Publications by authors named "Tracy L Stockley"

41 Publications

Validation of BRCA testing on cytologic samples of high-grade serous carcinoma.

Cancer Cytopathol 2021 Jun 22. Epub 2021 Jun 22.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Background: Testing for BRCA1/2 gene alterations in patients with high-grade serous carcinoma (HGSC) is a critical determinant of treatment eligibility for poly(adenosine diphosphate-ribose) polymerase inhibitors in addition to providing vital information for genetic counselling. Many patients present with effusions necessitating therapeutic drainage, and this makes cytologic specimens (CySs) the initial diagnostic material for HGSC, often before histologic sampling. Initiating somatic BRCA testing on a CyS allows the BRCA status to be determined sooner, and this affects clinical management.

Methods: Retrospectively, 8 cases of formalin-fixed, paraffin-embedded (FFPE) CySs of peritoneal or pleural fluid from patients with HGSC and known BRCA1/2 alterations previously established by the testing of FFPE surgical specimens (SpSs) underwent next-generation sequencing (NGS). Prospectively, 11 cases of peritoneal or pleural fluid from patients with HGSC but an unknown BRCA1/2 status underwent NGS with fresh, alcohol-fixed, and FFPE CySs, and they were compared with subsequent NGS on 4 SpSs.

Results: CySs yielded high-quantity and high-quality DNA for NGS analysis when sufficient tumor cellularity was present. Fresh, alcohol-fixed, and FFPE CySs were all suitable for NGS and provided identical NGS results. SpS and CyS BRCA testing was concordant in 10 of 12 cases. The 2 discordant cases showed low tumor cellularity and quality in the CyS and the SpS, respectively.

Conclusion: Effusion CySs of HGSC are excellent sources for NGS testing for BRCA1/2 genetic alterations when sufficient tumor cellularity is present. Fresh, alcohol-fixed, and FFPE CySs are equivalent for NGS of BRCA1/2. NGS testing of HGSC CySs demonstrates good concordance with SpSs for the BRCA1/2 status.
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http://dx.doi.org/10.1002/cncy.22484DOI Listing
June 2021

Consensus Recommendations for MRD Testing in Adult B-Cell Acute Lymphoblastic Leukemia in Ontario.

Curr Oncol 2021 Mar 30;28(2):1376-1387. Epub 2021 Mar 30.

Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology, Toronto, ON M5G 2M9, Canada.

Measurable (minimal) residual disease (MRD) is an established, key prognostic factor in adult B-cell acute lymphoblastic leukemia (B-ALL), and testing for MRD is known to be an important tool to help guide treatment decisions. The clinical value of MRD testing depends on the accuracy and reliability of results. Currently, there are no Canadian provincial or national guidelines for MRD testing in adult B-ALL, and consistent with the absence of such guidelines, there is no uniform Ontario MRD testing consensus. Moreover, there is great variability in Ontario in MRD testing with respect to where, when, and by which technique, MRD testing is performed, as well as in how the results are interpreted. To address these deficiencies, an expert multidisciplinary working group was convened to define consensus recommendations for improving the provision of such testing. The expert panel recommends that MRD testing should be implemented in a centralized manner to ensure expertise and accuracy in testing for this low volume indication, thereby to provide accurate, reliable results to clinicians and patients. All adult patients with B-ALL should receive MRD testing after induction chemotherapy. Philadelphia chromosome (Ph)-positive patients should have ongoing monitoring of MRD during treatment and thereafter, while samples from Ph-negative B-ALL patients should be tested at least once later during treatment, ideally at 12 to 16 weeks after treatment initiation. In Ph-negative adult B-ALL patients, standardized, ideally centralized, protocols must be used for MRD testing, including both flow cytometry and immunoglobulin () heavy chain and T-cell receptor () gene rearrangement analysis. For Ph-positive B-ALL patients, MRD testing using a standardized protocol for reverse transcription real-time quantitative PCR (RT-qPCR) for the gene fusion transcript is recommended, with gene rearrangement analysis done in parallel likely providing additional clinical information.
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http://dx.doi.org/10.3390/curroncol28020131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025812PMC
March 2021

Can variant negative be high-grade serous ovarian carcinoma? A case series.

Gynecol Oncol Rep 2021 May 12;36:100729. Epub 2021 Feb 12.

Division of Medical Oncology & Hematology, Bras Family Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1Z5, Canada.

• variant negative high-grade serous ovarian cancer is rare and can still show p53 abnormal immunohistochemistry.•Diagnostic and therapeutic considerations include pathologic, molecular and clinical domains.•Genetic reassessment through more comprehensive assays should be considered to ensure no missed rare or complex variants.•Presence of mutations can occur in variant high-grade serous ovarian cancer.
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http://dx.doi.org/10.1016/j.gore.2021.100729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910505PMC
May 2021

Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population-based testing program.

Mol Oncol 2021 01 22;15(1):80-90. Epub 2020 Oct 22.

Laboratory Medicine Program, Division of Clinical Laboratory Genetics, University Health Network, Toronto, Canada.

The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PVs) in high-grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large-scale, population-based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PVs were detected in 38 tumors (19%); 58% were somatic (22/38); and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor-only and paired cohorts), reported to date, and our data show that an effectively designed and validated population-based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk.
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http://dx.doi.org/10.1002/1878-0261.12817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782089PMC
January 2021

Year 1: Experiences of a tertiary cancer centre following implementation of reflex BRCA1 and BRCA2 tumor testing for all high-grade serous ovarian cancers in a universal healthcare system.

