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Molecular Genetic Alterations In Endometrial And Ovarian Cancers

Koul, Anjila LU (2001)
Abstract (Swedish)
Popular Abstract in Swedish

Svensk Sammanfattning Gen-förändringar i endometrie- och ovarial cancer: Endometriecancer (EC, cancer i livmoderslemhinnan) är den vanligaste gynekologiska cancerformen i västvärlden. Tumörutvecklingen kan associeras till en östrogen-inducerad stimulans av endometriets tillväxt i avsaknad av den differentierande effekten av progesteron. Den maligna cancern föregås i vissa fall av benigna förstadier, såsom hyperplasi eller komplex atypisk hyperplasi (CAH), vilket är vanligare hos yngre kvinnor i mindre avancerat sjukdomsstadie och med bättre prognos, liksom i tumörer av gynnsam histologisk typ och positiv progesteronreceptor-status. De distinkta molekylärgenetiska förändringar som kännetecknar... (More)
Popular Abstract in Swedish

Svensk Sammanfattning Gen-förändringar i endometrie- och ovarial cancer: Endometriecancer (EC, cancer i livmoderslemhinnan) är den vanligaste gynekologiska cancerformen i västvärlden. Tumörutvecklingen kan associeras till en östrogen-inducerad stimulans av endometriets tillväxt i avsaknad av den differentierande effekten av progesteron. Den maligna cancern föregås i vissa fall av benigna förstadier, såsom hyperplasi eller komplex atypisk hyperplasi (CAH), vilket är vanligare hos yngre kvinnor i mindre avancerat sjukdomsstadie och med bättre prognos, liksom i tumörer av gynnsam histologisk typ och positiv progesteronreceptor-status. De distinkta molekylärgenetiska förändringar som kännetecknar utvecklingen av EC, med eller utan CAH, är däremot ofullständigt kända. Hereditär icke-polypös coloncancer orsakas av konstitutionella (germline) mutationer i DNA mismatch reparations (MMR) gener, och syndromet kännetecknas huvudsakligen av coloncancer men även av cancer i endometriet och ovarierna. Tumörvävnad från dessa patienter har karakteristiska förändringar i repetitiva DNA element (mikrosatellitinstabilitet, MSI). MSI kan även orsakas av somatiska MMR-gen mutationer i vissa sporadiska colontumörer, och en andel av sporadisk EC kännetecknas också MSI, dock utan påvisade mutationer i MMR-gener. Denna avhandling innefattar studier av ett histologiskt välkarakteriserat material av EC. Tumörer med/utan CAH har analyserats för mutationer i TP53, PTEN, KRAS, B-catenin, CDKN2A, BRCA1 och BRCA2 generna, liksom för DNA ploidi och MSI. Mutationer i PTEN, KRAS, B-catenin och TP53 identifierades i tumörer både med och utan associerad CAH. Mutationer i PTEN korrelerade med MSI och DNA-diploid, medan TP53 mutation var associerat med DNA-aneuploid. Två tredjedelar av detta EC material hade mutation i endera av de analyserade generna, men enbart ett fåtal tumörer hade mutation i mer än en gen, vilket talar för att EC utvecklas via olika genetiska samspel. Cirka 90% av EC diagnostiseras i stadium I eller II, och har en femårs-överlevnad av 85% respektive 70%. Behovet är stort av markörer för identifiering av en hög-risk grupp bland dessa patienter. I denna avhandling sågs en signifikant korrelation mellan förändringar i TP53 genen (mutation eller överuttryck av proteinprodukten) och ett flertal kända prognostiska faktorer, liksom till en sämre överlevnad, både hos patienter med tidigt och avancerat stadium av