Publications by authors named "Lily Hoang"

9 Publications

  • Page 1 of 1

Association of Family Cancer History With Pathogenic Variants in Specific Breast Cancer Susceptibility Genes.

JCO Precis Oncol 2021 22;5. Epub 2021 Dec 22.

Department of Internal Medicine, University of Michigan and Center for Clinical Management Research, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI.

Purpose: Family cancer history is an important component of genetic testing guidelines that estimate which patients with breast cancer are most likely to carry a germline pathogenic variant (PV). However, we do not know whether more extensive family history is differentially associated with PVs in specific genes.

Methods: All women diagnosed with breast cancer in 2013-2017 and reported to statewide SEER registries of Georgia and California were linked to clinical genetic testing results and family history from two laboratories. Family history was defined as strong (suggestive of PVs in high-penetrance genes such as or , including male breast, ovarian, pancreatic, sarcoma, or multiple female breast cancers), moderate (any other cancer history), or none. Among established breast cancer susceptibility genes (, , , , , , , , , , and ), we evaluated PV prevalence according to family history extent and breast cancer subtype. We used a multivariable model to test for interaction between affected gene and family history extent for , , and .

Results: A total of 34,865 women linked to genetic results. Higher PV prevalence with increasing family history extent ( < .001) was observed only with (3.04% with none, 3.22% with moderate, and 4.06% with strong history) and in triple-negative breast cancer with (0.75% with none, 2.23% with moderate, and 2.63% with strong history). In a multivariable model adjusted for age and subtype, there was no interaction between family history extent and PV prevalence for any gene except ( = .037).

Conclusion: Extent of family cancer history is not differentially associated with PVs across established breast cancer susceptibility genes and cannot be used to personalize genes selected for testing.
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http://dx.doi.org/10.1200/PO.21.00261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710333PMC
March 2022

Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity.

Genet Med 2022 03 30;24(3):673-680. Epub 2021 Nov 30.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Electronic address:

Purpose: Some variants identified by multigene panel testing of DNA from blood present with low variant allele fraction (VAF), often a manifestation of clonal hematopoiesis. Research has shown that the proportion of variants with low VAF is especially high in TP53, the Li-Fraumeni syndrome gene. Based on the hypothesis that variants with low VAF are positively selected as drivers of clonal hematopoiesis, we investigated the use of VAF as a predictor of TP53 germline variant pathogenicity.

Methods: We used data from 260,681 TP53 variants identified at 2 laboratories to compare the distribution of pathogenic and benign variants at different VAF intervals.

Results: Likelihood ratios toward pathogenicity associated with a VAF < 26% equated to the American College of Medical Genetics/Association of Molecular Pathology strong strength level and were applicable for 1 in 5 variants of unknown significance.

Conclusion: In conclusion, detection of variants with low VAF in blood can be considered an in vivo functional assay to aid assessment of TP53 variant pathogenicity.
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http://dx.doi.org/10.1016/j.gim.2021.10.018DOI Listing
March 2022

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

Sci Rep 2020 08 11;10(1):13518. Epub 2020 Aug 11.

Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.

Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC.
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http://dx.doi.org/10.1038/s41598-020-70449-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419503PMC
August 2020

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

NPJ Precis Oncol 2020 24;4. Epub 2020 Feb 24.

19Smilow Cancer Center, Yale New Haven Health, New Haven, CT USA.

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (, , , , , , , , , , , , , , , , , and ) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.
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http://dx.doi.org/10.1038/s41698-020-0109-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039900PMC
February 2020

Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer.

JAMA Netw Open 2019 10 2;2(10):e1913900. Epub 2019 Oct 2.

Ambry Genetics, Aliso Viejo, California.

Importance: Performing DNA genetic testing (DGT) for hereditary cancer genes is now a well-accepted clinical practice; however, the interpretation of DNA variation remains a challenge for laboratories and clinicians. Adding RNA genetic testing (RGT) enhances DGT by clarifying the clinical actionability of hereditary cancer gene variants, thus improving clinicians' ability to accurately apply strategies for cancer risk reduction and treatment.

