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

ObjectiveEndometrial 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.MethodsPrimary 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).ResultsPIK3CA, 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).ConclusionsMutations 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.

► Mutations in PIK3CA as well as specific PIK3CA exon 20 mutations correlate with high-grade endometrial tumors in 1063 patients.
► We confirm that mutations in TP53 and PTEN are more frequently observed in type II and type I tumors, respectively.
► The specific mutation in PIK3CA (H1047R) correlates with shorter survival and FBXW7 mutations correlate with tumors showing lymph node invasion.