OR07: Age stratified surveillance strategies Lynch syndrome-associated cancer according to mismatch repair mutation

Neil Ryan1, Kate Green2, Emma Crosbie3, Gareth Evans4,

1 – Medical Research Council Clinical Research Fellow, Institute of Cancer Sciences, University of Manchester, United Kingdom. 2 – Data base manager, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 3 – NIHR Clinician Scientist, Senior Lecturer and Honorary Consultant in Gynaecological Oncology  ,Institute of Cancer Sciences, University of Manchester, United Kingdom. 4 – Professor of Medical Genetics and Cancer Epidemiology, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom

Aim

Lynch syndrome is a dominantly inherited germline mutation that predisposes individuals to colorectal (CRC), endometrial (EC) and other cancers through inactivation of the cellular mismatch repair system. This in turn leads to a loss of DNA fidelity during replication. Colorectal surveillance is well established for Lynch patients and has been shown to save lives.  There is a growing consensus that women with Lynch syndrome who choose to avoid hysterectomy should also be offered EC surveillance. The age at which cancer surveillance should start is disputed. Our work aims to explore the association between the age of cancer diagnosis and the mutational profile of the patient.

Method

This was a retrospective study of subjects with Lynch syndrome-associated EC and/or CRC. The database is clinical data set of a large region within the UK. Data quality is ensured by the use of lateral data source collaboration utilising the National Cancer Registry and death certification among others. Subjects were stratified by mutated gene (MLH1, MSH2 & MSH6) and the age of diagnosis. Statistical analysis was investigated using one-way analysis of variance (ANOVA) with post hoc Newman-Keuls multiple comparison test and Student’s t-test.

Results

In total, 226 women with EC and 228 men and women with CRC were identified. In women with EC, MSH2 mutations were most common (n= 114), followed by MLH1 (n=70) and MSH6 (n=42). In CRC, MLH1 mutations (n=121) were most common, followed by MSH2 (n=80), MSH6 (n=21) and PMS2 (n=6) mutations. When stratified by mutation, mean age of EC diagnosis was 50 years for MLH1, 48 years for MSH2 and 54 years for MSH6 mutation (p = 0.0001). For CRC, the mean age at diagnosis was 44, 45, 53 and 47 years for MLH1, MSH2, MSH6 and PMS2 mutations, respectively. Mutations in MSH6 presented significantly later with CRC than mutations in the other genes (p= 0.0014). When stratified by type of mutation (truncating, splicing or large re-arrangement), no significant difference was found for EC. However, in the CRC cohort, truncating mutations presented earlier than other types of mutations (p=0.04). In these data, CRC and not EC was the most common sentinel cancer.

Conclusion

Our data indicate that women with known Lynch syndrome could be risk stratified by age and type of mutation and offered tailored surveillance programmes. Specifically, individuals with an MSH6 non-truncating mutation could be offered cancer surveillance from a later age.

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