Objective: To evaluate whether RGT is associated with improvement in the diagnostic outcome of DGT and in the delivery of personalized cancer risk management for patients with hereditary cancer predisposition.

Design, Setting, And Participants: Diagnostic study in which patients and/or families with inconclusive variants detected by DGT in genes associated with hereditary breast and ovarian cancer, Lynch syndrome, and hereditary diffuse gastric cancer sent blood samples for RGT from March 2016 to April 2018. Clinicians who ordered genetic testing and received a reclassification report for these variants were surveyed to assess whether RGT-related variant reclassifications changed clinical management of these patients. To quantify the potential number of tested individuals who could benefit from RGT, a cohort of 307 812 patients who underwent DGT for hereditary cancer were separately queried to identify variants predicted to affect splicing. Data analysis was conducted from March 2016 and September 2018.

Main Outcomes And Measures: Variant reclassification outcomes following RGT, clinical management changes associated with RGT-related variant reclassifications, and the proportion of patients who would likely be affected by a concurrent DGT and RGT multigene panel testing approach.

Results: In total, 93 if 909 eligible families (10.2%) submitted samples for RGT. Evidence from RGT clarified the interpretation of 49 of 56 inconclusive cases (88%) studied; 26 (47%) were reclassified as clinically actionable and 23 (41%) were clarified as benign. Variant reclassifications based on RGT results changed clinical management recommendations for 8 of 18 patients (44%) and 14 of 18 families (78%), based on responses from 18 of 45 clinicians (40%) surveyed. A total of 7265 of 307 812 patients who underwent DGT had likely pathogenic variants or variants of uncertain significance potentially affecting splicing, indicating that approximately 1 in 43 individuals could benefit from RGT.

Conclusions And Relevance: In this diagnostic study, conducting RNA testing resolved a substantial proportion of variants of uncertain significance in a cohort of individuals previously tested for cancer predisposition by DGT. Performing RGT might change the diagnostic outcome of at least 1 in 43 patients if performed in all individuals undergoing genetic evaluation for hereditary cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.13900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820040PMC
October 2019

A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients.

Genet Med 2020 02 13;22(2):407-415. Epub 2019 Aug 13.

Ambry Genetics, Aliso Viejo, CA, USA.

Purpose: Despite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include.

Methods: To inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT.

Results: We identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria.

Conclusion: Opportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.
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http://dx.doi.org/10.1038/s41436-019-0633-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000322PMC
February 2020

Genotype-phenotype associations among panel-based TP53+ subjects.

Genet Med 2019 11 20;21(11):2478-2484. Epub 2019 May 20.

Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Panel testing has led to the identification of TP53 pathogenic/likely pathogenic (P/LP) variant carriers (TP53+) who exhibit a broad range of phenotypes. We sought to evaluate and compare genotype-phenotype associations among TP53+ panel-ascertained subjects.

Methods: Between 2012 and 2017, 317 TP53+ subjects (279 females and 38 males) identified through panel testing at one testing laboratory were found to have evaluable clinical histories and molecular results. Subject cancer histories were obtained from test requisition forms. P/LP variants were categorized by type and were examined in relation to phenotype.

Results: Loss-of-function (LOF) variants were associated with the earliest age at first cancer, with a median age of 30.5 years (P = 0.014); increased frequency of a sarcoma diagnosis (P = 0.016); and more often meeting classic LFS testing and Chompret 2015 criteria (P = 0.004 and 0.002 respectively), as compared with dominant-negative missense, other missense, or miscellaneous (splice or in-frame deletion) P/LP variant categories.

