A Nation-wide mapping programme for genetic syndromes associated with cancer

Abstract

Introduction: Gibraltar Health Authority in collaboration with Dr Terri McVeigh (Geneticist at Royal Marsden NHS Foundation Trust) have implemented a cutting-edge programme to screen for patients with certain cancer types who meet criteria for Specialist-led germline testing since January 2023. This initiative aligns with NICE guidance (DG27 and DG42), NHS Long Term Plan and NHS England National Genomic Test Directory.A - Lynch Syndrome (LS) is a hereditary condition associated with increased risk of several cancer types, including colorectal, gastrointestinal and biliary tract, genitourinary system and pancreatic cancer. It is caused by a germline pathogenic variant in one of four DNA MisMatch Repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2.Approximately one in 250 individuals have Lynch Syndrome; half of whom are estimated to develop colorectal cancer.B - BRCA1 and BRCA2 are 2 important tumour-suppressor genes against breast, ovarian, prostate, pancreatic and other cancers. BRCA1 gene mutations can increase a woman's risk of developing breast cancer by the age of 70 to 65–85% and ovarian cancer to 30–50%. However, BRCA2 gene mutations can increase a woman's risk of developing breast cancer by the age of 70 to 40–85% and ovarian cancer to 10–20%. This compares to the 12.5% lifetime risk of breast cancer and 2% risk of ovarian cancer for the average British woman.Approximately one in 400 individuals are estimated to carry a BRCA1/BRCA2 mutation. Materials and methods: Tissue-based samples from biopsy or surgery are identified at weekly Oncology Multi-Disciplinary Team (MDT) meeting; based on the criteria outlined by NHS England National Genomic Test Directory.These samples are air-shipped to Royal Marsden for testing; with target Turn Around Time (TAT) of 14 days from the date of sample arrival to Clinical Genomics laboratory.Strong family history of cancer, alterations on MMR or BRCA1-2 routinely prompt referral to Dr McVeigh for consideration of germline testing. Results and discussion: At 13-month landmark, a total of 94 non-breast probands have been screened as eligible for initial testing at MDT; 89 of whom have proceeded to testing. One case was taken off programme for overseas location of tissue blocks; remaining four are planned for surgery, which will provide with further material.Excluding breast cases on this first interim analysis, 11 referrals have been sent to Dr McVeigh for germline testing: four MSI-high colon cancers; four Micro-Satellite Stable (MSS) colon cancer patients aged 40 or with family history; a co-mutation in ATM/CDK12 in prostate and two BRCA2 mutations in prostate and pancreatic cancer probands. Conclusion: From 93 non-breast probands, four colon cancers are pending conclusion on LS and two are awaiting outcome on BRCA2 mutation (prostate and pancreatic) over 30,000 Gibraltarian population; which falls well below general estimates.Counselling on individual cancer risk over life time, risk-reducing surgery, chemo-prevention, tailored screening and surveillance programmes are the main aimed benefits.Hand-in-hand liaison with Royal Marsden and Clinical Nurse Specialists have been key to implement and conduct this programme successfully.Stepped processes are being audited for Quality Improvement, care excellence, patients and caregivers' satisfaction.