwie zmiany: polimorfizm R175H G>A (CGC>CAC) w egzonie 5 oraz zmianę synonimiczną R213R (CGA>CGG) w egzonie 6 u 15% badanych (2/13 przypadków raka endometrium). W sekwencji DNA egzonu 3 genu MSH6 u 29% pacjentek został wykryty polimorfizm: D180D (GAT>GAC). U żadnej z pacjentek nie została wykryta zmiana w sekwencji DNA genu CDKN2A oraz w egzonach 2; 5; 7 i 8 genu PTEN.

Keywords

EN

CDKN2A; PTEN; TP53; endometrial cancer; endometrial hyperplasia; hMSH6.

Discipline

• MEDICINE: MEDICINE

• Publisher: Łódzkie Towarzystwo Naukowe
• Journal: Folia Medica Lodziensia
• Year: 2014
• Volume: 41
• Issue: 1
• Pages: 17-32

Contributors

author

Michał Bednarek

• Chair of Clinical and Laboratory Genetics, Department of Clinical Genetics, Medical University of Lodz

author

Maria Constantinou

• Chair of Clinical and Laboratory Genetics, Department of Clinical Genetics, Medical University of Lodz

author

Bogdan Kałużewski

• Chair of Clinical and Laboratory Genetics, Department of Clinical Genetics, Medical University of Lodz

References

• Didkowska J, Wojciechowska U, Tarkowski W, Zatoński W. Nowotwory złośliwe w Polsce w 2006 r. Centrum Onkologii – Instytut im. M. Skłodowskiej- Curie, Warszawa 2008.
• Silverberg SG, Kurman RJ, Nogales F, Mutter G, Kubik-Huch RA, Tavassoli FA. Epithelial tumors and related lesions. In: Devilee P, Tavassoli FA, editors. Pathology and Genetics of Tumors of the Breast and Female Organs. Lyon, France: IARC Press; 2003.
• Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983; 15(1): 10-17.
• Koul A, Willen R, Bendahl PO, Nilbert M, Borg A. Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis. Cancer. 2002; 94: 2369-2379.
• Salvesen HB, Akslen LA. Molecular pathogenesis and prognostic factors in endometrial carcinoma. APMIS. 2002; 110: 673-689.
• Prat J, Gallardo A, Cuatrecasas M, Catasus L. Endometrial carcinoma: pathology and genetics. Pathology. 2007; 39: 72-87.
• Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet. 2005; 366: 491-505.
• Salvesen HB, Stefansson I, Kretzschmar EI, Gruber P, MacDonald ND, Ryan A et al. Significance of PTEN alterations in endometrial carcinoma: a populationbased study of mutations, promoter methylation and PTEN protein expression. Int J Oncol. 2004; 25: 1615-1623.
• Maxwell GL, Risinger JI, Gumbs C, Shaw H, Bentley RC, Barrett JC et al. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res. 1998; 58: 2500-25003.
• Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000; 92: 924-930.
• Ricci R, Komminoth P, Bannwart F, Torhorst J, Wight E, Heitz PU et al. PTEN as a molecular marker to distinguish metastatic from primary synchronous endometrioid carcinomas of the ovary and uterus. Diagn Mol Pathol. 2003; 12: 71-78.
• Bussaglia E, del Rio E, Matias-Guiu X, Prat J. PTEN mutations in endometrial carcinomas: a molecular and clinicopathologic analysis of 38 cases. Hum Pathol. 2000; 31(3): 312-317.
• Risinger JI, Hayes K, Maxwell GL, Carney ME, Dodge RK, Barrett JC, et al. PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics. Clin Cancer Res. 1998; 4(12): 3005-3010.
• Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L. p53 mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Amer. J. Pathol. 1997; 150: 177-185.
• Okuda T, Sekizawa A, Purwosunu Y, Nagatsuka M, Morioka M, Hayashi M et al. Genetics of endometrial cancers. Obstet Gynecol Int. 2010: 1-8.
• Soong R, Knowles S, Williams KE, Hammond IG, Wysocki SJ, Iacopetta BJ. Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma. Br J Cancer. 1996; 74: 562-567.
• Pisani AL, Barbuto DA, Chen D, Ramos L, Lagasse LD, Karlan BY. HER-2/neu, p53, and DNA analyses as prognosticators for survival in endometrial carcinoma. Obstet Gynecol. 1995; 85: 729-734.
• Reinartz JJ, George E, Lindgren BR, Niehans GA. Expression of p53, transforming growth factor alpha, epidermal growth factor receptor, and c-erbB-2 in endometrial carcinoma and correlation with survival and known predictors of survival. Hum Pathol. 1994; 25: 1075-1083.
• Tsang WP, Ho FY, Fung KP, Kong SK, Kwok TT. p53-R175H mutant gains new
• function in regulation of doxorubicin-induced apoptosis. Int J Cancer. 2005;
• 10;114(3): 331-336.
• Samarnthai N, Hall K, Yeh I-T. Molecular Profiling of endometrial Malignancies. Obstet Gynecol Int. 2010; 2010: 1-16.
• Hannemann MM, Alexander HM, Cope NJ, Acheson N, Phillips A. Endometrial hyperplasia: a clinician's review. Obstetrics, Gynaecology & Reproductive Medicine 2010; 20 (4): 116–120.
• Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L. The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer. 2000; 88(4): 814-824.

• Document Type: paper