Large-scale group genetic counseling: Evaluation of a novel service delivery model in a Canadian hereditary cancer clinic.

Increasing demand for genetic services has led to the development of streamlined genetic counseling (GC) models. We piloted large-scale group pre-test GC with up to 50 patients per group and compared this to a traditional one-on-one approach. Patients referred to the British Columbia (BC) Cancer Hereditary Cancer Program were eligible if they had: (a) family history meeting our program's referral criteria; (b) no relevant personal history of cancer; (c) no prior genetic testing in the family; and (d) no living testable relative in BC. Patient-reported outcome measures included: (a) Genetic Counselling Outcome Scale (GCOS) prior to pre-test GC (T1) and at 4 weeks post-test GC (T2); (b) Satisfaction Survey after pre-test GC; and (c) the Multidimensional Impact of Cancer Risk Assessment (MICRA) for patients undergoing testing (4 weeks after post-test GC). In total, 391 patients underwent GC, 184 by group and 207 by one-on-one appointments. Between May 2018 and May 2019, 6 pre-test group sessions were conducted (median number of patients per group = 28; range 15-48). 8% of patients (n = 32) declined large group GC due to personal preference for one-on-one GC. There were no statistically significant differences in MICRA and GCOS survey results when comparing the pre-test large group versus traditional pre-test one-on-one models (based on 3 MICRA subscales: p = 0.063, p = 0.612, p = 0.842; and GCOS p = 0.169). Overall, the large group pre-test counseling approach was more time-efficient with 15-48 patient group sessions conducted over a mean duration of 80 min as compared to 42 min per patient with the traditional one-on-one GC model. Large-scale group GC was feasible and acceptable to patients and represents a novel streamlined model for GC to enable timely access to cancer genetic services.

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

Oncology Clinic-Based Hereditary Cancer Genetic Testing in a Population-Based Health Care System.

New streamlined models for genetic counseling and genetic testing have recently been developed in response to increasing demand for cancer genetic services. To improve access and decrease wait times, we implemented an oncology clinic-based genetic testing model for breast and ovarian cancer patients in a publicly funded population-based health care setting in British Columbia, Canada. This observational study evaluated the oncology clinic-based model as compared to a traditional one-on-one approach with a genetic counsellor using a multi-gene panel testing approach. The primary objectives were to evaluate wait times and patient reported outcome measures between the oncology clinic-based and traditional genetic counselling models. Secondary objectives were to describe oncologist and genetic counsellor acceptability and experience. Wait times from referral to return of genetic testing results were assessed for 400 patients with breast and/or ovarian cancer undergoing genetic testing for hereditary breast and ovarian cancer from June 2015 to August 2017. Patient wait times from referral to return of results were significantly shorter with the oncology clinic-based model as compared to the traditional model (403 vs. 191 days; p < 0.001). A subset of 148 patients (traditional n = 99; oncology clinic-based n = 49) completed study surveys to assess uncertainty, distress, and patient experience. Responses were similar between both models. Healthcare providers survey responses indicated they believed the oncology clinic-based model was acceptable and a positive experience. Oncology clinic-based genetic testing using a multi-gene panel approach and post-test counselling with a genetic counsellor significantly reduced wait times and is acceptable for patients and health care providers.

Severe Late Toxicity After Adjuvant Breast Radiotherapy in a Patient with a Germline Ataxia Telangiectasia Mutated Gene: Future Treatment Decisions.

Ataxia telangiectasia mutated (ATM) gene mutations may confer increased sensitivity to ionizing radiation and increased risk of late toxicity for cancer patients. We present the case of a 55-year-old female treated with adjuvant breast and regional nodal radiation following lumpectomy and axillary lymph node dissection for stage II invasive ductal carcinoma of the breast. She developed severe telangiectasia, fibrosis, induration, chest wall pain (with evidence of rib fractures on imaging), and painful limitation in her range of motion at the shoulder. She was subsequently found to have a likely pathogenic germline ATM gene mutation. At relapse, she elected to pursue systemic therapy alone for intracranial metastases.

Breast Cancer and Mammography Screening: Knowledge, Beliefs and Predictors for Asian Immigrant Women Attending a Specialized Clinic in British Columbia, Canada.