EC. DNA-aneuplodi var, emellertid, en ännu starkare markör för aggressiv sjukdom hos kvinnor med EC stadium I-II. Den starkaste riskfaktorn för utveckling av ovariecancer (OC) är en känd familje historia för OC eller bröstcancer. De flesta familjära fallen av OC är associerade med germline BRCA1 eller BRCA2 mutation, men frekvensen av dessa mutationer i OC ej selekterad för familjehistoria är dåligt utredd. Denna avhandling innefattar en pilotstudie av ett mindre antal OC, där en överraskande hög frekvens av BRCA-mutationer kunde identifieras, vilket har föranlett en utvidgad studie i ett populations baserat material. Tumörer med BRCA-mutation var uteslutande av histologisk serös/seropapillär typ, och en oväntad upptäckt var förekomsten av BRCA1 mutation i två fall av OC med metastasering till hjärnan. (Less)
Abstract
Endometrial cancer is the most common gynecological cancer diagnosed in western countries. Complex atypical hyperplasia (CAH) reflects a state of hyperestrinism and its role as a precursor lesion of this cancer is established. Endometrial cancers arising in association with CAH are reported in women of younger age, with early stage disease, favorable histological types, higher progesterone receptor levels and clinically better survival prognosis. However, the molecular events delineated in these two pathogenetic types are less known. Hereditary nonpolyposis colon cancer is caused by germline mutations in DNA mismatch repair (MMR) genes, and associated mainly with cancer in the colon, while endometrial and ovarian cancer are the most common... (More)
Endometrial cancer is the most common gynecological cancer diagnosed in western countries. Complex atypical hyperplasia (CAH) reflects a state of hyperestrinism and its role as a precursor lesion of this cancer is established. Endometrial cancers arising in association with CAH are reported in women of younger age, with early stage disease, favorable histological types, higher progesterone receptor levels and clinically better survival prognosis. However, the molecular events delineated in these two pathogenetic types are less known. Hereditary nonpolyposis colon cancer is caused by germline mutations in DNA mismatch repair (MMR) genes, and associated mainly with cancer in the colon, while endometrial and ovarian cancer are the most common extracolonic malignancies in these patients. Tumors from mutation carriers are characterized by an microsatellite instability (MSI) phenotype, and a subset of sporadic colon cancer demonstrates MSI and somatic mutations in MMR genes. MSI is also reported in a subset of sporadic endometrial cancers, although without identifiable mutation in MMR genes. In this study, endometrial cancers histologically checked for presence/absence of CAH were analyzed for mutations in the TP53, PTEN, KRAS, B-catenin, CDKN2A, BRCA1, and BRCA2 genes, as well as for their DNA ploidy and MSI. Two thirds of the endometrial tumors included in the study contained mutation in either of the seven genes analyzed, but very few cases with coexisting mutations were recorded, suggesting alternate genetic pathways in tumorigenesis. We found that PTEN, KRAS, B-catenin, and TP53 mutations were present in tumors both with and without CAH. PTEN mutations associated with MSI and DNA diploidy, while TP53 mutations related to DNA nondiploidy.



