30 year experience of index case identification and outcomes of cascade testing in high-risk breast and colorectal cancer predisposition genes

Emma R Woodward,George J Burghel,Michael Bulman,Helene Schlecht,Tara Clancy,Kate Green,Fiona Lalloo,Andrew J Wallace,D Gareth Evans

doi:10.1038/s41431-021-01011-8

Abstract

It is 30 years since the first diagnostic cancer predisposition gene (CPG) test in the Manchester Centre for Genomic Medicine (MCGM), providing opportunities for cancer prevention, early detection and targeted treatments in index cases and at-risk family members. Here, we present time trends (1990–2020) of identification of index cases with a germline CPG variant and numbers of subsequent cascade tests, for 15 high-risk breast and gastro-intestinal tract cancer-associated CPGs: BRCA1, BRCA2, PALB2, PTEN, TP53, APC, BMPR1a, CDH1, MLH1, MSH2, MSH6, PMS2, SMAD4, STK11 and MUTYH. We recorded 2082 positive index case diagnostic screening tests, generating 3216 positive and 3140 negative family cascade (non-index) tests. This is equivalent to an average of 3.05 subsequent cascade tests per positive diagnostic index test, with 1.54 positive and 1.51 negative non-index tests per family. The CPGs with the highest numbers of non-index positive cases identified on cascade testing were BRCA1/2 (n = 1999) and the mismatch repair CPGs associated with Lynch Syndrome (n = 731). These data are important for service provision and health economic assessment of CPG diagnostic testing, in terms of cancer prevention and early detection strategies, and identifying those likely to benefit from targeted treatment strategies.

Highlights

The identification of the TP53 gene as a high-risk Cancer Predisposition Gene (CPG) in 1990, followed in rapid succession by the APC, BRCA1, BRCA2 and Lynch genes in 1991–1995, enabled the introduction of CPG testing into the cancer genetics clinic.The detection of a high-risk germline CPG variant in an index case provides cancer prevention and treatment opportunities in that individual but, through family cascade testing, subsequent cancer prevention and early detection opportunities in at-risk family members testing positive
Testing began with TP53 in 1990 following its identification as being causative of Li Fraumeni Syndrome in 1990 [6], followed by APC in 1993, BRCA1 in 1994 and BRCA2, MLH1 and MSH2 in 1996
The latest CPG to be included in clinical diagnostic testing in the Manchester Centre for Genomic Medicine (MCGM) was PALB2 in 2016; having been identified as causative of hereditary breast cancer in 2007 [7], it was not introduced until later studies confirmed its role as a high-risk breast cancer CPG [8, 9]

Summary

Introduction

The identification of the TP53 gene as a high-risk Cancer Predisposition Gene (CPG) in 1990, followed in rapid succession by the APC, BRCA1, BRCA2 and Lynch (formerly HNPCC) genes in 1991–1995, enabled the introduction of CPG testing into the cancer genetics clinic.The detection of a high-risk germline CPG variant in an index case provides cancer prevention and treatment opportunities in that individual but, through family cascade testing, subsequent cancer prevention and early detection opportunities in at-risk family members testing positive. Outcomes of clinical CPG testing in the clinic, both diagnostic and predictive, have been recorded by the MCGM through the use of family registers since diagnostic CPG testing first started in 1990 [1, 2]. This record provides a clinical tool to ensure appropriate screening is in place, family members are offered predictive genetic testing as appropriate, and provides a resource for identifying patients when new management approaches or research opportunities become available

Methods

Results

Conclusion