Gynecol Oncol 2020 09 14;158(3):747-753. Epub 2020 Jul 14.

Lawrence S Bloomberg Faculty of Nursing, University of Toronto, 155 College Street, Toronto, ON M5T 1P8, Canada; Women's College Research Institute, 72 Grenville Street, Toronto, ON M5S 1B2, Canada.

Objective: This study compares the rate and time to genetic referral, and patient uptake of germline genetic services, before and after implementation of reflex BRCA1/2 tumor testing for high-grade serous ovarian cancer (HGSOC) in a universal healthcare system.

Methods: A retrospective chart review of HSGOC patients diagnosed in the year before (PRE) and after (POST) implementation of reflex BRCA1/2 tumor testing was conducted. Clinical information (date/age at diagnosis, personal/family history of breast/ovarian cancer, cancer stage, primary treatment, tumor results) and dates of genetics referral, counseling, and germline testing were obtained. Incident rate ratios (IRR) and 95% CI were calculated using negative binomial regression. Time to referral was evaluated using Kaplan-Meier survival analysis. Fisher Exact tests were used to evaluate uptake of genetic services.

Results: 175 HGSOC patients were identified (81 PRE; 94 POST). Post-implementation of tumor testing, there was a higher rate of genetics referral (12.88 versus 7.10/1000 person-days; IRR = 1.60, 95% CI: 1.07-2.42) and a shorter median time from diagnosis to referral (59 days PRE, 33 days POST; p = .04). In the POST cohort, most patients were referred prior to receiving their tumor results (n = 63/77; 81.8%). Once referred, most patients attended genetic counseling (94.5% PRE, 97.6% POST; p = .418) and pursue germline testing (98.6% PRE; 100% POST; p = .455).

Conclusions: Following implementation of reflex BRCA1/2 tumor testing for HGSOC, significant improvements to the rate and time to genetics referral were identified. Additional studies are needed to evaluate physician referral practices and the long-term impact of reflex tumor testing.
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http://dx.doi.org/10.1016/j.ygyno.2020.06.507DOI Listing
September 2020

Clinical implementation of circulating tumour DNA testing for T790M for detection of treatment resistance in non-small cell lung cancer.

J Clin Pathol 2021 Feb 29;74(2):91-97. Epub 2020 May 29.

Division of Clinical Laboratory Genetics, University Health Network, Toronto, Ontario, Canada

Aims: Epidermal growth factor receptor () T790M mutations can be detected in the circulating tumour DNA from plasma of patients with non-small cell lung cancer (NSCLC) to triage patients for osimertinib eligibility and monitor patients longitudinally for development of T790M-mediated resistance.

Methods: Using droplet digital PCR (ddPCR), we examined the T790M status of 343 sequential patients with NSCLC and correlated mutational status with demographic and clinical features. Where available, serial T790M blood test results were assessed to identify clinical triggers and timing of repeat testing.

Results: Of the 343 patients with liquid biopsy test results, 24% were T790M positive. No clear clinical correlation with a T790M positive test result was identified in this study, although the number of metastatic sites did correlate significantly with the presence of sensitising mutations (L858R or exon 19 deletion) in patient plasma, as a measure of tumour DNA shedding. Of the 59 serial blood tests from patients that initially tested negative, 14% were positive on sequential testing, at a time interval up to 6 months after an initially negative blood test.

Conclusions: The ddPCR test for T790M mutations effectively triaged 24% of patients for treatment with osimertinib, avoiding the need for invasive tissue biopsy in these patients. Our findings suggest that initial and repeat ctDNA testing can be used to monitor for acquired T790M resistance for NSCLC.
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http://dx.doi.org/10.1136/jclinpath-2020-206668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841482PMC
February 2021

Molecular profiling for precision cancer therapies.

Genome Med 2020 01 14;12(1). Epub 2020 Jan 14.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University Avenue, University of Toronto, Toronto, Ontario, M5G 1Z5, Canada.

The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics.
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http://dx.doi.org/10.1186/s13073-019-0703-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961404PMC
January 2020

Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.

Mod Pathol 2019 12 15;32(12):1823-1833. Epub 2019 Jul 15.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Gastric-type endocervical adenocarcinoma is an uncommon aggressive type of endocervical adenocarcinoma that is not associated with human papillomavirus (HPV). At present, this tumor is classified under the spectrum of mucinous carcinoma of the uterine cervix. The clinical stage of gastric-type endocervical adenocarcinoma at the time of diagnosis is usually more advanced compared to the HPV-associated endocervical adenocarcinoma. Widespread dissemination to unusual sites, such as omentum, peritoneum, and distant organs, can be present. Owing to its rare incidence, diagnostic dilemmas, and aggressive behavior, clinical management can be challenging. In this study, we aimed to elucidate the molecular characteristics of these tumors by using next-generation sequencing (NGS) to assess 161 unique cancer-driver genes for single-nucleotide and copy-number variations, gene fusions, and insertions/deletions within gastric-type endocervical adenocarcinoma tumors. In total, 92 variants were detected across the 14 samples tested (7 variants on average per tumor). TP53 was the most recurrently mutated gene followed by MSH6, CDKN2A/B, POLE, SLX4, ARID1A, STK11, BRCA2, and MSH2. Abnormal p53 expression was observed in nine cases by immunohistochemistry, of which TP53 variants were present in four cases. MDM2 gene amplification in 12q15 (69202190-69233452) locus was seen in two cases that express normal p53 levels by immunohistochemistry. Four cases had STK11 null (frameshift/nonsense) variants, three of which were previously reported in Peutz-Jeghers syndrome. Overall, genes that are implicated in DNA damage, repair, cell cycle, Fanconi anemia pathway, and the PI3K-AKT signaling pathways were found to be mutated. Of note, genes known to have acquired and/or inherited variants in endometrial tumors were enriched within our cohort. In conclusion, our study shows the genetic heterogeneity of gastric-type endocervical adenocarcinoma with some potentially actionable molecular alterations, which highlights the importance of further molecular characterization for better identification of this rare entity, and hence better clinical management.
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http://dx.doi.org/10.1038/s41379-019-0305-xDOI Listing
December 2019

