High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma

Garcia-Dios, Diego A., Lambrechts, Diether, Coenegrachts, Lieve, Vandenput, Ingrid, Capoen, An, Webb, Penelope M., Ferguson, Kaltin, Akslen, Lars A., Claes, Bart, Vergote, Ignace, Moerman, Philippe, Van Robays, Johan, Marcickiewicz, Janusz, Salvesen, Helga B., Spurdle, Amanda B. and Amant, Frederic (2013) High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma. Gynecologic Oncology, 128 2: 327-334. doi:10.1016/j.ygyno.2012.11.037

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Author Garcia-Dios, Diego A.
Lambrechts, Diether
Coenegrachts, Lieve
Vandenput, Ingrid
Capoen, An
Webb, Penelope M.
Ferguson, Kaltin
Akslen, Lars A.
Claes, Bart
Vergote, Ignace
Moerman, Philippe
Van Robays, Johan
Marcickiewicz, Janusz
Salvesen, Helga B.
Spurdle, Amanda B.
Amant, Frederic
Title High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma
Journal name Gynecologic Oncology   Check publisher's open access policy
ISSN 0090-8258
Publication date 2013-02-01
Year available 2012
Sub-type Article (original research)
DOI 10.1016/j.ygyno.2012.11.037
Volume 128
Issue 2
Start page 327
End page 334
Total pages 8
Place of publication Maryland Heights, MO, U.S.A.
Publisher Academic Press
Collection year 2013
Language eng
Abstract Objective Endometrial cancer patients may benefit from systemic adjuvant chemotherapy, alone or in combination with targeted therapies. Prognostic and predictive markers are needed, however, to identify patients amenable for these therapies. Methods Primary endometrial tumors were genotyped for > 100 hot spot mutations in genes potentially acting as prognostic or predictive markers. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n = 1063). Results PIK3CA, PTEN and KRAS mutations were most frequently detected, respectively in 172 (16.2%), 164 (15.4%) and 161 (15.1%) tumors. Binary logistic regression revealed that PIK3CA mutations were more common in high-grade tumors (OR = 2.03; P = 0.001 for grade 2 and OR = 1.89; P = 0.012 for grade 3 compared to grade 1), whereas a positive TP53 status correlated with type II tumors (OR = 11.92; P < 0.001) and PTEN mutations with type I tumors (OR = 19.58; P = 0.003). Conversely, FBXW7 mutations correlated with positive lymph nodes (OR = 3.38; P = 0.045). When assessing the effects of individual hot spot mutations, the H1047R mutation in PIK3CA correlated with high tumor grade and reduced relapse-free survival (HR = 2.18; P = 0.028). Conclusions Mutations in PIK3CA, TP53, PTEN and FBXW7 correlate with high tumor grade, endometrial cancer type and lymph node status, whereas PIK3CA H1047R mutations serve as prognostic markers for relapse-free survival in endometrial cancer patients.
Formatted abstract
Objective

Endometrial cancer patients may benefit from systemic adjuvant chemotherapy, alone or in combination with targeted therapies. Prognostic and predictive markers are needed, however, to identify patients amenable for these therapies.
Methods

Primary endometrial tumors were genotyped for > 100 hot spot mutations in genes potentially acting as prognostic or predictive markers. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n = 1063).
Results

PIK3CA, PTEN and KRAS mutations were most frequently detected, respectively in 172 (16.2%), 164 (15.4%) and 161 (15.1%) tumors. Binary logistic regression revealed that PIK3CA mutations were more common in high-grade tumors (OR = 2.03; P = 0.001 for grade 2 and OR = 1.89; P = 0.012 for grade 3 compared to grade 1), whereas a positive TP53 status correlated with type II tumors (OR = 11.92; P < 0.001) and PTEN mutations with type I tumors (OR = 19.58; P = 0.003). Conversely, FBXW7 mutations correlated with positive lymph nodes (OR = 3.38; P = 0.045). When assessing the effects of individual hot spot mutations, the H1047R mutation in PIK3CA correlated with high tumor grade and reduced relapse-free survival (HR = 2.18; P = 0.028).
Conclusions

Mutations in PIK3CA, TP53, PTEN and FBXW7 correlate with high tumor grade, endometrial cancer type and lymph node status, whereas PIK3CA H1047R mutations serve as prognostic markers for relapse-free survival in endometrial cancer patients.
Keyword Endometrial cancer
Clinical molecular genetics
Molecular biomarkers
Oncogenes
Tumor suppressor genes
Cancer-Specific Mutations
Serous Carcinoma
Microsatellite Instability
Tumor-Suppressor
Poor-Prognosis
High-Frequency
Gene
Expression
Amplification
Identification
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 4 December 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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Created: Sun, 31 Mar 2013, 22:40:40 EST by Matthew Lamb on behalf of School of Medicine