Approximately 90% of all endometrial cancers are diagnosed in surgical stage disease I and II, with a five-year survival of 85% to 70%, respectively. A consensus opinion regarding useful prognostic markers to identify a “high-risk” subset among these patients is, however, lacking. In this study, TP53 alterations (mutation or protein overexpression) correlated to several clinicopathological markers of poor prognosis in endometrial cancer, and decreased progression-free survival in both early and advanced stage disease. However, DNA nondiploidy seemed to be an even better marker of poor prognosis in patients with early stage disease (I-II).



The strongest risk factor for ovarian cancer is a positive family history of ovarian or breast cancer. While the majority of familial cases are associated with germline BRCA1 or BRCA2 mutation, the frequency of mutations in cases unselected for family history is still unclear. In the present pilot study of ovarian tumors, we detected a surprisingly high frequency of both germline and somatic BRCA-gene mutations, emphasizing the importance of extended analysis of population-based series of patients to determine the true contribution of these predisposing genes to the overall incidence of ovarian cancer in this population. BRCA-gene mutations strongly associated with a serous/seropapillary histological type. Unexpectedly, BRCA1 mutations were seen in two cases of ovarian cancer with brain metastasis. (Less)
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author
opponent
  • Docent Grönberg, Henrik
organization
publishing date
type
Thesis
publication status
published
subject
keywords
KRAS, PTEN, TP53, Overexpression, Mutation, Microsatellite instability, Complex atypical hyperplasia, Endometrial cancer, Ovarian cancer, cancer, onkologi, Cytologi, cancerology, oncology, Cytology, CNS metastasis, Cytogenetic analysis, BRCA2, BRCA1, B-catenin, CDKN2A
pages
105 pages
publisher
Department of Oncology, Clinical Sciences, Lund University
defense location
Lecture Hall, Department of Oncology
defense date
2001-10-08 09:00
external identifiers
  • Other:ISRN: LUMEDW/MEOK-1029-SE
ISBN
91-628-4940-9
language
English
LU publication?
yes
id
481e736a-50f9-4a20-8264-c488b00a431d (old id 41811)
date added to LUP
2007-06-21 12:10:49
date last changed
2016-09-19 08:45:04
@misc{481e736a-50f9-4a20-8264-c488b00a431d,
  abstract     = {Endometrial cancer is the most common gynecological cancer diagnosed in western countries. Complex atypical hyperplasia (CAH) reflects a state of hyperestrinism and its role as a precursor lesion of this cancer is established. Endometrial cancers arising in association with CAH are reported in women of younger age, with early stage disease, favorable histological types, higher progesterone receptor levels and clinically better survival prognosis. However, the molecular events delineated in these two pathogenetic types are less known. Hereditary nonpolyposis colon cancer is caused by germline mutations in DNA mismatch repair (MMR) genes, and associated mainly with cancer in the colon, while endometrial and ovarian cancer are the most common extracolonic malignancies in these patients. Tumors from mutation carriers are characterized by an microsatellite instability (MSI) phenotype, and a subset of sporadic colon cancer demonstrates MSI and somatic mutations in MMR genes. MSI is also reported in a subset of sporadic endometrial cancers, although without identifiable mutation in MMR genes. In this study, endometrial cancers histologically checked for presence/absence of CAH were analyzed for mutations in the TP53, PTEN, KRAS, B-catenin, CDKN2A, BRCA1, and BRCA2 genes, as well as for their DNA ploidy and MSI. Two thirds of the endometrial tumors included in the study contained mutation in either of the seven genes analyzed, but very few cases with coexisting mutations were recorded, suggesting alternate genetic pathways in tumorigenesis. We found that PTEN, KRAS, B-catenin, and TP53 mutations were present in tumors both with and without CAH. PTEN mutations associated with MSI and DNA diploidy, while TP53 mutations related to DNA nondiploidy.<br/><br>
<br/><br>
Approximately 90% of all endometrial cancers are diagnosed in surgical stage disease I and II, with a five-year survival of 85% to 70%, respectively. A consensus opinion regarding useful prognostic markers to identify a “high-risk” subset among these patients is, however, lacking. In this study, TP53 alterations (mutation or protein overexpression) correlated to several clinicopathological markers of poor prognosis in endometrial cancer, and decreased progression-free survival in both early and advanced stage disease. However, DNA nondiploidy seemed to be an even better marker of poor prognosis in patients with early stage disease (I-II).<br/><br>
<br/><br>
The strongest risk factor for ovarian cancer is a positive family history of ovarian or breast cancer. While the majority of familial cases are associated with germline BRCA1 or BRCA2 mutation, the frequency of mutations in cases unselected for family history is still unclear. In the present pilot study of ovarian tumors, we detected a surprisingly high frequency of both germline and somatic BRCA-gene mutations, emphasizing the importance of extended analysis of population-based series of patients to determine the true contribution of these predisposing genes to the overall incidence of ovarian cancer in this population. BRCA-gene mutations strongly associated with a serous/seropapillary histological type. Unexpectedly, BRCA1 mutations were seen in two cases of ovarian cancer with brain metastasis.},
  author       = {Koul, Anjila},
  isbn         = {91-628-4940-9},
  keyword      = {KRAS,PTEN,TP53,Overexpression,Mutation,Microsatellite instability,Complex atypical hyperplasia,Endometrial cancer,Ovarian cancer,cancer,onkologi,Cytologi,cancerology,oncology,Cytology,CNS metastasis,Cytogenetic analysis,BRCA2,BRCA1,B-catenin,CDKN2A},
  language     = {eng},
  pages        = {105},
  publisher    = {ARRAY(0x8631ef8)},
  title        = {Molecular Genetic Alterations In Endometrial And Ovarian Cancers},
  year         = {2001},
}