Racial differences in the molecular profile of endometrial carcinoma

Endometrial cancer (EC) is the commonest gynaecologic malignancy in developed countries and its incidence is rising. Although excellent prognosis is associated with early stage disease, treatment for late stage cases is challenging and the treatment options limited.Racial differences have been shown in Black and Caucasian women diagnosed with EC however, evidence for other racial groups is limited with Asian patients being particularly under-represented in the literature.The aims of the study were to propose effective targeted drug treatments suitable for subsequent testing in animal models of EC and to identify differences in the mutational profile of endometrial tumours between British White (BW) and South Asian (BSA) women.CUDC-907, a PI3K and HDAC inhibitor, was the most effective monotherapy treatment in EC cells. Several combination treatments showed synergism and efficacy in EC cell lines with the most efficacious being CUDC-907 and S63845 (MCL1 inhibitor) combined with the MEK inhibitor PD0325901.Although there was no significant difference in the overall mutation frequency of the 10 genes analyzed, numerous differences were observed between the two racial groups. PIK3CA and PTEN mutations were positively associated in the BSA but not in the BW group. On the contrary, BW women had co-existent ARID1A and PI3K pathway mutations, which was not shown in BSA women. BSA women had higher grade disease in our cohort and survival data are eagerly anticipated.A range of targeted inhibitory drugs emerged from this study showing in vitro efficacy, alone or in combination, in endometrial cancer cells. Further validation of these therapeutic options in animal models is needed prior to confirming their suitability for use in EC. This study, the first to attempt a comparison between a Caucasian and South Asian cohort of women in genes frequently driving carcinogenesis in EC, showed several differences with translational and clinical relevance.</div

Racial differences in endometrial cancer molecular portraits in The Cancer Genome Atlas.

Endometrial cancer (EC) is now the most prevalent gynaecological malignancy in the Western world. Black or African American women (BoAA) have double the mortality of Caucasian women, and their tumours tend to be of higher grade. Despite these disparities, little is known regarding the mutational landscape of EC between races. Hence, we wished to investigate the molecular features of ECs within The Cancer Genome Atlas (TCGA) dataset by racial groupings. In total 374 Caucasian, 109 BoAA and 20 Asian patients were included in the analysis. Asian women were diagnosed at younger age, 54.2 years versus 64.5 years for Caucasian and 64.9 years for BoAA women (OR 3.432; p=0.011); BoAA women were more likely to have serous type tumors (OR 2.061; p=0.008). No difference in overall survival was evident. The most frequently mutated gene in Caucasian and Asian tumours was PTEN (63% and 85%), unlike BoAA cases where it was TP53 (49%). Mutation and somatic copy number alteration (SCNA) analysis revealed an enrichment of TP53 mutations in BoAAs; whereas POLE and RPL22 mutations were more frequent in Caucasians. Major recurrent SCNA racial differences were observed at chromosomes 3p, 8, 10, and 16, which clustered BoAA tumors into 4 distinct groups and Caucasian tumors into 5 groups. There was a significantly higher frequency of somatic mutations in DNA mismatch repair genes in Asian tumours, in particular PMS2 (p=0.0036). In conclusion, inherent racial disparities appear to be present in the molecular profile of EC, which could have potential implications on clinical management

Comparing Characteristics of Endometrial Cancer in Women of South Asian and White Ethnicity in England

Differences in patient demographic and tumour characteristics between patients of South Asian and White ethnicity diagnosed with an endometrial cancer (EC) and currently living in England are not well described. We undertook a retrospective study of EC cases diagnosed at the University Hospitals of Leicester, UK. A total of 1884 cases were included, with 13% of the patients being of South Asian ethnicity. South Asian women were diagnosed at a significantly younger age (mean age of 60.3 years) compared to women of White ethnicity (mean age of 66.9 years) with a mean difference of 6.6 years (95% CI 5.1 to 8.1, p < 0.001). Rising body mass index (BMI) in the White patient group was significantly correlated with younger age at diagnosis (p < 0.001); however, this association was not seen in South Asian patients. A linear regression that adjusted for diabetes status, BMI, and the interaction terms of diabetes status with BMI and ethnicity with BMI, highlighted a younger age of diagnosis in South Asian patients with a BMI less than 45 kg/m2. The difference was greatest at lower BMIs for both non-diabetics and diabetics. Further investigation is needed to explain these differences and to determine their impact on suspected cancer referral criteria.</p