Abstract
BackgroundActivating KRAS mutations are common in ovarian carcinomas of low histological grade, less advanced clinical stage and mucinous histological subtype, and form part of the distinct molecular alterations associated with type I tumors in the dualistic model of ovarian carcinogenesis. Here, we investigated the occurrence, clinicopathological correlates and prognostic significance of specific KRAS mutations in tumours from 153 epithelial ovarian cancer (EOC) cases from a pooled, prospective cohort.MethodsKRAS codon 12,13 and 61 mutations were analysed by pyrosequencing in tumours from 163 incident EOC cases in the Malmö Diet and Cancer Study and Malmö Preventive Project. Associations of mutational status with clinicopathological and molecular characteristics were assessed by Pearson Chi Square test. Ovarian cancer-specific survival (OCSS) according to mutational status was explored by Kaplan-Meier analysis and Cox proportional hazards modelling. KRAS-mutation status was also analysed in 28 concomitantly sampled benign-appearing fallopian tubes.ResultsSeventeen (11.1%) EOC cases harboured mutations in the KRAS gene, all but one in codon 12, and one in codon 13. No KRAS mutations were found in codon 61 and all examined fallopian tubes were KRAS wild-type. KRAS mutation was significantly associated with lower grade (p = 0.001), mucinous histological subtype (p = < 0.001) and progesterone receptor expression (p = 0.035). Kaplan-Meier analysis revealed a significantly improved OCSS for patients with KRAS-mutated compared to KRAS wild-type tumours (p = 0.015). These associations were confirmed in unadjusted Cox regression analysis (HR = 2.51; 95% CI 1.17-5.42) but did not remain significant after adjustment for age, grade and clinical stage. The beneficial prognostic impact of KRAS mutation was ony evident in tumours of low-intermediate differentiation grade (p = 0.023), and in a less advanced clinical stage (p = 0.014). Moreover, KRAS mutation was associated with a significantly improved OCSS in the subgroup of endometroid carcinomas (p = 0.012).ConclusionsThe results from this study confirm previously demonstrated associations of KRAS mutations with well-differentiated and mucinous ovarian carcinomas. Moreover, KRAS-mutated tumours had a significantly improved survival in unadjusted, but not adjusted, analysis. A finding that merits further study is the significant prognostic impact of KRAS mutation in endometroid carcinomas, potentially indicating that response to Ras/Raf/MEK/ERK-targeting therapies may differ by histological subtype.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1788330379100147
Highlights
Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are common in ovarian carcinomas of low histological grade, less advanced clinical stage and mucinous histological subtype, and form part of the distinct molecular alterations associated with type I tumors in the dualistic model of ovarian carcinogenesis
All fallopian tube samples were KRAS wild-type, and KRAS mutations were only seen in two of three corresponding mucinous tumours. These findings do not allow any further conclusions regarding the putative origin of different epithelial ovarian cancer (EOC) types, it would be of interest to analyse the occurrence of KRAS mutations in a larger set of matched fallopian tubes and invasive serous carcinomas, since the majority of these seem to derived from tubal epithelium [14]
We found no significant association between KRAS mutation status and clinical stage in this study, the proportion of patients with FIGO Stage III-IV disease was higher in KRAS wild-type patients compared to KRAS mutated patients
Summary
Activating KRAS mutations are common in ovarian carcinomas of low histological grade, less advanced clinical stage and mucinous histological subtype, and form part of the distinct molecular alterations associated with type I tumors in the dualistic model of ovarian carcinogenesis. The 2-type system for classification of EOC, proposed by Shih and Kurman in 2004, has become generally accepted [7]. According to this system, Type 2 cancers, encompassing the clinically more aggressive high-grade serous carcinomas, are defined by frequent mutations in p53 and BRCA1/2 genes, leading to genomic instability, while type 1 tumours, encompassing low-grade serous and endometroid carcinomas, clear cell, mucinous and transitional cell (Brenner) tumours, are characterized by common KRAS mutations [8,9]. KRAS mutations seem to occur early in the development of low-grade tumours, since they can be found in benign and borderline areas within the same neoplasm [10,11,12,13,14]
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