Youqin Tian

Common attributes in mutation carriers identified in a 32-gene hereditary cancer panel

The use of multi-gene panel testing (MGPT) with next generation sequencing (NGS) to detect hereditary cancer syndromes has become increasingly common in the United States. MGPT has identified more individuals with increased cancer risk than traditional methods, including mutations in genes that were not suspected and in patients with cancers not routinely considered for genetic testing. Which patients should have MGPT and what results may be found are common questions among clinicians, and the likelihood of finding a mutation is heavily considered in determining who should have testing. Our study aims to assess and compare the mutation frequencies among patients on CancerNext, an NGS panel of 22-32 genes during the time studied. METHODS De-identified clinical and demographic data from 11,363 consecutive cases submitted to Ambry Genetics for CancerNext testing between March 2012 and June 2015 were retrospectively reviewed. Mutation rates and ages at diagnosis were compared for 9 cancer types using logistic regression analysis, controlling for other cancer diagnoses.

Abstract P2-02-07: Predicting germline mutations in BRCA1/2 and beyond: A comparison of women with single and multiple breast primaries

Synchronous or metachronous breast primaries are a well-known indication of hereditary breast cancer, particularly within BRCA1/2 mutation carriers. However, the frequency of gene mutations within this patient group has not been well defined, especially in the setting of multi-gene panel testing (MGPT). We conducted a retrospective review of mutation carrier status in a population of females with breast cancer(s), but no other reported cancer diagnoses, and who had MGPT at a single diagnostic laboratory. Among 31,864 females tested, the following were excluded from analysis: 5389 (17%) had variants of unknown significance (VUS), 133 (0.4%) had moderate risk mutations and 316 (1.0%) had MUTYH monoallelic mutations. For the remaining 26,026 females, we evaluated whether mutation status is associated with risk of multiple breast primaries using Fisher9s exact test and logistic regression analysis adjusting for age at testing, age at first breast cancer diagnosis, and mutations in other genes. The number of genes analyzed ranged from 5-49, depending on the panel ordered. Gene-specific analyses were limited to with 10 or more mutations in this cohort ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, MRE11A, MUTYH, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, and TP53 ). In this cohort the average age of first breast cancer diagnosis was 47.7 (range 12-95) and the average age of second diagnosis was 56 years (range 17-89). A positive result (pathogenic mutation or variant, likely pathogenic) in any gene was more likely for women with three or more breast cancer primaries (p=0.007) and two or more primaries (p=1.2e-08) than those with one breast primary. Overall, women with a mutation in any gene were more likely to have multiple primary breast cancers than those without mutations. Specifically, women with mutations in ATM, BRCA1, CDH1, PALB2, PTEN , and TP53 mutations were more likely to have multiple breast primaries than non-carriers of mutations in those genes (table 1). Our results show that women with multiple breast primaries are more likely to have mutations in some genes than others. Interestingly, all genes with significant odds ratios are well-described and most are known to cause high risk for breast cancer, with the exception of ATM . Additional studies are needed to confirm these results and quantify risks for second primary breast cancers. With further work defining the risks of multiple primary breast cancers, this information could be implemented into clinical practice to aid women in risk management following a positive result. Citation Format: Panos Smith L, Tian Y, Qian D, McFarland R, Espenschied CR. Predicting germline mutations in BRCA1/2 and beyond: A comparison of women with single and multiple breast primaries [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 P2-02-07.