Screening mammography (MMG) reduces breast cancer mortality; however, Asian immigrant women underutilize MMG. The Asian Women's Health Clinic (AWHC) was established to promote women's cancer screening amongst this population. This study evaluated the rate, and predictors, of MMG amongst women attending the AWHC. Women (N = 98) attending the AWHC completed a questionnaire. Descriptive statistics and multivariable logistic regression evaluated rate and predictors of MMG. Most participants (87 %, n = 85) reported having had a mammogram. Significant MMG predictors were: lower perceived MMG barriers [lifetime: OR (CI) 1.19 (1.01-1.49); past 2 years: OR (CI) 1.11 (1.01-1.25)], and knowing someone with breast cancer [past year: OR (CI) 3.42 (1.25-9.85); past 2 years: OR (CI) 4.91 (1.32-2.13)]. Even amongst women using preventive medicine, 13 % report never having had a mammogram. More research is needed into innovative interventions, e.g. the AWHC, and breast cancer-related outcomes amongst Asian immigrant women.

Evidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women.

INTRODUCTION: Combination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period. METHODS: This prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR. RESULTS: Over a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001). CONCLUSIONS: In the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy.

Obstetrical and neonatal outcomes among women infected with hepatitis C and their infants.

OBJECTIVES: (1) To describe obstetrical and neonatal outcomes among a cohort of hepatitis C virus (HCV) infected women, comparing HCV RNA positive to HCV RNA negative women; (2) to characterize virologic and hepatic parameters associated with HCV infection during pregnancy; and (3) to describe the rate of HCV vertical transmission. METHODS: We prospectively enrolled 145 HCV-positive pregnant women across British Columbia between 2000 and 2003. Participating women were monitored during pregnancy and their infants were followed to assess them for HCV infection. Maternal HCV RNA was assessed close to delivery. RESULTS: Seventy percent of women reported injection drug use as their primary risk factor for HCV acquisition. Observed rates of intrauterine fetal death, preterm delivery, small for gestational age, and low birth weight infants were 3.4%, 17.9%, 11.3%, and 12.5%, respectively, without a significant association with maternal HCV RNA status. The rate of cholestasis was 5.6% in the HCV RNA-positive group (6/108) and 2.8% in the HCV RNA-negative group (1/37) (P = 0.496). Serum alanine aminotransferase levels decreased significantly through pregnancy, and were significantly higher in HCV RNA-positive women than in HCV RNA-negative women after controlling for cholestasis, co-infections, and alcohol consumption. Among the HCV RNA-positive women, the median FIB-4 score was 0.67 (IQR 0.56 to 0.76) in the first trimester, 0.74 (IQR 0.52 to 1.18) in the second trimester, and 0.89 (IQR 0.52 to 1.09) in the third trimester (P = 0.02). The median HCV viral load at delivery was 424 561 IU/mL. The vertical transmission rate was 4.7% in HCV RNA-positive women, with no cases in HCV RNA-negative women. CONCLUSION: Because of the high rates of poor obstetrical outcomes found in this prospective cohort, population-level screening for HCV in pregnancy should be considered.

Objectifs : 1) Décrire les issues obstétricales et néonatales au sein d'une cohorte de femmes infectées par le virus de l'hépatite C (VHC), en comparant des femmes séropositives pour l'ARN du VHC à des femmes séronégatives pour l'ARN du VHC; 2) caractériser les paramètres virologiques et hépatiques associés à l'infection par le VHC pendant la grossesse; et 3) décrire le taux de transmission verticale du VHC. Méthodes : Nous avons sollicité, de manière prospective, la participation de 145 femmes enceintes séropositives pour le VHC provenant des quatre coins de la Colombie-Britannique, entre 2000 et 2003. Les participantes ont fait l'objet d'un suivi pendant la grossesse, tandis que leurs nouveau-nés ont été suivis afin de déterminer la présence ou non d'une infection par le VHC. La présence d'ARN du VHC chez la mère a été évaluée peu avant l'accouchement. Résultats : Soixante-dix pour cent des femmes ont indiqué que la consommation de drogues par injection constituait leur principal facteur de risque d'acquisition du VHC. Les taux constatés de mort fœtale intra-utérine, d'accouchement préterme, d'hypotrophie fœtale et de faible poids à la naissance étaient, respectivement, de 3,4 %, de 17,9 %, de 11,3 % et de 12,5 %, sans association significative avec le statut maternel quant à l'ARN du VHC. Le taux de cholestase était de 5,6 % chez les femmes séropositives pour l'ARN du VHC (6/108) et de 2,8 % chez les femmes séronégatives pour l'ARN du VHC (1/37) (P = 0,496). Les taux sériques d'alanine aminotransférase ont diminué considérablement tout au long de la grossesse et étaient nettement plus élevés chez les femmes séropositives pour l'ARN du VHC que chez les femmes séronégatives pour l'ARN du VHC, à la suite de la neutralisation des effets de la cholestase, des co-infections et de la consommation d'alcool. Chez les femmes séropositives pour l'ARN du VHC, le score FIB-4 médian était de 0,67 (IIQ 0,56 - 0,76) pendant le premier trimestre, de 0,74 (IIQ 0,52 - 1,18) pendant le deuxième trimestre et de 0,89 (IIQ 0,52 - 1,09) pendant le troisième trimestre (P = 0,02). La charge virale médiane en ce qui concerne le VHC au moment de l'accouchement était de 424 561 UI/ml. Le taux de transmission verticale était de 4,7 % chez les femmes séropositives pour l'ARN du VHC; aucun cas n'a été recensé chez les femmes séronégatives pour l'ARN du VHC. Conclusion : Compte tenu des taux élevés de piètres issues obstétricales qui sont constatés au sein de cette cohorte prospective, la mise en œuvre d'un dépistage populationnel du VHC pendant la grossesse devrait être envisagée.

