Universal germline testing among patients with colorectal cancer: clinical actionability and optimised panel

Abstract

PurposeUniversal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management.MethodsWe prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes.ResultsThe prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years.ConclusionUniversal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks.Trial registration numberNCT03365986.

Review article: Lynch Syndrome—a mechanistic and clinical management update

“…Among the 1462 individuals who had testing based on these criteria, 16% had a PV in a cancer risk gene; 142 had a PV in an LS‐associated gene, and 101 in a non‐LS associated gene. Other studies have been consistent in demonstrating among individuals with CRC that MGPT has comparable or even higher yield for detection of LS compared to tumour‐based testing, and that an additional 3%‐13% of individuals with a personal history of CRC tested with this approach will have a PV in a non‐LS associated cancer risk gene 71‐74 . Of note, all studies to date are subject to potential selection bias that could have resulted in higher yield for cancer risk gene detection, as these studies either enrolled patients with CRC at tertiary referral centres or included some preselection criteria based on age, number of LS‐associated tumours or family history.…”

“…Available evidence suggests that MGPT testing has comparable, or even higher yield for identifying individuals with a personal history of CRC and LS compared to tumour and family history-based selection for screening. [70][71][72] Further, MGPT identifies PVs in cancer susceptibility genes beyond those associated with LS. For example, in a populationbased study in Ohio of 3310 individuals with CRC, MGPT with a panel including at least 25 cancer susceptibility genes was offered to those with MMR deficiency in their tumours, age <50 at diagnosis, multiple primary tumours or a first-degree relative with CRC or EC.…”

“…A simplified strategy of offering germline MGPT to evaluate for LS‐associated and other cancer risk genes, without preselection based on family history or tumour characteristics has been best studied for individuals with a personal history of CRC. Available evidence suggests that MGPT testing has comparable, or even higher yield for identifying individuals with a personal history of CRC and LS compared to tumour and family history‐based selection for screening 70‐72 . Further, MGPT identifies PVs in cancer susceptibility genes beyond those associated with LS.…”

“…Other studies have been consistent in demonstrating among individuals with CRC that MGPT has comparable or even higher yield for detection of LS compared to tumour-based testing, and that an additional 3%-13% of individuals with a personal history of CRC tested with this approach will have a PV in a non-LS associated cancer risk gene. [71][72][73][74] Of note, all studies to date are subject to potential selection bias that could have resulted in higher yield for cancer risk gene detection, as these studies either Selection of patients for evaluation for LS and other cancer risk syndromes based on family history also has potential to be simplified and made more feasible through risk prediction calculators. For example, nearly half of patients included in one study evaluating the simple online PREMM 5 risk calculator had no personal history of LS, yet accounted for 20% of the individuals with LS-associated PVs identified in the study 75 (risk calculator available at: https://premm.…”

What can we learn from more than 1,000 Brazilian patients at risk of hereditary cancer?

“…epithelial ovarian cancer) and has been debated for other clinical scenarios (e.g. breast cancer, colorectal cancer) ( 7 , 9 , 42 ). Higher rates of positive genetic test results are achieved with the universal testing approach in comparison to the criteria-based ( 9 , 31 ).…”