Publications by authors named "Jordan Lerner-Ellis"

56 Publications

BCOR Internal Tandem Duplication Associated Uterine Sarcoma: Expanding the Clinicopathologic Spectrum.

Int J Gynecol Pathol 2021 Aug 30. Epub 2021 Aug 30.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto (S.A.T., J.L.-E., G.T.) The Centre for Applied Genomics, The Hospital for Sick Children (T.A.P.) Advanced Molecular Diagnostics, Mount Sinai Hospital (A.W., D.Y., E.A., J.M., J.L.-E.), Toronto Department of Pathology and Laboratory Medicine, London Health Sciences Centre and Western University (H.E., E.A.G.) Department of Obstetrics & Gynecology, London Health Sciences Centre (M.P.), London, ON, Canada.

The diagnosis of high-grade endometrial stromal sarcoma has become more refined following molecular characterization of these tumors. Recently BCOR internal tandem duplications (ITD) have been identified in a small number of high-grade endometrial stromal sarcoma. Here we present an additional case of this rare entity in a young woman in her late teens. She presented with menorrhagia and underwent resection of 2 uterine lesions. The tumor was a spindle cell neoplasm composed of long fascicles with low to moderate cellularity, mild to moderate cytologic atypia, and up to 2 mitotic figures per 10 high power fields. Necrosis was not identified. Immunohistochemical stains showed the tumor to be positive for cyclin D1 in >50% of tumor cells, focally positive for CD10, and negative for SMA, desmin, h-caldesmon, and ALK1. BCOR ITD was confirmed by polymerase chain reaction with subsequent Sanger sequencing. Clues to the diagnosis of BCOR ITD uterine sarcoma include young patient age, uniform nuclear features, and diffuse positivity for cyclin D1. These features should prompt further molecular interrogation for definitive diagnosis, which is important for prognostication.
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http://dx.doi.org/10.1097/PGP.0000000000000822DOI Listing
August 2021

Maximizing cancer prevention through genetic navigation for Lynch syndrome detection in women with newly diagnosed endometrial and nonserous/nonmucinous epithelial ovarian cancer.

Cancer 2021 Sep 13;127(17):3082-3091. Epub 2021 May 13.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre/University Health Network/Sinai Health Systems, Toronto, Ontario, Canada.

Background: Despite recommendations for reflex immunohistochemistry (IHC) for mismatch repair (MMR) proteins to identify Lynch syndrome (LS), the uptake of genetic assessment by those who meet referral criteria is low. The authors implemented a comprehensive genetic navigation program to increase the uptake of genetic testing for LS in patients with endometrial cancer (EC) or nonserous/nonmucinous ovarian cancer (OC).

Methods: Participants with newly diagnosed EC or OC were prospectively recruited from 3 cancer centers in Ontario, Canada. Family history questionnaires were used to assess LS-specific family history. Reflex IHC for MMR proteins was performed with the inclusion of clinical directives in pathology reports. A trained genetic navigator initiated a genetic referral on behalf of the treating physician and facilitated genetic referrals to the closest genetics center.

Results: A total of 841 participants (642 with EC, 172 with OC, and 27 with synchronous EC/OC) consented to the study; 194 (23%) were MMR-deficient by IHC. Overall, 170 women (20%) were eligible for a genetic assessment for LS: 35 on the basis of their family history alone, 24 on the basis of their family history and IHC, 82 on the basis of IHC alone, and 29 on the basis of clinical discretion. After adjustments for participants who died (n = 6), 149 of 164 patients (91%) completed a genetic assessment, and 111 were offered and completed genetic testing. Thirty-four women (4.0% of the total cohort and 30.6% of those with genetic testing) were diagnosed with LS: 5 with mutL homolog 1 (MLH1), 9 with mutS homolog 2 (MSH2), 15 with mutS homolog 6 (MSH6), and 5 with PMS2.

Conclusions: The introduction of a navigated genetic program resulted in a high rate of genetic assessment (>90%) in patients with gynecologic cancer at risk for LS.
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http://dx.doi.org/10.1002/cncr.33625DOI Listing
September 2021

Data sharing to improve concordance in variant interpretation across laboratories: results from the Canadian Open Genetics Repository.

J Med Genet 2021 Apr 19. Epub 2021 Apr 19.

Trillium Health Partners, Mississauga, Ontario, Canada.

Background: This study aimed to identify and resolve discordant variant interpretations across clinical molecular genetic laboratories through the Canadian Open Genetics Repository (COGR), an online collaborative effort for variant sharing and interpretation.

Methods: Laboratories uploaded variant data to the Franklin Genoox platform. Reports were issued to each laboratory, summarising variants where conflicting classifications with another laboratory were noted. Laboratories could then reassess variants to resolve discordances. Discordance was calculated using a five-tier model (pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B)), a three-tier model (LP/P are positive, VUS are inconclusive, LB/B are negative) and a two-tier model (LP/P are clinically actionable, VUS/LB/B are not). We compared the COGR classifications to automated classifications generated by Franklin.

