The Role of Hypoxia as a Selective Pressure for TP53 Mutations

Overview

The study aims to develop scans that tell the investigators about the oxygen content of tumours using Magnetic Resonance Imaging (MRI) and seeing whether regions of low oxygen content are related to mutations in cancer genes such as TP53. MRI is a method of obtaining pictures of inside of the body that shows the appearance and structure of soft tissues. To get the information about the oxygen content of tumours, MRI is carried out while breathing 100% oxygen. The variation of oxygen supply to different regions of the tumour will help the investigators to predict tumour behavior and tumour response to treatment.

Cancer tissue harbours a multitude of genetic alterations, and it is well-established that when certain key alterations develop, they are powerful determinants of tumour behaviour (growth rate, potential to spread). One of the most sinister and well-recognized alterations is in a gene called TP53. Another feature of tumours that results in resistance to treatment and poor outcome is a low oxygen level within tumour tissue. However, whether alterations in TP53 are driven by low oxygen levels is not established. Endometrial cancer is a good model to study the relationship between low tumour oxygen levels and alterations in TP53 within tumour. Firstly, it is a common gynaecological malignancy, (9,300 new cases annually in the UK) with two recognized types based on the appearance and behaviour of the tumour. In type I (endometrioid and mucinous carcinomas), alterations in TP53 are uncommon (15%), while in type II (serous and clear cell carcinomas) they are common (88%). In-line with this, the survival of patients with Type 2 cancer is worse. Secondly, endometrial cancer is routinely assessed at diagnosis using Magnetic Resonance Imaging. This non-invasive scanning technique can be manipulated to derive additional information about the oxygen status of the whole tumour and regions within it. Finally, the primary management of endometrial cancer is surgical and involves hysterectomy. This means it is possible to obtain fresh tumour tissue at the time of surgery from regions that have been identified on imaging as having low vs.high levels of oxygen and to establish their TP53 status. In this study, therefore, the investigator will establish the regional oxygen distribution within endometrial cancers at diagnosis, and relate them to the alterations in TP53 from fresh tissue samples from selected regions using gene sequencing. Understanding how highly deleterious mutations arise in cancer might provide new avenues for intervention and control.