CCMG practice guideline: laboratory guidelines for next-generation sequencing.

J Med Genet 2019 12 12;56(12):792-800. Epub 2019 Jul 12.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

PurposeThe purpose of this document is to provide guidance for the use of next-generation sequencing (NGS, also known as massively parallel sequencing or MPS) in Canadian clinical genetic laboratories for detection of genetic variants in genomic DNA and mitochondrial DNA for inherited disorders, as well as somatic variants in tumour DNA for acquired cancers. They are intended for Canadian clinical laboratories engaged in developing, validating and using NGS methods. METHODS OF STATEMENT DEVELOPMENT: The document was drafted by the Canadian College of Medical Geneticists (CCMG) Ad Hoc Working Group on NGS Guidelines to make recommendations relevant to NGS. The statement was circulated for comment to the CCMG Laboratory Practice and Clinical Practice committees, and to the CCMG membership. Following incorporation of feedback, the document was approved by the CCMG Board of Directors. DISCLAIMER: The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. The current CCMG Practice Guidelines were developed as a resource for clinical laboratories in Canada and should not be considered to be inclusive of all information laboratories should consider in the validation and use of NGS for a clinical laboratory service.
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http://dx.doi.org/10.1136/jmedgenet-2019-106152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929709PMC
December 2019

The presence and variant allele fraction of EGFR mutations in ctDNA and development of resistance.

Lung Cancer 2019 05 20;131:86-89. Epub 2019 Mar 20.

Princess Margaret Cancer Centre/University Health Network, Toronto, Canada. Electronic address:

Background: Peripheral blood sampling for detection of EGFR T790M in cell-free circulating tumour (ct) DNA in TKI-resistant EGFR mutant (EGFRm) lung cancer is now standard. The value of more comprehensive sequencing is unknown.

Methods: Prospective ctDNA analysis in patients with EGFRm NSCLC was performed using a next generation sequencing (NGS) panel of regions of 11 genes detecting single nucleotide variants and small insertions/deletions at ≥0.1% variant allele frequency (VAF) was performed. Patients were grouped according to treatment phase, including: (A) pre EGFR-TKI, (B) stable or responding to EGFR-TKI, (C) radiographic progression during EGFR-TKI, and (D) during chemotherapy treatment.

Results: Seventy-two patients with stage IV EGFRm NSCLC were enrolled and first blood samples were analysed. Primary sensitizing mutations in del19 or L858R were present in 66 (92%) and uncommon EGFRm in 6 (8%). Mutations in ctDNA were found in 53 samples (74%). T790M was detected in 3 of 4 patients with T790M-negative tissue. Other co-occurring EGFRm were found in 10 patients (7%) including K745R during first-line osimertinib. TP53 (n = 10), KRAS (n = 1), PI3KCA (n = 1) and ALK (n = 3) gene mutations also were detected. The presence of an EGFRm (excluding T790M) was associated with untreated or progressive disease, p = 0.04. In TKI-treated patients without radiologic progression, median progression free survival (PFS) was 10 months versus 2.1 months (HR 2.22, 95% CI: 0.89-5.54, p = 0.08) if an EGFRm in ctDNA was detected. If T790M was present in ctDNA, median PFS was 3.0 months versus 9.7 months (HR 4.59, 95% CI: 1.43-14.73, p = 0.005). High % VAF of both EGFRm and T790M correlated with inferior PFS (p = 0.01 and p = 0.03 respectively).

Conclusion: In addition to the emergence of resistance mutations, the presence of the primary or co-occurring EGFRm in patients receiving EGFR-TKIs may associate with shorter PFS and may be useful in longitudinal analyses of ctDNA to direct therapy.
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http://dx.doi.org/10.1016/j.lungcan.2019.03.019DOI Listing
May 2019

Somatic Tumor Variant Filtration Strategies to Optimize Tumor-Only Molecular Profiling Using Targeted Next-Generation Sequencing Panels.

J Mol Diagn 2019 03 19;21(2):261-273. Epub 2018 Dec 19.