Results: Twelve laboratories submitted classifications for 44 510 unique variants. 2419 variants (5.4%) were classified by two or more laboratories. From baseline to after reassessment, the number of discordant variants decreased from 833 (34.4% of variants reported by two or more laboratories) to 723 (29.9%) based on the five-tier model, 403 (16.7%) to 279 (11.5%) based on the three-tier model and 77 (3.2%) to 37 (1.5%) based on the two-tier model. Compared with the COGR classification, the automated Franklin classifications had 94.5% sensitivity and 96.6% specificity for identifying actionable (P or LP) variants.

Conclusions: The COGR provides a standardised mechanism for laboratories to identify discordant variant interpretations and reduce discordance in genetic test result delivery. Such quality assurance programmes are important as genetic testing is implemented more widely in clinical care.
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http://dx.doi.org/10.1136/jmedgenet-2021-107738DOI Listing
April 2021

Widening the lens of actionability: A qualitative study of primary care providers' views and experiences of managing secondary genomic findings.

Eur J Hum Genet 2021 Mar 29. Epub 2021 Mar 29.

University of Toronto, Toronto, Canada.

Most secondary genomic findings (SFs) fall in the scope of primary care practice. However, primary care providers' (PCPs) capacity to manage these findings is not well understood. We explored PCPs' views and experiences of managing SFs through a qualitative study. PCPs participated in semi-structured interviews about SFs from a patient in their practice or a hypothetical patient. The interpretive descriptive methodology was used to analyze transcripts thematically through constant comparison. Fifteen family physicians from Ontario, Canada participated (ten females; 6-40 years in practice across community and academic settings). PCPs made sense of SFs through the lens of actionability: they actively looked for clinical relevance by considering a wide range of immediate and future actions, including referrals, genetic testing, screening, lifestyle changes, counseling about family planning, informing family members, future medication choice, increased vigilance/surveillance, and managing results in the electronic medical record. PCPs saw clinical actionability as the main benefit mitigating the potential harms of learning SFs, namely patient anxiety and unnecessary investigations. PCPs conceptualized actionability more broadly than it is traditionally defined in medical genetics. Further research will be needed to determine if PCPs' emphasis on actionability conflicts with patients' expectations of SFs and if it leads to overutilization of healthcare resources.
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http://dx.doi.org/10.1038/s41431-021-00876-zDOI Listing
March 2021

The role of digital tools in the delivery of genomic medicine: enhancing patient-centered care.

Genet Med 2021 06 2;23(6):1086-1094. Epub 2021 Mar 2.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Purpose: Alternative models of genetic counseling are needed to meet the rising demand for genomic sequencing. Digital tools have been proposed as a method to augment traditional counseling and reduce burden on professionals; however, their role in delivery of genetic counseling is not established. This study explored the role of the Genomics ADvISER, a digital decision aid, in delivery of genomic counseling.

Methods: We performed secondary analysis of 52 pretest genetic counseling sessions that were conducted over the course of a randomized controlled trial evaluating the effectiveness of the Genomics ADvISER. As part of the trial, participants were randomized to receive standard counseling or use the tool and then speak with a counselor. A qualitative interpretive description approach using thematic analysis and constant comparison was used for analysis.

Results: In the delivery of genomic counseling, the Genomics ADvISER contributed to enhancing counseling by (1) promoting informed dialogue, (2) facilitating preference-sensitive deliberation, and (3) deepening personalization of decisions, all of which represent fundamental principles of patient-centered care: providing clear high-quality information, respecting patients' values, preferences, and expressed needs, and providing emotional support.

Conclusion: This study demonstrates that our digital tool contributed to enhancing patient-centered care in the delivery of genomic counseling.
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http://dx.doi.org/10.1038/s41436-021-01112-1DOI Listing
June 2021

Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study.

Gynecol Oncol 2021 04 19;161(1):221-227. Epub 2021 Jan 19.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network/Sinai Health Systems, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada; Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: Findings on impact of mismatch repair deficiency (MMRd) on patient outcomes in endometrial cancer (EC) have been inconsistent to date. The objective of this study was to compare the oncologic outcomes and recurrence patterns between MMRd and MMR-intact (MMRi) endometrioid EC (EEC).

Methods: Between 2015 and 2018, we prospectively recruited 492 EEC cases from three cancer centers in Ontario, Canada. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinicopathological, survival and recurrence patterns were compared between MMRd and MMRi cases.

Results: Of 492 EEC, 348 were MMRi (71%) and 144 were MMRd (29%) with median follow-up of 16.8 months (0-69.6). MMRd tumors tended to be grade 2 or 3 (56% vs. 29%, p < 0.001), with propensity for lymphovascular space invasion (28% vs. 18%, p = 0.024), lymph node involvement (7% vs. 5%, p < 0.001) and received more adjuvant treatment (46% vs. 33%, p = 0.027). This group also had significantly lower 3-year recurrence-free survival (78% vs. 90%, p = 0.014) although there was no difference in OS (p = 0.603). MMRd cases were more likely to recur in retroperitoneal lymph nodes (p = 0.045). Upon subgroup analysis, MLH1 methylated tumors had the worst prognostic features and survival outcomes.

Conclusions: MLH1 methylated EECs exhibit more aggressive features compared to other MMRd and MMRi EECs. This may indicate an inherent difference in tumor biology, suggesting the importance of individualized management based on EC molecular phenotype.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.002DOI Listing
April 2021

An Integrative DNA Sequencing and Methylation Panel to Assess Mismatch Repair Deficiency.

