This study provides preliminary evidence that the underlying molecular biology of some subtypes of histologically similar endometrial cancers differ by race. PIK3CA and KRAS mutations were found in endometrial tumors from African American and white women. However, AA women with low grade endometrioid carcinoma of the uterus were more likely to harbor an oncogene mutation than white women. It is notable that no hotspot mutations in the 17 other oncogenes examined were identified in these tumors.
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate a variety of pathways involved in carcinogenesis, including cell proliferation, adhesion and survival 11
. PIK3CA codes for the catalytic subunit p110α of PI3K and has been reported to be somatically mutated in a number of cancers 12
. Previous data suggest various mutations in the PIK3CA gene, including mutations found in our samples, induce a gain of PI3K function, with oncogenic potency varying by location 13, 14
. Findings from a phase I study of advanced cancers treated with PI3K/AKT/mTOR inhibitors report the response rate to therapeutic agents targeting this pathway was significantly higher among individuals with PIK3CA mutations (in exons 9 and 20), suggesting that these mutations have clinical predictive value15
PIK3CA mutations have been previously described in endometrial cancers. In a series of 45 endometrial serous carcinomas, Hayes et al. reported 15% of tumors harbored mutations 16
. Konstantinova et al. found PIK3CA mutations were more frequent in serous and mixed tumors compared to endometrioid tumors (p-value=0.02), and noted that the location of the mutation differed by pathological characteristics 17
. Similarly, Catasus et al. described location of the PIK3CA mutations varied by histologic type and grade, with exon 20 mutations more common in high-grade carcinomas and in tumors with myometrial invasion18
. Our study did not identify PIK3CA, or any other mutations, in the 18 serous carcinomas examined, but the tumors with exon 20 mutations were all high grade.
Point mutations in KRAS are relatively common in endometrial cancers, particularly in Type I tumors, but their prognostic significance is unclear 19–23
. These mutations have been found in endometrial hyperplasia, suggesting they are early events in carcinogenesis 23
. Three of the four KRAS mutations identified in our population were in women with stage I disease. All mutations were found in AA women. It is feasible that mutation rates differ by race/ethnicity, with a study by Sasaki et al. finding KRAS mutations in endometrial cancers nearly twice as common among Japanese women compared with white women from the United States 23
. Larger studies are needed to clarify whether racial differences in mutation status exist, and if they are clinically significant.
Our study had limitations that should be noted. First, the Sequenom OncoCarta V1.0 Panel is not specific to all mutations expected in endometrial cancers, and includes only oncogenes, not tumor suppressor genes (such as PTEN or p53, common in endometrioid and serous carcinomas, respectively) or other molecular characteristics that may have prognostic or predictive value. In addition, while many of the activating mutations are found at the hot spots tested for by this panel, it does not detect all of the variation that other methods (i.e. next generation sequencing) could. The Sequenom MassARRAY system does offer a sensitive, high throughput approach that can screen tumors for a large number of mutations in a cost-effective manner, and can detect mutations in a heterogeneous mixture of cancerous and normal tissue 10. Our study population was also limited by sample size, with only 18 serous and one clear cell carcinoma. Some groupings (i.e., endometrioid versus non-endometrioid) may not have strong clinical relevance. Lastly, due to the relatively low proportions of tumors harboring mutations and the excellent endometrial-cancer specific survival of the study population (with only one endometrial cancer-related death among women with tumors harboring mutations), we were unable to examine whether these mutations were significant predictors of prognosis or not.