Advanced Molecular Diagnostics Laboratory, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Clinical Laboratory Genetics, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

A common approach in clinical diagnostic laboratories to variant assessment from tumor molecular profiling is sequencing of genomic DNA extracted from both tumor (somatic) and normal (germline) tissue, with subsequent variant comparison to identify true somatic variants with potential impact on patient treatment or prognosis. However, challenges exist in paired tumor-normal testing, including increased cost of dual sample testing and identification of germline cancer predisposing variants. Alternatively, somatic variants can be identified by in silico tumor-only variant filtration precluding the need for matched normal testing. The barrier to tumor-only variant filtration is defining a reliable approach, with high sensitivity and specificity to identify somatic variants. In this study, we used retrospective data sets from paired tumor-normal samples tested on small (48 gene) and large (555 gene) targeted next-generation sequencing panels, to model algorithms for tumor-only variants classification. The optimal algorithm required an ordinal filtering approach using information from variant population databases (1000 Genomes Phase 3, ESP6500, ExAC), clinical mutation databases (ClinVar), and information on recurring clinically relevant somatic variants. Overall the tumor-only variant filtration strategy described in this study can define clinically relevant somatic variants from tumor-only analysis with sensitivity of 97% to 99% and specificity of 87% to 94%, and with significant potential utility for clinical laboratories implementing tumor-only molecular profiling.
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http://dx.doi.org/10.1016/j.jmoldx.2018.09.008DOI Listing
March 2019

Additional germline findings from a tumor profiling program.

BMC Med Genomics 2018 Aug 9;11(1):65. Epub 2018 Aug 9.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON, M5G 2M9, Canada.

Background: Matched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants (gMAVS) in cancer predisposition genes. We report patient preferences for the return of additional germline results, and describe various gMAV scenarios delivered through a clinical genetics service.

Methods: Tumor profiling was offered to 1960 advanced cancer patients, of which 1556 underwent tumor-normal sequencing with multigene hotspot panels containing 20 cancer predisposition genes. All patients were provided with an IRB-approved consent for return of additional gMAVs.

Results: Of the whole cohort 94% of patients consented to be informed of additional germline results and 5% declined, with no statistically significant differences based on age, sex, race or prior genetic testing. Eight patients were found to have gMAVs in a cancer predisposition gene. Five had previously unidentified gMAVs: three in TP53 (only one fulfilled Chompret's Revised criteria for Li-Fraumeni Syndrome), one in SMARCB1 in the absence of schwannomatosis features and one a TP53 variant at low allele frequency suggesting an acquired event in blood.

Conclusion: Interest in germline findings is high among patients who undergo tumor profiling. Disclosure of previously unidentified gMAVs present multiple challenges, thus supporting the involvement of a clinical genetics service in all tumor profiling programs.
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http://dx.doi.org/10.1186/s12920-018-0383-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085686PMC
August 2018

Evolution of genetic assessment for BRCA-associated gynaecologic malignancies: a Canadian multisociety roadmap.

J Med Genet 2018 09 24;55(9):571-577. Epub 2018 Jul 24.

Familial Breast & Ovarian Cancer Clinic, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

The landscape of genetic testing in ovarian cancer patients has changed dramatically in recent years. The therapeutic benefits of poly ADP-ribose polymerase (PARP) inhibitors in treatment of -related ovarian cancers has resulted in an increased demand and urgency for genetic testing results, while technological developments have led to widespread use of multi-gene cancer panels and development of tumour testing protocols. Traditional genetic counselling models are no longer sustainable and must evolve to match the rapid evolution of genetic testing technologies and developments in personalized medicine. Recently, representatives from oncology, clinical genetics, molecular genetics, pathology, and patient advocacy came together to create a national multi-disciplinary Canadian consortium. By aligning stakeholder interests, the BRCA Testing to Treatment (BRCA TtoT) Community of Practice aims to develop a national strategy for tumour and germline testing and genetic counselling in women with ovarian cancer. This article serves to provide an overview of the recent evolution of genetic assessment for -associated gynecologic malignancies and outline a Canadian roadmap to facilitate change, improve genetic testing rates, and ultimately improve outcomes for hereditary ovarian cancer patients and their families.
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http://dx.doi.org/10.1136/jmedgenet-2018-105472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119348PMC
September 2018

P53 Gene Mutation Identified by Next Generation Sequencing in Poorly Differentiated Neuroendocrine Carcinoma of the Nasal Cavity.

Head Neck Pathol 2019 Sep 29;13(3):516-522. Epub 2018 May 29.

Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.

Neuroendocrine carcinomas (NECs) are epithelial neoplasms showing morphologic, immunophenotypic or ultrastructural evidence of neuroendocrine differentiation. The 2017 WHO Classification of Head and Neck Tumours classifies NECs into well, moderately and poorly differentiated NECs according to light microscopic features, mitotic rate and presence of tumour necrosis. In this study, we performed next generation sequencing (NGS) using a targeted 161 cancer gene panel on a poorly differentiated NEC of the nasal cavity. The tumour was composed of large cells arranged in poorly formed glands and solid nests. The mitotic count rate was 30/10 HPFs and p53 protein was strongly expressed in all tumour cells. NGS identified a missense mutation, c.764T > G (p.Ile255Ser) in the TP53 gene with an allele frequency of 85%. This mutation results in an isoleucine to serine substitution and a non-functional protein. No other mutations were identified. These results suggest that TP53 mutations may drive oncogenesis in poorly differentiated NECs of the head and neck.
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http://dx.doi.org/10.1007/s12105-018-0934-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684699PMC
September 2019

AML refractory to primary induction with Ida-FLAG has a poor clinical outcome.

