Abstract 4817: Microsatellite instability status in endometrioid endometrial carcinomas is associated with distinct types and patterns of PI3K pathway mutations
Authors: Marchio Caterina , De Filippo Maria R. , Ng Charlotte KY , Soslow Robert A. , Reis-Filho Jorge S. , Weigelt Britta 
Published: August 2015

Abstract
Background: Endometrioid endometrial carcinomas (EECs) frequently harbor mutations in the PI3K pathway. In contrast with other cancer types (e.g. breast cancer) where PIK3CA mutations are generally mutually exclusive with PTEN mutations, in EECs mutations affecting these genes often co-occur. Here we sought to determine whether the type and pattern of mutations targeting different components of the PI3K pathway are distinct between microsatellite stable (MSS) and high-level microsatellite instable (MSI-H) EECs, and to define the mutational signatures in MSI-H and MSS EECs.
Methods: Whole exome massively parallel sequencing-based mutation data from EECs of The Cancer Genome Atlas (TCGA) project were used to define the number, type and pattern of mutations affecting PI3K pathway-related genes (i.e., AKT1, INPP4B, MTOR, PIK3CA, PIK3R1 and PTEN). Based on seven MSI markers assessed by TCGA, EECs were classified as MSI-H (n = 70) and MSS (n = 109). POLE ultramutated cases were excluded. Mutational signatures were defined using EMu, a method based upon the expectation-maximization algorithm.
Results: Although the mutation rates of MSS and MSI-H EECs were significantly different, the prevalence of mutations affecting PI3K pathway genes was similar between these two groups (all p&gt;0.05), with the exception of PTEN mutations, which were more prevalent in MSI-H (87%) than in MSS EECs (72%; p = 0.017). The PIK3CA hotspot mutations E542K, E545K, and H1047R were found to be significantly more prevalent in PIK3CA-mutant MSS EECs (36%) than in PIK3CA-mutant MSI-H EECs (13.5%; p = 0.019). In both MSI-H and MSS EECs a mutational signature related to age was identified, characterized by C&gt;T transitions at NpCpG trinucleotides; in MSS tumors a C&gt;T and C&gt;G at TpCpN trinucleotides mutational signature, attributed to the APOBEC family of cytidine deaminases, was identified, whereas in MSI-H tumors, a DNA-MMR deficiency-like signature was found.
Conclusion: Although the prevalence of mutations targeting different components of the PI3K pathway is similar between MSS and MSI-H EECs, PIK3CA hotspot mutations, which result in constitutive kinase activation, are significantly more prevalent in MSS than in MSI-H EECs. We have observed that the mutational processes operating in MSI-H and MSS EECs are distinct, and that the landscape of mutations affecting PI3K pathway-related genes might be shaped by multiple mutational processes in these cancers. Our findings warrant further investigation of the role of different types of PIK3CA mutations in and their predictive impact on distinct subtypes of EECs.
Citation Format: Caterina Marchio, Maria R. De Filippo, Charlotte KY Ng, Robert A. Soslow, Jorge S. Reis-Filho, Britta Weigelt. Microsatellite instability status in endometrioid endometrial carcinomas is associated with distinct types and patterns of PI3K pathway mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4817. doi:10.1158/1538-7445.AM2015-4817