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Sunday, June 19, 2016

Yield of multiplex panel testing compared to expert opinion and validated prediction models



Background: Genetic testing is a powerful tool for stratifying cancer risk. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. However, the diagnostic yield and clinical utility of panels remain to be further delineated.  

Methods: A planned interim analysis was conducted of the first 1001 patients undergoing cancer-risk assessment. Patients were enrolled in a multicenter prospective cohort study where diagnostic yield and off-target mutation detection was evaluated of a 25 gene MGP comprised of APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were enrolled if they met standard testing guidelines or were predicted to have a ≥ 2.5% mutation probability by validated models. Differential diagnoses (DDx) were generated after expert clinical genetics assessment, formulating up to 8 inherited cancer syndromes ranked by estimated likelihood.  

Results: 1001 patients had MGP testing. Women constituted 82% of the samples, and 41% were Hispanic; 115 tested positive for at least 1 pathogenic mutation (Pos) (11.5%) and 375 (37.5%) patients carried at least 1 variant of uncertain significance (VUS). The most frequently identified mutations were in BRCA1 (18%, n = 21), BRCA2 (18%, n = 21), MUTYH (17%, n = 20), APC (6%, n = 7), CHEK2 (6%, n = 7), ATM (4%, n = 5).21 patients (18%) had at least 1 Pos in a mismatch repair (MMR) gene (MLH1, n = 6; MSH2, n = 5; MSH6, n = 5; PMS2, n = 5). 20 individuals (17%) had MUTYH mutations – 19 were monoallelic. 6 patients had mutations in APC – 5 were APCI1307K. Only 69% (n = 79) of Pos results were included in the DDx, with 24% (n = 28) of mutations not clinically suspected.  

Conclusions: In a diverse cohort, multiplex panel use increased genetic testing yield substantially: 24% carried pathogenic mutations in unsuspected genes, suggesting a significant contribution of expanded multiplex testing to clinical cancer risk assessment. The identification of off-target mutations broadens our understanding of cancer risk and genotype-phenotype correlations.

Follow-up is ongoing to assess the clinical utility of multiplex gene panel testing. Clinical trial information: NCT02324062.


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