Leuk Res 2018 05 20;68:22-28. Epub 2018 Feb 20.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Electronic address:

We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High risk cytogenetics and TP53 mutations were associated with failure to achieve remission. In those reaching remission, allogeneic bone marrow transplantation was associated with better relapse-free and overall survival. Those not achieving remission with induction therapy were extremely unlikely to reach remission with further therapy and had a dismal prognosis. Exploratory molecular analysis confirmed persistence of the dominant genetic mutations identified at diagnosis. Ex vivo chemosensitivity did not demonstrate significant differences between responders and non-responders. Thus, Ida-FLAG induction has a high chance of inducing remission in patients with high risk AML. Those achieving remission require allogeneic transplantation to achieve cure; those not achieving remission rarely respond to salvage chemotherapy and have a dismal outcome. Alternatives to conventional chemotherapy must be considered in this group.
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http://dx.doi.org/10.1016/j.leukres.2018.02.012DOI Listing
May 2018

Impact of multi-gene mutational profiling on clinical trial outcomes in metastatic breast cancer.

Breast Cancer Res Treat 2018 Feb 24;168(1):159-168. Epub 2017 Nov 24.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 7-723 700 University Avenue, Toronto, Canada.

Purpose: Next-generation sequencing (NGS) has identified recurrent genomic alterations in metastatic breast cancer (MBC); however, the clinical utility of incorporating routine sequencing to guide treatment decisions in this setting is unclear. We examine the frequency of genomic alterations in MBC patients from academic and community hospitals and correlate with clinical outcomes.

Methods: MBC patients with good performance status were prospectively recruited at the Princess Margaret Cancer Centre (PM) in Canada. Molecular profiling on DNA extracted from FFPE archival tissues was performed on the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel (TSACP) on the MiSeq platform. Clinical trial outcomes by RECIST 1.1 and time on treatment were reviewed retrospectively.

Results: From January 2012 to November 2015, 483 MBC patients were enrolled and 440 were genotyped. At least one somatic mutation was identified in 46% of patients, most commonly in PIK3CA (28%) or TP53 (13%). Of 203 patients with ≥ 1 mutation(s), 15% were treated on genotype-matched and 9% on non-matched trials. There was no significant difference for median time on treatment for patients treated on matched vs. non-matched therapies (3.6 vs. 3.8 months; p = 0.89).

Conclusions: This study provides real-world outcomes on hotspot genotyping and small targeted panel sequencing of MBC patients from academic and community settings. Few patients were matched to clinical trials with targeted therapies. More comprehensive profiling and improved access to clinical trials may increase therapeutic options for patients with actionable mutations. Further studies are needed to evaluate if this approach leads to improved clinical outcomes.
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http://dx.doi.org/10.1007/s10549-017-4580-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847065PMC
February 2018

Identifying actionable variants using next generation sequencing in patients with a historical diagnosis of undifferentiated pleomorphic sarcoma.

Int J Cancer 2018 01 9;142(1):57-65. Epub 2017 Oct 9.

Sarcoma Program, Mount Sinai Hospital, Toronto, Canada.

There are limited data regarding the molecular characterization of undifferentiated pleomorphic sarcomas (UPS; formerly malignant fibrous histiocytoma). This study aimed to investigate the utility of next generation sequencing (NGS) in UPS to identify subsets of patients who harbour actionable mutations. Patients diagnosed with UPS underwent pathological re-evaluation by a pathologist specializing in sarcoma. Tumor DNA was isolated from archived fresh frozen tissue samples and genotyped using NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons). In total, 95 patients initially classified with UPS were identified. Following pathology re-review the histological subtypes were reclassified to include: Myxofibrosarcoma (MFS, N = 44); UPS(N = 18); and Others (N = 27; including undifferentiated spindle cell sarcoma (N = 15) and dedifferentiated liposarcoma (N = 6)). Seven cases were excluded from further analysis for other reasons. Baseline demographics of the finalized cohort (N = 88) showed a median age of 66 years (32-95), primarily with stage I-III disease (92%) and high-grade (86%) lesions. Somatic mutations were identified in 31 cases (35%)(Total mutations = 36: solitary mutation(n = 27); two mutations( =n = 3); three mutations(n = 1)). The most commonly identified mutations were in TP53 (n = 24), ATM (n = 3) and PIK3CA (n = 2). Three of 43 patients with MFS and one of 18 patients with UPS had clinically relevant mutations, mainly related to biomarkers of prediction of response; however few had targetable driver mutations. Somatic mutation status did not influence disease free or overall survival. Based on the small number of clinically relevant mutations, these data do not support the routine use of targeted NGS panels outside of research protocols in UPS.
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http://dx.doi.org/10.1002/ijc.31039DOI Listing
January 2018

Improving validation methods for molecular diagnostics: application of Bland-Altman, Deming and simple linear regression analyses in assay comparison and evaluation for next-generation sequencing.

J Clin Pathol 2018 Feb 26;71(2):117-124. Epub 2017 Jul 26.

Advanced Molecular Diagnostics Laboratory, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Aims: A standard approach in test evaluation is to compare results of the assay in validation to results from previously validated methods. For quantitative molecular diagnostic assays, comparison of test values is often performed using simple linear regression and the coefficient of determination (R), using R as the primary metric of assay agreement. However, the use of R alone does not adequately quantify constant or proportional errors required for optimal test evaluation. More extensive statistical approaches, such as Bland-Altman and expanded interpretation of linear regression methods, can be used to more thoroughly compare data from quantitative molecular assays.