Conclusion: Loss-of-function variants were more often associated with characteristic LFS cancer histories than other variant categories in TP53+ carriers ascertained through multigene panel testing. These findings require validation in other TP53+ cohorts. Genetic counseling for panel-ascertained TP53+ individuals should reflect the dynamic expansion of the Li-Fraumeni syndrome phenotype.
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http://dx.doi.org/10.1038/s41436-019-0541-yDOI Listing
November 2019

Structurally distinct elements mediate internal ribosome entry within the 5'-noncoding region of a voltage-gated potassium channel mRNA.

J Biol Chem 2004 Nov 31;279(46):47419-30. Epub 2004 Aug 31.

Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, California 92697, USA.

The approximately 1.2-kb 5'-noncoding region (5'-NCR) of mRNA species encoding mouse Kv1.4, a member of the Shaker-related subfamily of voltage-gated potassium channels, was shown to mediate internal ribosome entry in cells derived from brain, heart, and skeletal muscle, tissues known to express Kv1.4 mRNA species. We also show that the upstream approximately 1.0 kb and the downstream approximately 0.2 kb of the Kv1.4 5'-NCR independently mediated internal ribosome entry; however, separately, these sequences were less efficient in mediating internal ribosome entry than when together in the complete (and contiguous) 5'-NCR. Using enzymatic structure probing, the 3'-most approximately 0.2 kb was predicted to form three distinct stem-loop structures (stem-loops X, Y, and Z) and two defined single-stranded regions (loops Psi and Omega) in the presence and absence of the upstream approximately 1.0 kb. Although the systematic deletion of sequences within the 3'-most approximately 0.2 kb resulted in distinct changes in expression, enzymatic structure probing indicated that local RNA folding was not completely altered. Structure probing analysis strongly suggested an interaction between stem-loop X and a downstream polypyrimidine tract; however, opposing changes in activity were observed when sequences within these two regions were independently deleted. Moreover, deletions correlating with positive as well as negative changes in expression altered RNase cleavage within stem-loop X, indicating that this structure may be an integral element. Therefore, these findings indicate that Kv1.4 expression is mediated through a complex interplay between many distinct RNA regions.
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http://dx.doi.org/10.1074/jbc.M405885200DOI Listing
November 2004

Characterization of muscle-regulatory genes, Myf5 and myogenin, from striped bass and promoter analysis of muscle-specific expression.

Mar Biotechnol (NY) 2002 Dec;4(6):537-45

Center of Marine Biotechnology, University of Maryland Biotechnology Institute, 701 E. Pratt Street, Baltimore, MD 21202, USA.

Myf5 and Myogenin are basic helix-loop-helix transcription factors that belong to the muscle regulatory factor (MRF) gene family, which plays important roles in regulating skeletal muscle development and growth. Members of the MRF family, including Myf5, MyoD, Myogenin, and MRF4 are specifically expressed in skeletal muscle cells. They have the remarkable property of converting a variety of cells into myoblasts and myotubes when ectopically expressed in other cell types. To better understand their role and regulation of expression in fish muscle cells, Myf5 and myogenin genomic genes were isolated from striped bass (Morone saxatilis). Sequence analysis revealed that these 2 genes shared similar structures. They both contained 3 exons and 2 introns, and a highly conserved basic helix-loop-helix domain. Promoter analysis identified several putative E box sites in both Myf5 and myogenin promoters that might confer muscle-specific expression. To determine if the striped bass Myf5 and myogenin promoters could control muscle-specific expression, the Myf5 or myogenin promoter was linked with the green fluorescent protein (GFP) reporter gene, and their promoter activity was analyzed in zebrafish embryos by transient expression assay. Our data showed that both striped bass Myf5 and myogenin promoters could drive muscle-specific GFP expression in zebrafish. These data demonstrated that a muscle-specific regulatory element or elements were located within the striped bass Myf5 and myogenin promoters, and were conserved between striped bass and zebrafish. Moreover, these data suggested the muscle-specific regulatory element could function across fish species in regulating gene expression.
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http://dx.doi.org/10.1007/s10126-002-0013-1DOI Listing
December 2002
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