Characterization of the vaginal microbiota of healthy Canadian women through the menstrual cycle.

BACKGROUND: The vaginal microbial community plays a vital role in maintaining women's health. Understanding the precise bacterial composition is challenging because of the diverse and difficult-to-culture nature of many bacterial constituents, necessitating culture-independent methodology. During a natural menstrual cycle, physiological changes could have an impact on bacterial growth, colonization, and community structure. The objective of this study was to assess the stability of the vaginal microbiome of healthy Canadian women throughout a menstrual cycle by using cpn60-based microbiota analysis. Vaginal swabs from 27 naturally cycling reproductive-age women were collected weekly through a single menstrual cycle. Polymerase chain reaction (PCR) was performed to amplify the universal target region of the cpn60 gene and generate amplicons representative of the microbial community. Amplicons were pyrosequenced, assembled into operational taxonomic units, and analyzed. Samples were also assayed for total 16S rRNA gene content and Gardnerella vaginalis by quantitative PCR and screened for the presence of Mollicutes by using family and genus-specific PCR. RESULTS: Overall, the vaginal microbiome of most women remained relatively stable throughout the menstrual cycle, with little variation in diversity and only modest fluctuations in species richness. Microbiomes between women were more different than were those collected consecutively from individual women. Clustering of microbial profiles revealed the expected groupings dominated by Lactobacillus crispatus, Lactobacillus iners, and Lactobacillus jensenii. Interestingly, two additional clusters were dominated by either Bifidobacterium breve or a heterogeneous mixture of nonlactobacilli. Direct G. vaginalis quantification correlated strongly with its pyrosequencing-read abundance, and Mollicutes, including Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum, were detected in most samples. CONCLUSIONS: Our cpn60-based investigation of the vaginal microbiome demonstrated that in healthy women most vaginal microbiomes remained stable through their menstrual cycle. Of interest in these findings was the presence of Bifidobacteriales beyond just Gardnerella species. Bifidobacteriales are frequently underrepresented in 16S rRNA gene-based studies, and their detection by cpn60-based investigation suggests that their significance in the vaginal community may be underappreciated.

Perspectives of expectant women and health care providers on birth plans.

OBJECTIVE: A birth plan is a document detailing a woman's preferences and expectations related to labour and delivery. Empirical research exploring the value of birth plans has shown conflicting findings about whether birth plans have a positive or negative effect on labour and delivery, suggesting a need for further study. This study aimed to understand the perspectives of women, health care providers, and support persons regarding the use of birth plans. METHODS: A cross-sectional questionnaire was distributed to a convenience sample of expectant or postpartum women, health care providers, and support persons from January 2012 to March 2012 in British Columbia. RESULTS: In total, 122 women and 110 health care providers and support persons completed the questionnaire. Both women and their attendants viewed the birth plan as being valuable for acting as both a communication and education tool. However, the respondents noted that women may be disappointed or dissatisfied if a birth plan cannot be implemented. The most important elements of a birth plan identified included pain management, comfort measures (e.g., mobility during labour), postpartum preferences (e.g., breastfeeding), atmosphere (e.g., privacy), and birthing beliefs (e.g., cultural views). CONCLUSION: This is the first study to identify advantages and disadvantages of using a birth plan as well as the most important aspects of a birth plan from the perspectives of both women and their attendants in Canada. The findings could be applied to optimize the efficacy of birth plans in Canada and potentially internationally as well.