Methods: We present the application of Bland-Altman and linear regression statistical methods to evaluate quantitative outputs from next-generation sequencing assays (NGS). NGS-derived data sets from assay validation experiments were used to demonstrate the utility of the statistical methods.

Results: Both Bland-Altman and linear regression were able to detect the presence and magnitude of constant and proportional error in quantitative values of NGS data. Deming linear regression was used in the context of assay comparison studies, while simple linear regression was used to analyse serial dilution data. Bland-Altman statistical approach was also adapted to quantify assay accuracy, including constant and proportional errors, and precision where theoretical and empirical values were known.

Conclusions: The complementary application of the statistical methods described in this manuscript enables more extensive evaluation of performance characteristics of quantitative molecular assays, prior to implementation in the clinical molecular laboratory.
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http://dx.doi.org/10.1136/jclinpath-2017-204520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800325PMC
February 2018

Integration of Technical, Bioinformatic, and Variant Assessment Approaches in the Validation of a Targeted Next-Generation Sequencing Panel for Myeloid Malignancies.

Arch Pathol Lab Med 2017 Jun 9;141(6):759-775. Epub 2017 Mar 9.

From the Laboratory Medicine Program, Advanced Molecular Diagnostics Laboratory, Departments of Pathology and Genetics (Drs Thomas, Sukhai, Garg, Misyura, Stockley, and Kamel-Reid), the Princess Margaret Cancer Centre (Drs Thomas, Sukhai, Garg, Misyura, Pugh, Stockley, and Kamel-Reid and Ms Zhang), and High Performance Computing and Bioinformatics Services, Princess Margaret Genomics Centre (Dr Harbi and Mr Dolatshahi), University Health Network, Toronto, Ontario, Canada; and the Departments of Medical Biophysics (Drs Pugh and Kamel-Reid) and Laboratory Medicine and Pathobiology (Drs Stockley and Kamel-Reid), The University of Toronto, Toronto, Ontario, Canada.

Context: - Detection of variants in hematologic malignancies is increasingly important because of a growing number of variants impacting diagnosis, prognosis, and treatment response, and as potential therapeutic targets. The use of next-generation sequencing technologies to detect variants in hematologic malignancies in a clinical diagnostic laboratory setting allows for efficient identification of routinely tested markers in multiple genes simultaneously, as well as the identification of novel and rare variants in other clinically relevant genes.

Objective: - To apply a systematic approach to evaluate and validate a commercially available next-generation sequencing panel (TruSight Myeloid Sequencing Panel, Illumina, San Diego, California) targeting 54 genes. In this manuscript, we focused on the parameters that were used to evaluate assay performance characteristics.

Data Sources: - Analytical validation was performed using samples containing known variants that had been identified previously. Cases were selected from different disease types, with variants in a range of genes. Panel performance characteristics were assessed and genomic regions requiring additional analysis or wet-bench approaches identified.

Conclusions: - We validated the performance characteristics of a myeloid next-generation sequencing panel for detection of variants. The TruSight Myeloid Sequencing Panel covers more than 95% of target regions with depth greater than 500×. However, because of unique variant types such as large insertions or deletions or genomic regions of high GC content, variants in CEBPA, FLT3, and CALR required supplementation with non-next-generation sequencing assays or with informatics approaches to address deficiencies in performance. The use of multiple bioinformatics approaches (2 variant callers and informatics scripts) allows for maximizing calling of true positives, while identifying limitations in using either method alone.
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http://dx.doi.org/10.5858/arpa.2016-0547-RADOI Listing
June 2017

CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions.

Am J Hum Genet 2017 May;100(5):773-788

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address:

Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7) and lysine (K) methyltransferase 2D (KMT2D), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7 or KMT2D identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of the DNAm targets in each gene-specific signature identified both common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics.
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http://dx.doi.org/10.1016/j.ajhg.2017.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420353PMC
May 2017

Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial.

Genome Med 2016 10 25;8(1):109. Epub 2016 Oct 25.

Cancer Genomics Program, Princess Margaret Cancer Centre, Toronto, Canada.

Background: The clinical utility of molecular profiling of tumor tissue to guide treatment of patients with advanced solid tumors is unknown. Our objectives were to evaluate the frequency of genomic alterations, clinical "actionability" of somatic variants, enrollment in mutation-targeted or other clinical trials, and outcome of molecular profiling for advanced solid tumor patients at the Princess Margaret Cancer Centre (PM).

Methods: Patients with advanced solid tumors aged ≥18 years, good performance status, and archival tumor tissue available were prospectively consented. DNA from archival formalin-fixed paraffin-embedded tumor tissue was tested using a MALDI-TOF MS hotspot panel or a targeted next generation sequencing (NGS) panel. Somatic variants were classified according to clinical actionability and an annotated report included in the electronic medical record. Oncologists were provided with summary tables of their patients' molecular profiling results and available mutation-specific clinical trials. Enrolment in genotype-matched versus genotype-unmatched clinical trials following release of profiling results and response by RECIST v1.1 criteria were evaluated.

