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

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.

Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort

“…It is a cost-effective approach for identifying at-risk individuals, especially in young, unaffected relatives [ 9 , 10 , 11 ]. Monitoring variant-harboring families provides important information for planning adequate quantity and quality of services and long-term coordination of cancer care [ 12 ]. However, despite the benefits of cascade testing, studies report that a significant number of relatives remain unaware of the availability and benefits of genetic testing.…”

Mainstream genetic testing for high‐grade ovarian, tubal and peritoneal cancers: A tertiary referral centre experience

“…All patients with BRCA1/2 LPV/PVs were appropriately referred to the FCS. The median number of cascade tests per positive index case was four, which was higher than recent UK‐based data which included index cases identified through the traditional testing model 22 …”

“…The median number of cascade tests per positive index case was four, which was higher than recent UK-based data which included index cases identified through the traditional testing model. 22 Another important component of mainstreaming is to reduce inequity of access. Four eligible patients that were not mainstreamed were potentially missed because they were having a component of their treatment at a regional or rural centre.…”

MSH2is the very young onset ovarian cancer predisposition gene, notBRCA1

“…These women had been referred to Manchester Centre for Genomic Medicine (MCGM) within the last two decades following diagnosis with VYOC in the North-West of England. The genetic testing described was performed as part of standard diagnostic testing within MCGM 5. A series of 77 women with ovarian cancer (9 borderline and 1 granulosa cell tumour in addition to EOCs) were screened for MMRD and HRD germline PVs by sequencing, multiple ligation-dependent probe amplification and a prescreen for MMR immunohistochemistry (IHC) as previously described 5.…”