J Mol Diagn 2021 02 28;23(2):242-252. Epub 2020 Nov 28.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Electronic address:

Clinical testing for mismatch repair (MMR) deficiency often entails serial testing of tumor and constitutional DNA using multiple assays. To minimize cost and specimen requirements of MMR testing, we developed an integrated targeted sequencing protocol (termed MultiMMR) that tests for promoter methylation, mutations, copy number alterations, copy neutral loss of heterozygosity, and microsatellite instability from a single aliquot of DNA. Hybrid capture of DNA-sequencing libraries constructed with methylated adapters was performed on 142 samples (60 tumors and 82 constitutional samples) from 82 patients with MMR-associated colorectal, endometrial, and brain cancers as well as a synthetic DNA mix with 11 known mutations. The captured material was split to enable parallel bisulfite and conventional sequence analysis. The panel targeted microsatellite regions and 13 genes associated with MMR, hypermutation, and hereditary colorectal cancer. MultiMMR recapitulated clinical testing results in 23 of 24 cases, was able to explain MMR loss in an additional 29 of 48 patients with incomplete or inconclusive testing, and identified all 11 MMR variants within the synthetic DNA mix. Promoter methylation and microsatellite instability analysis found 95% and 97% concordance with clinical testing, respectively. We report the feasibility for amalgamation of the current stepwise and complex clinical testing workflow into an integrated test for hereditary and somatic causes of MMR deficiency.
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http://dx.doi.org/10.1016/j.jmoldx.2020.11.006DOI Listing
February 2021

Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements.

Cancers (Basel) 2020 Nov 21;12(11). Epub 2020 Nov 21.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, Canada.

Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in or , characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3-7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma.

Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%.

Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size ( ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks ( > 0.05).

Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.
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http://dx.doi.org/10.3390/cancers12113468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700467PMC
November 2020

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers.

Int J Gynecol Cancer 2020 12 20;30(12):1951-1958. Epub 2020 Oct 20.

Gynecologic Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada

Objectives: For synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.

Methods: 30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.

Results: Of 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.

Conclusions: There was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.
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http://dx.doi.org/10.1136/ijgc-2020-001927DOI Listing
December 2020

Rapid Genetic Testing for BRCA1 and BRCA2 Mutations at the Time of Breast Cancer Diagnosis: An Observational Study.

Ann Surg Oncol 2021 Apr 28;28(4):2219-2226. Epub 2020 Sep 28.

Women's College Research Institute, Toronto, Canada.

Background: This study aimed to evaluate the impact of rapid genetic testing (RGT) for BRCA1 and BRCA2 at the time of breast cancer diagnosis on treatment choices. Bilateral mastectomy for the treatment of breast cancer in women with a BRCA1 or BRCA2 mutation offers a reduction in the risk of contralateral breast cancer. It is unclear whether offering RGT at the time of breast cancer diagnosis has an impact on women's surgical decision-making.

Methods: Women with breast cancer diagnosed between June 2013 and May 2018 were recruited from four academic health sciences centers in Toronto, Canada. The participants completed a questionnaire before genetic testing, then one week and one year after disclosure of the genetic test result. Before surgery, RGT was performed. Diagnostic, pathologic, and treatment data were compared between those with and those without a BRCA mutation.

Results: The study enrolled 1007 women who consented to RGT. The mean age of the participants was 46.3 years, and the median time to result disclosure was 10 days. A BRCA mutation was found in 6% of the women. The women with a BRCA mutation were significantly more likely to elect for bilateral mastectomy than the women without a BRCA mutation (p < 0.0001). Of the BRCA-positive patients, 95.7% reported that they used their genetic test result to make a surgical decision.

Conclusions: The women provided with RGT at the time of breast cancer diagnosis use the genetic information to make treatment decisions, and the majority of those identified with a BRCA mutation elect for a bilateral mastectomy.
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http://dx.doi.org/10.1245/s10434-020-09160-8DOI Listing
April 2021

Correction to: Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.

J Cancer Res Clin Oncol 2021 Aug;147(8):2487

Department of Laboratory Medicine and Pathobiology, University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.

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http://dx.doi.org/10.1007/s00432-020-03399-0DOI Listing
August 2021

Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically significant secondary findings.

Hum Genet 2021 Mar 6;140(3):493-504. Epub 2020 Sep 6.

St. Michael's Hospital, Toronto, ON, Canada.

Genomic sequencing advances have increased the potential to identify secondary findings (SFs). Current guidelines recommend the analysis of 59 medically actionable genes; however, patient preferences indicate interest in learning a broader group of SFs. We aimed to develop an analytical pipeline for the efficient analysis and return of all clinically significant SFs. We developed a pipeline consisting of comprehensive gene lists for five categories of SFs and filtration parameters for prioritization of variants in each category. We applied the pipeline to 42 exomes to assess feasibility and efficiency. Comprehensive lists of clinically significant SF genes were curated for each category: (1) 90 medically actionable genes and 28 pharmacogenomic variants; (2) 17 common disease risk variants; (3) 3166 Mendelian disease genes, (4) 7 early onset neurodegenerative disorder genes; (5) 688 carrier status results. Analysis of 42 exomes using our pipeline resulted in a significant decrease (> 98%) in variants compared to the raw analysis (13,036.56 ± 59.72 raw variants/exome vs 161.32 ± 7.68 filtered variants/exome), and aided in time and costs savings for the overall analysis process. Our pipeline represents a critical step in overcoming the analytic challenge associated with returning all clinically relevant SFs to allow for its routine implementation in clinical practice.
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http://dx.doi.org/10.1007/s00439-020-02220-9DOI Listing
March 2021

Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.

