Clinical implementation of genetic testing in adults for hereditary hematologic malignancy syndromes.

PURPOSE: As research on hereditary hematologic malignancy syndromes (HHMS) are accumulating, cancer genetics clinics are identifying more adult hematology patients with an inherited component to their disease. However, investigations for HHMS are complex, and there is no formal consensus on genetic testing criteria. METHODS: We developed genetic testing criteria for adult hematology patients through a comprehensive literature review and our experience at the Princess Margaret Cancer Centre. We validated our criteria by applying them retrospectively to patients referred to our clinic for HHMS assessment. RESULTS: Our genetic testing criteria are comprehensive of myeloid malignancies, lymphoid malignancies, and bone marrow failure, including age at diagnosis, family history, and genetic test results in blood and bone marrow. Of the 104 patients who met the criteria, 26% had at least 1 actionable variant in any gene associated with an increased risk of cancer and 13% had an actionable variant resulting in an HHMS diagnosis. A total of 15 patients had incidental findings, including 11 patients with a pathogenic variant associated with carrier status for an autosomal recessive disorder and 4 patients with a mosaic result. CONCLUSION: Our high gene positivity rate shows the utility of a broad approach to germline testing in an adult hematology population.

Stay at home: implementation and impact of virtualising cancer genetic services during COVID-19.

The COVID-19 pandemic has led to the rapid adoption of virtual clinic processes and healthcare delivery. Herein, we examine the impact of virtualising genetics services at Canada's largest cancer centre. A retrospective review was conducted to evaluate relevant metrics during the 12 weeks prior to and during virtual care, including referral and clinic volumes, patient wait times and genetic testing uptake. The number of appointments and new patients seen were maintained during virtual care. Likewise, there was a significant increase in the number of patients offered testing during virtual care who did not provide a blood sample (176/180 (97.7%) vs 180/243 (74.1%); p<0.001), and a longer median time from the date of pretest genetic counselling to the date a sample was given (0 vs 11 days; p<0.001). Referral volumes significantly decreased during virtual care (35 vs 22; p<0.001), which was accompanied by a decreased median wait time for first appointment (55 days vs 30 days; p<0.001). The rapid virtualisation of cancer genetic services allowed the genetics clinic to navigate the COVID-19 pandemic without compromising clinical volumes or access to genetic testing. There was a decrease in referral volumes and uptake of genetic testing, which may be attributable to pandemic-related clinical restrictions.

The correlation between BRCA status and surgical cytoreduction in high-grade serous ovarian carcinoma.

OBJECTIVE: BRCA-associated ovarian cancers are biologically unique; it is unclear if this translates to favorable outcomes at the time of primary cytoreduction (PCS). The aim of this study was to compare the amount of residual disease after PCS in BRCA mutated (BRCAm) and wild-type (BRCAwt) high-grade serous ovarian cancers (HGSC), and to assess whether BRCA status was an independent predictor of complete cytoreduction. METHODS: We conducted a retrospective analysis of patients with stage III/IV HGSC with known germline and somatic BRCA status, treated with PCS from 2000 to 2017. We compared the complete, optimal and suboptimal cytoreduction rates between the BRCAm and BRCAwt cohorts and built a predictive model to assess whether BRCA status was predictive of complete cytoreduction. RESULTS: Of 303 treated with PCS, 120 were germline/somatic BRCAm (40%) and 183 were BRCAwt (60%). BRCAm women tended to be younger, but there were no differences between the two groups in preoperative CA-125, disease burden, surgical complexity, length of surgery, or perioperative complications. BRCAm group had a higher rate of complete cytoreduction to no residual disease (0 mm) [72% vs. 48%] (p < 0.001). In a multivariate model, after accounting for age, length of surgery, CA-125 level, stage, disease burden and surgical complexity, BRCAm status was predictive of 0 mm residual disease with odds ratio of 5.3 (95% CI 2.45-11.5; p < 0.001). CONCLUSIONS: BRCAm status is predictive of complete cytoreduction at the time of PCS. Despite similar disease burden and surgical efforts, one is more likely to achieve complete resection in BRCAm HGSC.

A Comparison of Patient-Reported Outcomes Following Consent for Genetic Testing Using an Oncologist- or Genetic Counselor-Mediated Model of Care.

