Abstract PD8-06: Multiple-gene panel testing for hereditary cancer risk reveals a racial/ethnic disparity in genetic information
Authors: Caswell-Jin JL* , Gupta T* , Hall E , Petrovchich IM , Mills MA , Kingham KE , Koff R , Chun NM , Levonian P , Lebensohn AP , Ford JM , Kurian AW 
Published: March 2017

Background: Multiple-gene germline sequencing panels are increasingly used to evaluate hereditary cancer risk. However, little is known about the results of such testing in racially/ethnically diverse populations.

Methods: Patients who presented to the Stanford University Clinical Cancer Genetics Program from 1/1/2013 to 12/31/2015 and underwent multiple-gene panel testing were included in the cohort (N=1,483). Information on demographics, personal and family history of cancer, and tumor characteristics was collected at time of clinic visit. Odds ratios and 95% confidence intervals were calculated for mutation status by different patient and tumor characteristics, including race/ethnicity. Results were compared using the chi-square test and considered significant if P&lt;0.05 after Bonferroni correction for multiple hypothesis testing.

Results: Most patients (92%) were female. Patients were 51% Non-Hispanic White (NHW), 19% Asian, 14% Hispanic, 10% Ashkenazi Jewish, 5% other, and 1% unknown. Eighty-nine genes were tested in at least one patient; panel size ranged from six to 62 genes, with a median of 25 genes. The frequency of pathogenic or likely pathogenic mutations was 15% for any panel-tested gene, 5.5% for BRCA1/2, and 5.3% for other breast cancer-associated genes; mutation frequencies were similar between NHW, Asian, Hispanic, and Ashkenazi Jewish patients. Variables significantly associated with the carriage of a pathogenic BRCA1/2 mutation included personal or family history of ovarian cancer and personal history of triple-negative breast cancer (TNBC). No variable was significantly associated with the presence of a pathogenic mutation in the other breast cancer genes. The odds ratios for carrying a BRCA1/2 mutation with personal history of ovarian cancer (4.1 [2.2-7.3]), family history of ovarian cancer (3.1 [1.9-4.9]), and TNBC relative to other breast cancer subtypes (6.0 [2.9-12.4]) did not differ significantly between NHWs and non-Whites. The frequency of variants of unknown significance (VUS) in any panel-tested gene was higher in non-Whites (36%) than in NHWs (27%) (P=2E-4), with the highest odds ratio relative to NHWs among Asians (2.0 [1.5-2.7], vs 1.3 [0.9-1.7] among Hispanics and 1.2 [0.8-1.7] among Ashkenazi Jews). The odds ratio of finding a VUS for non-Whites compared to NHWs was similar for any panel (1.5 [1.2-1.9]), for BRCA1/2 (1.3 [0.8-2.3]), and for other known breast cancer-associated genes (1.5 [1.1-1.9]).

Conclusions: In this diverse cohort tested for hereditary cancer risk with multiple-gene panels, frequencies of pathogenic mutations were similar between racial/ethnic groups. By contrast, frequencies of VUS were significantly higher among non-Whites compared to NHWs. This higher VUS rate renders multiple-gene panel testing less informative for non-White patients. Efforts toward VUS re-classification, particular among non-Whites, are urgently needed to address this genetic information disparity.

Citation Format: Caswell-Jin* JL, Gupta* T, Hall E, Petrovchich IM, Mills MA, Kingham KE, Koff R, Chun NM, Levonian P, Lebensohn AP, Ford JM, Kurian AW. Multiple-gene panel testing for hereditary cancer risk reveals a racial/ethnic disparity in genetic information [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD8-06.