J Cancer Res Clin Oncol 2021 Mar 3;147(3):871-879. Epub 2020 Sep 3.

Department of Laboratory Medicine and Pathobiology, University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.

Purpose: The aim of this study was to determine the diagnostic yield of multigene panel testing among patients referred with hereditary breast and ovarian cancer (HBOC).

Methods: Patients who met provincial eligibility criteria were tested at the Advanced Molecular Diagnostic Laboratory at Mount Sinai Hospital, Toronto. Gene sequencing and exon-level copy number variant (CNV) analysis was performed. The referring physician had the opportunity to choose between several different gene panels based on patient phenotype. Cases were included in the analysis based on personal and family history of cancer and the type of panel ordered.

Results: 3251 cases that received panel testing were included in this analysis. Overall, 9.1% (295) had a positive (pathogenic or likely pathogenic) result and 27.1% (882) had an inconclusive result (variant of uncertain significance). The genes with the highest prevalence of positive results were in BRCA2 (2.2%, 71/3235), BRCA1 (1.9%, 62/3235), and CHEK2 (1.4%, 40/2916). Of the positive cases, 9.8% (29) had a pathogenic or likely pathogenic variant in a gene associated with Lynch syndrome (MSH6, MSH2, MLH1, or PMS2).

Conclusions: Our overall positive yield is similar to that reported in the literature. The yield of inconclusive results was three times that of positive results. By testing more individuals in families with HBOC and through data-sharing efforts, the clinical significance of most variants may eventually be determined and panel testing for monogenic cancer predisposition syndromes will have greater utility.
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http://dx.doi.org/10.1007/s00432-020-03377-6DOI Listing
March 2021

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer.

Cancer 2020 11 18;126(22):4886-4894. Epub 2020 Aug 18.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Sinai Health Systems, Toronto, Ontario, Canada.

Background: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.

Methods: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.

Results: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.

Conclusions: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.
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http://dx.doi.org/10.1002/cncr.33144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693219PMC
November 2020

Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study.

J Med Genet 2021 04 24;58(4):275-283. Epub 2020 Jun 24.

Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Exome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology.

Methods: Patients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing.

Results: Overall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results.

Conclusions: This study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.
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http://dx.doi.org/10.1136/jmedgenet-2020-106936DOI Listing
April 2021

Quality of life drives patients' preferences for secondary findings from genomic sequencing.

Eur J Hum Genet 2020 09 18;28(9):1178-1186. Epub 2020 May 18.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

There is growing impetus to include measures of personal utility, the nonmedical value of information, in addition to clinical utility in health technology assessment (HTA) of genomic tests such as genomic sequencing (GS). However, personal utility and clinical utility are challenging to define and measure. This study aimed to explore what drives patients' preferences for hypothetically learning medically actionable and non-medically actionable secondary findings (SF), capturing clinical and personal utility; this may inform development of measures to evaluate patient outcomes following return of SF. Semi-structured interviews were conducted with adults with a personal or family cancer history participating in a trial of a decision aid for selection of SF from genomic sequencing (GS) ( www.GenomicsADvISER.com ). Interviews were analyzed thematically using constant comparison. Preserving health-related and non-health-related quality of life was an overarching motivator for both learning and not learning SF. Some participants perceived that learning SF would help them "have a good quality of life" through informing actions to maintain physical health or leading to psychological benefits such as emotional preparation for disease. Other participants preferred not to learn SF because results "could ruin your quality of life," such as by causing negative psychological impacts. Measuring health-related and non-health-related quality of life may capture outcomes related to clinical and personal utility of GS and SF, which have previously been challenging to measure. Without appropriate measures, generating and synthesizing evidence to evaluate genomic technologies such as GS will continue to be a challenge, and will undervalue potential benefits of GS and SF.
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http://dx.doi.org/10.1038/s41431-020-0640-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609335PMC
September 2020

Effectiveness of the Genomics ADvISER decision aid for the selection of secondary findings from genomic sequencing: a randomized clinical trial.

Genet Med 2020 04 11;22(4):727-735. Epub 2019 Dec 11.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Purpose: To evaluate the effectiveness of the Genomics ADvISER (www.genomicsadviser.com) decision aid (DA) for selection of secondary findings (SF), compared with genetic counseling alone.

Methods: A randomized controlled trial (RCT) was conducted to evaluate whether the Genomics ADvISER is superior to genetic counseling when hypothetically selecting SF. Participants were randomized to use the DA followed by discussion with a genetic counselor, or to genetic counseling alone. Surveys were administered at baseline and post-intervention. Primary outcome was decisional conflict. Secondary outcomes were knowledge, preparation for, and satisfaction with decision-making, anxiety, and length of counseling session.

