Duveen Sturgeon

Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort

This study aims to assess multi-gene panel testing in an ethnically diverse clinical cancer genetics practice. We conducted a retrospective study of individuals with a personal or family history of cancer undergoing clinically indicated multi-gene panel tests of 6-110 genes, from six commercial laboratories. The 475 patients in the study included 228 Hispanics (47.6%), 166 non-Hispanic Whites (35.4%), 55 Asians (11.6%), 19 Blacks (4.0%), and seven others (1.5%). Panel testing found that 15.6% (74/475) of patients carried deleterious mutations for a total of 79 mutations identified. This included 7.4% (35/475) of patients who had a mutation identified that would not have been tested with a gene-by-gene approach. The identification of a panel-added mutation impacted clinical management for most of cases (69%, 24/35), and genetic testing was recommended for the first degree relatives of nearly all of them (91%, 32/35). Variants of uncertain significance (VUSs) were identified in a higher proportion of tests performed in ethnic minorities. Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment. VUSs represent an interpretive challenge due to less data available outside of White, non-Hispanic populations. Further studies are necessary to expand understanding of the implementation and utilization of panels across broad clinical settings and patient populations.

Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges

PurposeMutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management.Patients and MethodsThis cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were...

Patient communication of cancer genetic test results in a diverse population

Research on the communication of genetic test results has focused predominately on non-Hispanic White (NHW) mutation-positive families with high-risk hereditary cancer conditions. Little is known about this process for racially and ethnically diverse individuals or for those with mutations in moderate risk genes. The communication behaviors of study participants who carry a gene mutation were analyzed 3 months after disclosure of genetic test results. Participants were queried about communication of their results, as part of a prospective study of multi-gene panel genetic testing. The responses of particpants who tested positive were analyzed by race/ethnicity and by level of cancer risk (high vs. moderate). Of the 216 mutation-positive study participants, 136 (63%) responded. Self-reported race/ethnicity was 46% NHW, 41% Hispanic, 10% Asian, and 2% Black. The majority (99.0%, n = 135) had shared their results with someone and 96% had told a family member (n = 130). Hispanic respondents were less likely to have told a healthcare provider about their results than NHW (29% vs. 68%, p < .0001). Asian respondents were less likely than NHW to encourage family members to undergo testing (OR = 0.1, p = .03); but Asian family members were more likely to undergo testing (OR = 8.0, p = .03). There were no differences in communication between those with a mutation in a high- or moderate-risk gene. Three months post genetic testing, communication of results was very high; 30% reported a family member underwent genetic testing. Further studies are needed to better understand the communication process in individuals from diverse racial/ethnic backgrounds.

Abstract 491: Elucidatingde novoPATRR-mediated t(3;8) balanced translocation and clear cell renal cell carcinoma

Palindromic AT-Rich Repeat (PATRR) - mediated translocations entail exchange across chromosomes at sites enriched in palindromic repeats of the nucleotides adenine (A) and thymine (T). Their precise embryologic origin and associated pathobiology with clear cell renal cell carcinoma (ccRCC) remain incompletely described. In the present study we document an individual with familial non-VHL ccRCC (7 primary renal tumors) who harbors a germline de novo PATRR mediated balanced translocation involving chromosomes 3 and 8 [t(3;8)] validated by spectral karyotyping (SKY). Using translocation specific PCR and DNA sequencing we determined the chromosome 3 breakpoint to be located in an AT-rich palindromic sequence in the third intron of the FHIT gene (chr3p14.2) and the chromosome 8 breakpoint in the first intron of the TRC8 gene (chr8q24.1). Genotyping analysis, using a high density custom exomechip array by Illumina, revealed a loss of the entire aberrant chromosome 8 carrying the 3p segment [der(8)] in all renal tumors tested. We also determined that the [46, XY, t(3;8), (p14.2, q24.1)] translocation was paternally derived by performing a genotypic assessment of the regions that differ between the parental alleles and then establishing which haplotypes are associated with the translocation. The somatic mutational landscape was assessed by Whole Exome sequencing of the renal tumors and the proband’s germline DNA. No germline or somatic deleterious mutations were detected in VHL gene suggesting that the ccRCC phenotype is not associated with Von Hippel-Lindau disease. Furthermore, we measured the transcriptomic profiles of the renal tumors and matched normal tissues employing barcoded probe hybridization technology (NanoString) and RNASeq to fully characterize differential gene expression and define gene ontology networks that are dysregulated. Most significantly, no difference in expression of the VHL gene was detected between tumors and normal counterparts. Aberrant regulation was detected in members of WNT signaling pathway, TGF-beta and MAPK pathways, in addition to NOTCH signaling pathway genes and members of the VEGF family. In summary, in this study we employed advanced genomic and transcriptomic techniques, to delineate the embryologic origin and deleterious biological consequences of the PATRR-mediated t(3;8) balanced translocation associated with clear cell renal cell carcinoma. Citation Format: Marilena Melas, Kevin J. McDonnell, Christopher K. Edlund, Sarah J. Tash, Duveen Y. Sturgeon, Chenxu Qu, Charalampos Lazaris, Peter J. Gruber, Thomas W. Glover, Beverly S. Emanuel, Stephen B. Gruber. Elucidating de novo PATRR-mediated t(3;8) balanced translocation and clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2017-491