Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes

Abstract

IMPORTANCE Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment.OBJECTIVE To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. DESIGN, SETTING, AND PARTICIPANTSIn this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied.EXPOSURES Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. MAIN OUTCOMES AND MEASURESThe performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. RESULTSIn phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. CONCLUSIONS AND RELEVANCEIn this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

Clinical and molecular features of pediatric cancer patients with Lynch syndrome

“…Of the remaining five patients, based on available information at study entry, none met the criteria. Of note, three had gliomas, two of which were subsequently documented (see below) to have abnormal IHC for MMR genes and would meet MIPOGG criteria for a genetics referral at that point 10,11 …”

“…Of note, three had gliomas, two of which were subsequently documented (see below) to have abnormal IHC for MMR genes and would meet MIPOGG criteria for a genetics referral at that point. 10,11 Subsequent medical genetic evaluation occurred in five cases: physical examination revealed no skin findings or other features typical of CMMRD, including café au lait macules, axillary freckling, and neurofibromas. 20 Additional independent germline testing at an external laboratory for mutations and copy number variants in each case confirmed the MMR variants to be heterozygous without any second variant or copy number alteration detected as would be expected in CMMRD.…”

“…In addition, when possible, a patient germline sample was sent for comprehensive germline sequencing and copy number testing for the MMR gene of interest to an independent clinical diagnostic laboratory. Analysis included applying the 2022 version of the comprehensive McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes (MIPOGG) algorithm 10,11 to predict which children with cancer would be recommended to have genetic evaluation. The algorithm was applied using the information (tumor diagnosis, any specialized pathologic staining or molecular diagnostic testing, age, and family history) in the medical record available at study entry.…”

Genetic Disorders with Predisposition to Paediatric Haematopoietic Malignancies—A Review

“…MIPOGG exhibited a favourable accuracy profile for CPS screening and reduced the time to CPS diagnosis. A number of 410 of 412 patients with cancers and diagnosed CPSs were correctly evaluated with MIPOGG [ 115 ]. Moreover, MIPOGG was favourable for the identification of patients with a high predisposition to second malignancies, due to a possibility of decision making based on highly intensive surveillance [ 113 ].…”

Merged testing for colorectal cancer syndromes and re‐evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort

“…Introduction of paired sample tumor tissue DNA profiling for diagnostic and treatment decision purposes [32][33][34] as well as exome or genome sequencing of noncancer patients now contribute to the identification of cancer predisposition alleles, either as sought or unsolicited findings. These rapidly emerging fields bypass the traditional triage for genetic testing of patients with suspected cancer predisposition based on age at diagnosis and family history.…”