Results: Participants (n = 133) were predominantly White/European (74%), female (90%), and ≥50 years old (60%). Decisional conflict (mean difference 0.05; P = 0.60), preparation for decision-making (0.17; P = 0.95), satisfaction with decision (-2.18; P = 0.06), anxiety (0.72; P = 0.56), and knowledge of sequencing limitations (0.14; P = 0.70) did not significantly differ between groups. However, intervention participants had significantly higher knowledge of SF (0.39; P < 0.001) and sequencing benefits (0.97; P = 0.01), and significantly shorter counseling time (24.40 minutes less; P < 0.001) CONCLUSIONS: The Genomics ADvISER did not decrease decisional conflict but reduced counseling time and improved knowledge. This decision aid could serve as an educational tool, reducing in-clinic time and potentially health care costs.
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http://dx.doi.org/10.1038/s41436-019-0702-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425118PMC
April 2020

Retesting of women who are negative for a and mutation using a 20-gene panel.

J Med Genet 2020 06 29;57(6):380-384. Epub 2019 Nov 29.

Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada.

Background: The value of retesting women who previously tested negative for a pathogenic variant (mutation) in and using an expanded panel of breast and ovarian cancer genes is unclear.

Methods: We studied 110 -negative women who were retested using a panel of 20 breast and/or ovarian cancer susceptibility genes at the Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto between March 2017 and March 2019. All patients had previously tested negative for pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician.

Results: Overall, six pathogenic variants in genes other than and were found (prevalence 5.5%). There were two pathogenic variants found in , and one found in each of , , and . The prevalence of pathogenic variants was 6.5% for women affected with cancer (6 of 93), including 4.9% for women with breast cancer (4 of 82) and 22.2% for women with ovarian cancer (2 of 9). None of the 17 unaffected women had a clinically significant or pathogenic variant. There were 44 women (40%) for whom the result of the panel test was inconclusive due to the detection of a variant of uncertain significance.

Conclusions: Our findings indicate that the retesting of /-negative individuals with an expanded panel of 20 breast and ovarian cancer genes can produce clinically relevant results, with a yield of 5.5% for pathogenic variants in genes other than and .
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http://dx.doi.org/10.1136/jmedgenet-2019-106403DOI Listing
June 2020

Health outcomes, utility and costs of returning incidental results from genomic sequencing in a Canadian cancer population: protocol for a mixed-methods randomised controlled trial.

BMJ Open 2019 10 7;9(10):e031092. Epub 2019 Oct 7.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

Introduction: Genomic sequencing has rapidly transitioned into clinical practice, improving diagnosis and treatment options for patients with hereditary disorders. However, large-scale implementation of genomic sequencing faces challenges, especially with regard to the return of incidental results, which refer to genetic variants uncovered during testing that are unrelated to the primary disease under investigation, but of potential clinical significance. High-quality evidence evaluating health outcomes and costs of receiving incidental results is critical for the adoption of genomic sequencing into clinical care and to understand the unintended consequences of adoption of genomic sequencing. We aim to evaluate the health outcomes and costs of receiving incidental results for patients undergoing genomic sequencing.

Methods And Analysis: We will compare health outcomes and costs of receiving, versus not receiving, incidental results for adult patients with cancer undergoing genomic sequencing in a mixed-methods randomised controlled trial. Two hundred and sixty patients who have previously undergone first or second-tier genetic testing for cancer and received uninformative results will be recruited from familial cancer clinics in Toronto, Ontario. Participants in both arms will receive cancer-related results. Participants in the intervention arm have the option to receive incidental results. Our primary outcome is psychological distress at 2 weeks following return of results. Secondary outcomes include behavioural consequences, clinical and personal utility assessed over the 12 months after results are returned and health service use and costs at 12 months and 5 years. A subset of participants and providers will complete qualitative interviews about utility of incidental results.

Ethics And Dissemination: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System that provides ethical review and oversight for multiple sites participating in the same clinical trial in Ontario.Results from the trial will be shared through stakeholder workshops, national and international conferences, and peer-reviewed journals.

Trial Registration Number: NCT03597165.
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http://dx.doi.org/10.1136/bmjopen-2019-031092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797333PMC
October 2019

p53, Mismatch Repair Protein, and POLE Abnormalities in Ovarian Clear Cell Carcinoma: An Outcome-based Clinicopathologic Analysis.

Am J Surg Pathol 2019 12;43(12):1591-1599

Departments of Laboratory Medicine and Molecular Diagnostics.