Results: From March 2012 to July 2014, 1893 patients were enrolled and 1640 tested. After a median follow-up of 18 months, 245 patients (15 %) who were tested were subsequently treated on 277 therapeutic clinical trials, including 84 patients (5 %) on 89 genotype-matched trials. The overall response rate was higher in patients treated on genotype-matched trials (19 %) compared with genotype-unmatched trials (9 %; p < 0.026). In a multi-variable model, trial matching by genotype (p = 0.021) and female gender (p = 0.034) were the only factors associated with increased likelihood of treatment response.

Conclusions: Few advanced solid tumor patients enrolled in a prospective institutional molecular profiling trial were treated subsequently on genotype-matched therapeutic trials. In this non-randomized comparison, genotype-enrichment of early phase clinical trials was associated with an increased objective tumor response rate.

Trial Registration: NCT01505400 (date of registration 4 January 2012).
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http://dx.doi.org/10.1186/s13073-016-0364-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078968PMC
October 2016

Comparison of Next-Generation Sequencing Panels and Platforms for Detection and Verification of Somatic Tumor Variants for Clinical Diagnostics.

J Mol Diagn 2016 11;18(6):842-850

Advanced Molecular Diagnostics Laboratory, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Genetics, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Use of next-generation sequencing to detect somatic variants in DNA extracted from formalin-fixed, paraffin-embedded tumor tissues poses a challenge for clinical molecular diagnostic laboratories because of variable DNA quality and quantity, and the potential to detect low allele frequency somatic variants difficult to verify by non-next-generation sequencing methods. We evaluated somatic variant detection performance of the MiSeq and Ion Proton benchtop sequencers using two commercially available panels, the TruSeq Amplicon Cancer Panel and the AmpliSeq Cancer Hotspot Panel Version 2. Both the MiSeq-TruSeq Amplicon Cancer Panel and Ion Proton-AmpliSeq Cancer Hotspot Panel Version 2 were comparable in terms of detection of somatic variants and allele frequency determination using DNA extracted from tumor tissue. Concordance was 100% between the panels for detection of somatic variants in genomic regions tested by both panels, including 27 variants present at low somatic allele frequency (<15%). Use of both the MiSeq and Ion Proton platforms in a combined workflow enabled detection of potentially actionable variants with importance for patient diagnosis, prognosis, or treatment in 49% (305/621) of cases. Overall, a combined workflow using both platforms enabled successful molecular profiling of 96% (621/644) of tumor samples, and provided an approach for verification of somatic variants not amenable to verification by Sanger sequencing (<15% variant allele frequency).
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http://dx.doi.org/10.1016/j.jmoldx.2016.06.004DOI Listing
November 2016

Testing ERBB2 p.L755S kinase domain mutation as a druggable target in a patient with advanced colorectal cancer.

Cold Spring Harb Mol Case Stud 2016 Sep;2(5):a001016

Drug Development Program, Division of Medical Oncology and Hematology; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5S 1A8, Canada;; Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified. The hypothesis behind this ongoing molecular profiling effort is that improvement in patients' clinical outcomes will be achieved by inhibiting these discovered genetic driver events with matched targeted drugs. This hypothesis is currently being tested in oncology clinics with variable early results. Herein, we present our experience with a case of advanced colorectal cancer (CRC) with an ERBB2 p.L755S kinase domain mutation, a BRAF p.N581S mutation, and an APC p.Q1429fs mutation, together with a brief review of the literature describing the biological and clinical significance of ERRB2 kinase domain mutations in CRC. The patient was treated with trastuzumab combined with infusional 5-fluorouracil and leucovorin based on the presence of ERBB2 p.L755S kinase mutation in the tumor and based on the available evidence at the time when standard treatment options had been exhausted. However, there was no therapeutic response illustrating the challenges we face in managing patients with potentially targetable mutations where results from functional in vitro and in vivo studies lag behind those of genomic sequencing studies. Also lagging behind are clinical utility data from oncology clinics, hampering rapid therapeutic advances. Our case also highlights the logistical barriers associated with getting the most optimal therapeutic agents to the right patient in this era of personalized therapeutics based on cancer genomics.
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http://dx.doi.org/10.1101/mcs.a001016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002925PMC
September 2016

Establishment and Characterization of a Human Neuroendocrine Tumor Xenograft.

Endocr Pathol 2016 Jun;27(2):97-103

Princess Margaret Hospital, University Health Network, Toronto, Ontario, M5G 2M9, Canada.

Neuroendocrine tumors (NETs) are increasing in incidence yet the cause of these tumors remains unknown. Familial associations have shed light on the genetic basis of some of these tumors, but sporadic tumors seem to have primarily epigenetic dysregulation. The rarity of cell lines and animal models has been a barrier to studies of treatment modalities. We set out to develop a xenograft model of gastrointestinal NETs. Primary human NETs were collected at the time of surgery under sterile conditions and xenografted into the flanks of immunodeficient mice. Tumor growth was measured and when tumors reached 1500 mm(3), they were excised and half was re-xenografted through multiple generations. The other half was bisected; a part was frozen and a part was fixed for morphologic and immunohistochemical characterization as well as molecular validation of fidelity of a successful xenograft. Of 106 human NETs, seven were successfully engrafted of which only one tumor was successfully propagated for eight passages. Two years later, the tumor retains its neuroendocrine features and similarity to the original primary human tumor. It has retained expression of keratin as well as chromogranin A reactivity. The establishment of a NET xenograft provides a model for further study of the biological behavior of these tumors and can be used to examine the in vivo effects of various medical and targeted radiotherapeutic agents on tumor growth.
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http://dx.doi.org/10.1007/s12022-016-9429-4DOI Listing
June 2016

Whole-exome analysis of foetal autopsy tissue reveals a frameshift mutation in OBSL1, consistent with a diagnosis of 3-M Syndrome.