This study compares knowledge, experience and understanding of genetic testing, and psychological outcomes among breast and ovarian cancer patients undergoing multi-gene panel testing via genetic counselor-mediated (GMT) or oncologist-mediated (OMT) testing models. A pragmatic, prospective survey of breast and ovarian cancer patients pursuing genetic testing between January 2017 and August 2019 was conducted at the Princess Margaret Cancer Centre in Toronto, Canada. A total of 120 (80 GMT; 40 OMT) individuals completed a survey administered one week following consent to genetic testing. Compared to OMT, the GMT cohort had higher median knowledge (8 vs. 9; p = 0.025) and experience/understanding scores (8.5 vs. 10; p < 0.001) at the time of genetic testing. Significant differences were noted in the potential psychological concerns experienced, with individuals in the GMT cohort more likely to screen positive in the hereditary predisposition domain of the Psychosocial Aspects of Hereditary Cancer tool (55% vs. 27.5%; p = 0.005), and individuals in the OMT cohort more likely to screen positive in the general emotions domain (65.0% vs. 38.8%; p = 0.007). The results of this study suggest that OMT can be implemented to streamline genetic testing; however, post-test genetic counseling should remain available to all individuals undergoing genetic testing, to ensure any psychologic concerns are addressed and that individuals have a clear understanding of relevant implications and limitations of their test results.

Setting a baseline: A 7-year review of referral rates and outcomes for serous ovarian cancer prior to implementation of oncologist mediated genetic testing.

OBJECTIVE: Despite guidelines recommending that all women with invasive serous ovarian cancer (SOC) are offered genetic testing, published referral and testing rates have been poor. Many centers have implemented novel genetic counseling service delivery models to increase testing rates. In light of increased awareness and implementation of small process changes at our center, this study aims to establish baseline referral rates and testing outcomes prior to diverging from the traditional model of care. METHODS: A list of women diagnosed with SOC at Princess Margaret Cancer Center (PM) between 2010 and 2016 was obtained from the PM Cancer Registry and cross-referenced against the genetics database to determine referral rates and outcomes of genetic testing. RESULTS: Of 724 women with SOC, 68% were referred for genetic counseling, with an overall testing rate of 61%. Higher referral rates were seen among women with younger ages at diagnosis and high-grade tumors. Of women tested, 22% were found to have a pathogenic variant in BRCA1/2 and 9% in another cancer gene. Notably, 24% of women with a pathogenic variant reported no family history of breast or ovarian cancer. CONCLUSION: Genetic counseling referral and testing rates for women with SOC are higher than previously reported, yet barriers to referral remain. To maximize genetic testing rates and address increasing patient volumes, clinics may be faced with integrating novel genetic counseling delivery models. Findings from this study may serve as a more accurate baseline to which large scale service delivery changes can be compared.

SCN8A mutation in a child presenting with seizures and developmental delays.

The SCN8A gene encodes the sodium voltage-gated channel alpha subunit 8. Mutations in this gene have been associated with early infantile epileptic encephalopathy type 13. With the use of whole-exome sequencing, a de novo missense mutation in SCN8A was identified in a 4-yr-old female who initially exhibited symptoms of epilepsy at the age of 5 mo that progressed to a severe condition with very little movement, including being unable to sit or walk on her own.

KBG syndrome involving a single-nucleotide duplication in ANKRD11.

KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.

The importance of size and disorder in the cryoprotective effects of dehydrins.

Dehydrins protect plant proteins and membranes from damage during drought and cold. Vitis riparia K2 is a 48-residue protein that can protect lactate dehydrogenase from freeze-thaw damage by preventing the aggregation and denaturation of the enzyme. To further elucidate its mechanism, we used a series of V. riparia K2 concatemers (K4, K6, K8, and K10) and natural dehydrins (V. riparia YSK2, 60 kilodalton peach dehydrin [PCA60], barley dehydrin5 [Dhn5], Thellungiella salsuginea dehydrin2 [TsDHN-2], and Opuntia streptacantha dehydrin1 [OpsDHN-1]) to test the effect of the number of K-segments and dehydrin size on their ability to protect lactate dehydrogenase from freeze-thaw damage. The results show that the larger the hydrodynamic radius of the dehydrin, the more effective the cryoprotection. A similar trend is observed with polyethylene glycol, which would suggest that the protection is simply a nonspecific volume exclusion effect that can be manifested by any protein. However, structured proteins of a similar range of sizes did not show the same pattern and level of cryoprotection. Our results suggest that with respect to enzyme protection, dehydrins function primarily as molecular shields and that their intrinsic disorder is required for them to be an effective cryoprotectant. Lastly, we show that the cryoprotection by a dehydrin is not due to any antifreeze protein-like activity, as has been reported previously.