The PROMISE diagnostic algorithm, which uses p53, mismatch repair (MMR) protein immunohistochemistry, and DNA polymerase ε (POLE) exonuclease domain mutation testing, is a reliable surrogate of the molecular group in endometrial carcinoma. Its prognostic value has been validated in endometrial carcinoma and ovarian endometrioid carcinoma. Moreover, a similar prognostic grouping has been recently documented in endometrial clear cell carcinoma. Thus, we aimed to explore the role of these markers in ovarian clear cell carcinoma, another endometriosis-associated malignancy. A total of 90 cases were identified and confirmed after secondary review. Immunohistochemistry for p53, MLH1, MSH2, MSH6, and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. POLE mutational analysis was performed in 47 cases. Results were correlated with clinicopathologic variables including disease-free survival (DFS), overall survival, and disease-specific survival (DSS). Endometriosis was found in 67 (74%) cases. Six (7%) tumors were p53 abnormal, 82 (91%) were p53 normal, and 2 (2%) tumors had MMR deficiency (1 MSH6 loss and 1 MSH2/6 loss; both were p53 normal). Several POLE variants of unknown significance were detected, but no pathogenic mutations. The mean follow-up period was 43 months (median: 34, range: 1 to 189). Abnormal p53 status was associated with advanced Federation of Gynecology and Obstetrics stage, lymph node metastases, DFS and DSS (P<0.05, Fisher exact test). In univariate analysis, abnormal p53 and positive lymph node status had worse DFS, whereas bilaterality, surface involvement, and advanced stage were associated with worse DFS, overall survival and DSS (P<0.05, Cox regression). On multivariate analysis, only stage retained statistical association with survival. Using a molecular-based approach designed for endometrial carcinoma, most ovarian clear cell carcinomas fall into the copy-number-low molecular subgroup. However, a small but important subset has an abnormal p53 expression (copy-number-high group). This subset is associated with adverse features including extrapelvic disease, nodal metastases, and recurrence similar to endometrial and ovarian endometrioid cancer. Thus, testing for this marker has potential prognostic significance. The role of other markers in the PROMISE algorithm remains to be elucidated, as we found a low frequency of MMR abnormalities and no pathogenic POLE mutations in our series.
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http://dx.doi.org/10.1097/PAS.0000000000001328DOI Listing
December 2019

Phenotypic variability in deficiency of the α subunit of succinate-CoA ligase.

JIMD Rep 2019 Mar 14;46(1):63-69. Epub 2019 Mar 14.

Division of Genetics and Genomics, Manton Center for Orphan Disease Research Boston Children's Hospital, Harvard Medical School Boston Massachusetts.

Succinyl-CoA synthetase or succinate-CoA ligase deficiency can result from biallelic mutations in gene that encodes for the alpha subunit of the succinyl-CoA synthetase. Mutations in this gene were initially associated with fatal infantile lactic acidosis. We describe an individual with a novel biallelic pathogenic mutation in with a less severe phenotype dominated by behavioral problems. The mutation was identified to be c.512A>G corresponding to a p.Asn171Ser change in the protein. The liquid chromatography tandem mass spectrometry-based enzyme activity assay on cultured fibroblasts revealed a markedly reduced activity of succinyl-CoA synthetase enzyme when both ATP and GTP were substrates, affecting both ADP-forming and GDP-forming functions of the enzyme.
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http://dx.doi.org/10.1002/jmd2.12018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498818PMC
March 2019

Correction: Variant classification changes over time in BRCA1 and BRCA2.

Genet Med 2019 Oct;21(10):2406-2407

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

In the original version of this Article, the affiliation details for Drs. Jordan Lerner-Ellis and George Charames did not include the Department of Pathology and Laboratory Medicine at the University of Toronto. In addition, Drs. Jordan Lerner-Ellis and George Charames were incorrectly affiliated with the Institute of Health Policy, Management and Evaluation at the University of Toronto. These errors have now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-019-0526-xDOI Listing
October 2019

Variant classification changes over time in BRCA1 and BRCA2.

Genet Med 2019 10 11;21(10):2248-2254. Epub 2019 Apr 11.

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

Purpose: To report BRCA1 and BRCA2 (BRCA1/2) variant reassessments and reclassifications between 2012 and 2017 at the Advanced Molecular Diagnostics Laboratory (AMDL) in Toronto, Canada, which provides BRCA1/2 testing for patients in Ontario, and to compare AMDL variant classifications with submissions in ClinVar.

Methods: Variants were assessed using a standardized variant assessment tool based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology's guidelines and tracked in an in-house database. Variants were shared through the Canadian Open Genetics Repository and submitted to ClinVar for comparison against other laboratories.

Results: AMDL identified 1209 BRCA1/2 variants between 2012 and 2017. During this period, 32.9% (398/1209) of variants were reassessed and 12.4% (150/1209) were reclassified. The majority of reclassified variants were downgraded (112/150, 74.7%). Of the reclassified variants, 63.3% (95/150) were reclassified to benign, 20.7% (31/150) to likely benign, 10.0% (15/150) to variant of uncertain significance, 2.0% (3/150) to likely pathogenic, and 4.0% (6/150) to pathogenic. Discordant ClinVar submissions were found for 40.4% (488/1209) of variants.

Conclusion: BRCA1/2 variants may be reclassified over time. Reclassification presents ethical and practical challenges related to recontacting patients. Data sharing is essential to improve variant interpretation, to help patients receive appropriate care based on their genetic results.
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http://dx.doi.org/10.1038/s41436-019-0493-2DOI Listing
October 2019

Development of patient "profiles" to tailor counseling for incidental genomic sequencing results.

Eur J Hum Genet 2019 07 8;27(7):1008-1017. Epub 2019 Mar 8.

University of Toronto, Toronto, ON, Canada.