BMC Genomics 2015 15;16 Suppl 1:S12. Epub 2015 Jan 15.

Background: We report a consanguineous couple that has experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs. Post-termination examination revealed no skeletal dysplasia, but some subtle proximal limb shortening in two foetuses, and a spectrum of mildly dysmorphic features. Karyotype was normal in all three foetuses (46, XX) and comparative genomic hybridization microarray analysis detected no pathogenic copy number variants.

Results: Whole-exome sequencing and genome-wide homozygosity mapping revealed a previously reported frameshift mutation in the OBSL1 gene (c.1273insA p.T425nfsX40), consistent with a diagnosis of 3-M Syndrome 2 (OMIM #612921), which had not been anticipated from the clinical findings.

Conclusions: Our study provides novel insight into the early clinical manifestations of this form of 3-M syndrome, and demonstrates the utility of whole exome sequencing as a tool for prenatal diagnosis in particular when there is a family history suggestive of a recurrent set of clinical symptoms.
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http://dx.doi.org/10.1186/1471-2164-16-S1-S12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315153PMC
January 2016

A classification system for clinical relevance of somatic variants identified in molecular profiling of cancer.

Genet Med 2016 Feb 16;18(2):128-36. Epub 2015 Apr 16.

Laboratory Medicine Program, Advanced Molecular Diagnostics Laboratory, Department of Pathology, University Health Network, Toronto, Ontario, Canada.

Purpose: Interpretation systems for clinical laboratory reporting of genetic variants for inherited conditions have been widely published. By contrast, there are no existing systems for interpretation and classification of somatic variants found from molecular testing of cancer.

Methods: We designed an assessment protocol and classification system for somatic variants identified through next-generation sequencing molecular profiling of tumor-derived samples and applied these to a pilot dataset of somatic variants found by next-generation sequencing profiling of 158 tumor samples derived from advanced cancer patients examined at the Princess Margaret Cancer Centre.

Results: We present a classification system to interpret the significance of genetic variants in molecular analysis of cancer, including the following key factors: (i) known or predicted pathogenicity of the variant; (ii) primary site and tumor histology in which the variant is found; (iii) recurrence of the variant; and (iv) evidence of clinical actionability. We used these factors to develop a five-category somatic variant classification for simplified reporting of variant interpretations to treating oncologists.

Conclusion: Our somatic variant classification can be of practical value to other clinical molecular laboratories performing cancer genetic profiling by promoting consistent reporting of somatic variants and permitting harmonization of variant data among laboratories and clinical studies.
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http://dx.doi.org/10.1038/gim.2015.47DOI Listing
February 2016

Paternal germline mosaicism for a GPC3 deletion in X-linked Simpson-Golabi-Behmel syndrome.

Am J Med Genet A 2014 Oct 29;164A(10):2682-4. Epub 2014 Jul 29.

Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.

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http://dx.doi.org/10.1002/ajmg.a.36682DOI Listing
October 2014

X-linked hearing loss: two gene mutation examples provide generalizable implications for clinical care.

Am J Audiol 2014 Jun;23(2):190-200

Purpose: To describe the inheritance patterns and auditory phenotype features of 3 Canadian families with mutations in 2 X-linked "deafness" genes (DFNX).

Method: Audiological, medical, and family histories were collected and family members interviewed to compare hearing thresholds and case histories between cases with mutations in SMPX versus POU3F4.

Results: The family pedigrees reveal characteristic X-linked inheritance patterns. Phenotypic features associated with the SMPX (DFNX4) mutation include early onset in males with rapid progression from mild and flat to sloping sensorineural loss, with highly variable onset and hearing loss severity in females. In contrast, phenotypic features associated with the POU3F4 (DFNX2) mutation are characterized by an early onset, mixed hearing loss with fluctuation in males, and a normal hearing phenotype reported for females.

Conclusions: The study shows how this unique inheritance pattern and both gender and mutation-specific phenotype variations can alert audiologists to the presence of X-linked genetic etiologies in their clinical practice. By incorporating this knowledge into clinical decision making, audiologists can facilitate the early identification of X-linked hearing loss and contribute to the effective team management of affected families.
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http://dx.doi.org/10.1044/2014_AJA-13-0040DOI Listing
June 2014

CDKN1C mutations and genital anomalies.

Am J Med Genet A 2012 Jan 2;158A(1):265. Epub 2011 Dec 2.

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http://dx.doi.org/10.1002/ajmg.a.34388DOI Listing
January 2012

Novel duplication in glypican-4 as an apparent cause of Simpson-Golabi-Behmel syndrome.

Am J Med Genet A 2010 Dec;152A(12):3179-81

Division of Medical Genetics, Children's Hospital & Research Center Oakland, Oakland, California 94609, USA.

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http://dx.doi.org/10.1002/ajmg.a.33450DOI Listing
December 2010
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