Overview of current project

by Dr. Charlie Gourley


An investigation of mismatch repair defects in ovarian cancer in order to improve detection of HNPCC families and to improve therapy

Dr.Charlie Gourlay

 

What is HNPCC

HNPCC (Hereditary Non-Polyposis Colorectal Cancer) is the name given to a genetic syndrome that increases the risk of colorectal cancer. The patients with this genetic syndrome have tumours that are defective in a form of DNA repair known as mismatch repair (MMR).

Women with HNPCC

 Women who inherit mutations in the genes that cause HNPCC (MLH1, PMS2, MSH2 or MSH6) are also at increased risk of developing ovarian cancer.  In addition, and similar to colorectal cancer, a proportion of non-hereditary ovarian cancers (10-15%) have defects in the function of these genes even though they may not have inherited a defective copy of the genes from their parents.

While there has been extensive investigation of the HNPCC genes in colorectal cancer, their role in ovarian cancer is under-investigated.

Our interest in HNPCC at the Cancer Research Centre

We have a longstanding interest in HNPCC, DNA-repair defects in ovarian cancer, and the pathological testing of colorectal tumours to detect MMR-deficiency, such that we are the only institution in the UK to routinely screen all patients under 60 with colorectal cancer for these defects.

 There is therefore a unique opportunity to investigate MMR-defects in ovarian cancer in order to pave the way for a similar approach to the management of ovarian cancer patients with MMR-defects, and better detect those patients with HNPCC.

 

An investigation of mismatch repair defects in ovarian cancer in order to improve detection of HNPCC families and to improve therapy

In the first instance, we will characterise the MMR status (i.e. functional or deficient) in a cohort of 450 ovarian carcinomas using immunohistochemistry for MLH1, PMS2, MSH2 or MSH6, in order to establish the incidence of MMR-deficiency. Cases which show loss of MMR protein expression (also known as MMR deficiency) will have a second confirmatory genetic test (microsatellite instability status by PCR). Since the silencing of the MLH1 gene is the most common defect in non-hereditary MMR-deficient colorectal tumours and this is associated with mutation of another cancer-causing gene (BRAF), we will perform BRAF mutation testing in all MLH1-deficient ovarian tumours to check for a similar association in ovarian cancer. Those cases which are not accounted for by BRAF mutation will be sequenced in order to establish the causative mutation.

As well as being the largest study to investigate MMR-deficiency in ovarian cancer, this cohort of patients is fully annotated with comprehensive clinical and pathological data. This will permit a detailed analysis of the associations of MMR-status with tumour characteristics and clinical outcome. While some associations are recognised, such as MMR-deficiency being more common in clear cell and mucinous ovarian carcinomas, we will perform a detailed re-analysis of the histopathology for these tumours to establish whether they harbour any unique features. Clinical data will allow an assessment of the prognosis of these patients compared to MMR-competent tumours. Since MMR-deficiency is associated with response to chemotherapy in colorectal cancer, we will seek to establish whether this is also the case in ovarian cancer. The recent data suggesting some MMR mutants might respond to new drugs known as DNA polymerase inhibitors opens up the possibility of selectively targeting ovarian cancers with this deficiency.

 






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