Guidelines recommend that providers engage patients in shared decision-making about receiving incidental results (IR) prior to genomic sequencing (GS), but this can be time-consuming, given the myriad of IR and variation in patients' preferences. We aimed to develop patient profiles to inform pre-test counseling for IR. We conducted semi-structured interviews with participants as a part of a randomized trial of the GenomicsADvISER.com, a decision aid for selecting IR. Interviews explored factors participants considered when deliberating over learning IR. Interviews were analyzed by thematic analysis and constant comparison. Participants were mostly female (28/31) and about half of them were over the age of 50 (16/31). We identified five patient profiles that reflect common contextual factors, attitudes, concerns, and perceived utility of IR. Information Enthusiasts self-identified as "planners" and valued learning most or all IR to enable planning and disease prevention because "knowledge is power". Concerned Individuals defined themselves as "anxious," and were reluctant to learn IR, anticipating negative psychological impacts from IR. Contemplators were discerning about the value and limitations of IR, weighing health benefits with the impacts of not being able to "un-know" information. Individuals of Advanced Life Stage did not consider IR relevant for themselves and primarily considered their implications for family members. Reassurance Seekers were reassured by previous negative genetic test results which shaped their expectations for receiving no IR: "hopefully [GS will] be negative, too. And then I can rest easy". These profiles could inform targeted counseling for IR by providing a framework to address common values, concerns. and misconceptions.
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http://dx.doi.org/10.1038/s41431-019-0352-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777527PMC
July 2019

Oestrogen receptor status and survival in women with BRCA2-associated breast cancer.

Br J Cancer 2019 02 6;120(4):398-403. Epub 2019 Feb 6.

Women's College Research Institute, Toronto, ON, Canada.

Background: To evaluate the predictors of mortality, including ER status, in women with a BRCA2 mutation and breast cancer.

Methods: Eligible participants were identified from within two longitudinal cohorts. These patients were selected because they were diagnosed with breast cancer between 1975 and 2015 and carried a BRCA2 mutation. Data were abstracted from the medical record and pathology report. We analysed the effects of ER status and other variables on breast cancer specific survival using a Cox proportional hazards model.

Results: Three hundred ninety women with breast cancer and a BRCA2 mutation were included in the analysis. The mean follow-up time was 12.3 years (range 1-39 years) and 89 subjects died (22.8%). In the multivariate analysis, women with ER-positive tumours were more likely to die than women with ER-negative tumours (HR 2.08, 95% CI 0.99-4.36, p = 0.05), and this was of borderline significance. For the 233 women with ER-positive tumours the 20-year survival rate was 62.2%, compared to 83.7% for 58 women with ER-negative tumours (p = 0.03).

Conclusions: The majority of women with a BRCA2 mutation present with ER-positive breast cancer, and for these women, prognosis may be worse than for BRCA2 carriers with ER-negative breast cancer.
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http://dx.doi.org/10.1038/s41416-019-0376-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462020PMC
February 2019

Reply to 'Mutations in RECQL are not associated with breast cancer risk in an Australian population'.

Nat Genet 2018 10;50(10):1348-1349

Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1038/s41588-018-0233-6DOI Listing
October 2018

Real-world health services utilisation and outcomes after and testing in Ontario, Canada: the What Comes Next Cohort Study protocol.

BMJ Open 2018 09 4;8(9):e025317. Epub 2018 Sep 4.

Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Introduction: Women who have pathogenic mutations in the and genes are at greatly increased risks for breast and ovarian cancers. Although risk-reduction strategies can be undertaken by these women, knowledge regarding the uptake of these strategies is limited. Additionally, the healthcare behaviours of women who receive inconclusive test results are not known. This study protocol describes the creation of a retrospective cohort of women who have undergone genetic testing for and , linking genetic test results with administrative data to quantify the uptake of risk-reduction strategies and to assess long-term cancer and non-cancer outcomes after genetic testing.

Methods And Analysis: Approximately two-thirds of and testing in Ontario, Canada is performed at North York General Hospital (NYGH) and Mount Sinai Hospital (MSH), Toronto. We will use registries at these sites to assemble a cohort of approximately 17 000 adult women who underwent and testing from January 2007 to April 2016. Trained chart abstractors will obtain detailed information for all women tested over this period, including demographics, personal and family cancer histories and genetic test results. We will link these data to provincial administrative databases, enabling assessment of healthcare utilisation and long-term outcomes after testing. Study outcomes will include the uptake of breast cancer screening and prophylactic breast and ovarian surgery, cancer incidence and mortality and incidence of non-cancer health outcomes, including cardiovascular, osteoporotic and neurodegenerative disease.

Ethics And Dissemination: This study has been approved by the Research Ethics Boards at NYGH (no 16-0035), MSH (no 13-0124) and Sunnybrook Health Sciences Centre (no 275-2016). We plan to disseminate research findings through peer-reviewed publications and presentations at national and international meetings.
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http://dx.doi.org/10.1136/bmjopen-2018-025317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129086PMC
September 2018

The Genomics ADvISER: development and usability testing of a decision aid for the selection of incidental sequencing results.

Eur J Hum Genet 2018 07 27;26(7):984-995. Epub 2018 Apr 27.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Guidelines recommend patients be informed of their incidental results (IR) when undergoing genomic sequencing (GS), yet there are limited tools to support patients' decisions about learning IR. The aim of this study is to develop and test the usability of a decision aid (DA) to guide patients' selection of IR, and to describe patients' preferences for learning IR following use of the DA. We developed and evaluated a DA using an iterative, mixed-methods process consisting of (1) prototype development, (2) feasibility testing, (3) cognitive interviews, (4) design and programming, and (5) usability testing. We created an interactive online DA called the Genomics ADvISER, a genomics decision AiD about Incidental SEquencing Results. The Genomics ADvISER begins with an educational whiteboard video, and then engages users in a values clarification exercise, knowledge quiz and final choice step, based on a 'binning' framework. Participants found the DA acceptable and intuitive to use. They were enthusiastic towards GS and IR; all selected multiple categories of IR. The Genomics ADvISER is a new patient-centered tool to support the clinical delivery of incidental GS results. The Genomics ADvISER fills critical care gaps, given the health care system's limited genomics expertise and capacity to convey the large volume of IR and their myriad of implications.
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http://dx.doi.org/10.1038/s41431-018-0144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018661PMC
July 2018

Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial.

BMJ Open 2018 04 26;8(4):e021876. Epub 2018 Apr 26.

University of Toronto, Toronto, Ontario, Canada.

Introduction: Genome sequencing, a novel genetic diagnostic technology that analyses the billions of base pairs of DNA, promises to optimise healthcare through personalised diagnosis and treatment. However, implementation of genome sequencing faces challenges including the lack of consensus on disclosure of incidental results, gene changes unrelated to the disease under investigation, but of potential clinical significance to the patient and their provider. Current recommendations encourage clinicians to return medically actionable incidental results and stress the importance of education and informed consent. Given the shortage of genetics professionals and genomics expertise among healthcare providers, decision aids (DAs) can help fill a critical gap in the clinical delivery of genome sequencing. We aim to assess the effectiveness of an interactive DA developed for selection of incidental results.

Methods And Analysis: We will compare the DA in combination with a brief Q&A session with a genetic counsellor to genetic counselling alone in a mixed-methods randomised controlled trial. Patients who received negative standard cancer genetic results for their personal and family history of cancer and are thus eligible for sequencing will be recruited from cancer genetics clinics in Toronto. Our primary outcome is decisional conflict. Secondary outcomes are knowledge, satisfaction, preparation for decision-making, anxiety and length of session with the genetic counsellor. A subset of participants will complete a qualitative interview about preferences for incidental results.

Ethics And Dissemination: This study has been approved by research ethics boards of St. Michael's Hospital, Mount Sinai Hospital and Sunnybrook Health Sciences Centre. This research poses no significant risk to participants. This study evaluates the effectiveness of a novel patient-centred tool to support clinical delivery of incidental results. Results will be shared through national and international conferences, and at a stakeholder workshop to develop a consensus statement to optimise implementation of the DA in practice.

Trial Registration Number: NCT03244202; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-021876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922516PMC
April 2018

Characteristics of Adrenal Masses in Familial Adenomatous Polyposis.

Dis Colon Rectum 2018 Jun;61(6):679-685

Department of Surgery, University of Toronto, Toronto, Canada.

Background: Adrenal masses are a known extraintestinal manifestation of familial adenomatous polyposis. However, the literature on this association is largely confined to case reports.

Objective: This study aimed to determine the characteristics of adrenal masses in familial adenomatous polyposis and their clinical significance, as well as to estimate their prevalence. Mutational analysis was conducted to determine if any potential genotype-phenotype correlations exist.

Design: This is a retrospective cohort study.

Setting: Analysis included all patients meeting the criteria of classic familial adenomatous polyposis who were registered with the Familial Gastrointestinal Cancer Registry, a national Canadian database.

Patients: Appropriate imaging or autopsy reports were available in 311 registry patients. Patients with adrenal metastases were excluded.

Outcome Measures: Data collection included demographic data, mutation genotype, adrenal mass characteristics, surgical interventions and mortality.

Results: The prevalence of adrenal masses was 16% (n = 48/311). The median age at diagnosis of adrenal mass was 45 years. The median diameter of adrenal mass at diagnosis was 1.7 cm (interquartile range, 1.4-3.0) with a median maximal diameter of 2.5 cm (interquartile range, 1.7-4.1) with median imaging follow-up of 48 months. The majority of adrenal masses were benign (97%, n = 61/63). Surgery was performed on 7 patients because of concerns for size, malignancy, or hormonal secretion. One adrenal-related death was due to an adrenocortical carcinoma. Mutation analysis did not identify any specific genotype-phenotype correlations.

Limitations: There were incomplete or insufficient endocrinology data available in the registry to allow for the analysis of hormone secretion patterns.

Conclusions: Adrenal masses are approximately twice as prevalent in the familial adenomatous polyposis population as in previous studies of the general population. Nearly all mutations led to truncation of the APC gene; however, there was no genetic signature to help predict those at increased risk. The majority of adrenal lesions identified were of benign etiology; thus, an intensive management or surveillance strategy with imaging screening is likely unwarranted. See Video Abstract at http://links.lww.com/DCR/A507.
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http://dx.doi.org/10.1097/DCR.0000000000001008DOI Listing
June 2018
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