Objective : Un plan d'accouchement est un document détaillant les préférences et les attentes d'une femme à l'égard du travail et de l'accouchement. Les recherches empiriques explorant la valeur des plans d'accouchement ont obtenu des résultats contradictoires quant à la question de savoir si ces derniers exercent un effet positif ou négatif sur le travail et l'accouchement, ce qui semble souligner la nécessité de procéder à d'autres études sur le sujet. Cette étude avait pour but de comprendre les points de vue des femmes, des fournisseurs de soins et des accompagnateurs à l'égard de l'utilisation de plans d'accouchement. Méthodes : Un questionnaire transversal a été distribué à un échantillon de commodité de femmes enceintes ou ayant accouché, de fournisseurs de soins et d'accompagnateurs entre janvier 2012 et mars 2012 en Colombie-Britannique. Résultats : En tout, 122 femmes et 110 fournisseurs de soins de santé et accompagnateurs ont rempli le questionnaire. Tant les femmes que leurs fournisseurs de soins et de soutien estimaient que le plan d'accouchement était utile à titre d'outil de communication et d'éducation. Toutefois, les répondants ont souligné que les femmes pourraient être déçues ou mécontentes dans les cas où la mise en œuvre du plan d'accouchement s'avère impossible. Parmi les plus importants éléments du plan d'accouchement qui ont été identifiés, on trouvait la maîtrise de la douleur, les mesures visant le confort (p. ex. mobilité pendant le travail), les préférences postpartum (p. ex. allaitement), l'atmosphère (p. ex. intimité) et les croyances quant à l'accouchement (p. ex. aspects culturels). Conclusion : Il s'agit de la première étude à identifier les avantages et les désavantages de l'utilisation d'un plan d'accouchement, ainsi que les aspects les plus importants d'un tel plan, et ce, tant du point de vue des femmes que de celui de leurs fournisseurs de soins et de soutien au Canada. Les résultats pourraient être utilisés aux fins de l'optimisation de l'efficacité des plans d'accouchement au Canada et (potentiellement) à l'étranger.

"Nothing is absolute in life": understanding uncertainty in the context of psychiatric genetic counseling from the perspective of those with serious mental illness.

No genetic tests are currently clinically available for serious mental illnesses such as schizophrenia and bipolar disorder. Rather, the full spectrum of genetic variants that confer susceptibility remain unknown, and estimates of probability of condition recurrence typically have the form of ranges rather than single absolute numbers. Genetic counselors have been shown to feel that the information that can be provided for patients with serious mental illness could be more confusing than helpful. However, how those with serious mental illness perceive this uncertainty remains unknown. So, to investigate this, individuals with serious mental illness participated in a psychiatric genetic counseling (GC) session and responded to a single open ended question about their reactions towards the uncertainty that they encountered in their GC session immediately and one month post-counseling (from which themes were identified), and completed the Genetic Counseling Satisfaction Scale immediately post-session (descriptive statistics applied). While some of the 37 participants were disappointed with the uncertainty, twice as many were unconcerned. Overall, responses from immediately and one month after GC were very similar; participants were very satisfied with, and found value in GC despite uncertainty, and four approaches to coping with uncertainty emerged. Ultimately, these findings offer insight into providing GC for those with serious mental illness, and potentially could be applied to other areas of GC where uncertainty lies, with downstream impact on GC practice and future research.

Genetics professionals' perspectives on reporting incidental findings from clinical genome-wide sequencing.

Whole exome or whole genome analysis using massively parallel sequencing technologies will undoubtedly solve diagnostic dilemmas; however, incidental findings (IF) that may have medical and social implications will also be discovered. While there is consensus in the literature that analytically valid and medically actionable IF should be returned to patients if requested, there is debate regarding the return of other IF. There are currently no guidelines established for managing IF in the clinical context. We therefore distributed an online questionnaire to 496 geneticists and genetic counselors in Canada to explore this unresolved issue, and 210 professionals participated (response rate = 42%). The proportion of respondents who indicated that they would return IF to patients depended on the nature of the finding, ranging from 95% for information pertaining to a serious and treatable condition to 12% for information with only social implications (e.g., non-paternity). There was a lack of consensus around the disclosure of certain IF such as genetic carrier status, especially for pediatric patients. The most important considerations identified as impacting IF disclosure included condition-specific factors such as treatment availability, test accuracy, and evidence indicating pathogenicity. This is the first study to document the views of geneticists and genetic counselors in Canada towards the disclosure of IF, and represents a step towards evidence-based guidelines for clinical genome-wide sequencing investigations.

"I want to know what's in Pandora's Box": comparing stakeholder perspectives on incidental findings in clinical whole genomic sequencing.

Whole genomic sequencing (WGS) promises significant personalized health benefits, and its increasingly low cost makes wide clinical use inevitable. However, a core challenge is "incidental findings" (IF). Using focus groups, we explored attitudes about the disclosure of IF in clinical settings from three perspectives: Genetics health-care professionals, the general public, and parents whose children have experienced genetic testing. Analysis was based on a framework approach. All three groups considered practical and ethical considerations. There was consensus that IF presented challenges for disclosure and a pre-test patient-clinician discussion was vital for clarification and agreement. The professionals favored targeted analysis to limit data handling and focus pre-test discussions on medical relevance. Their perspective highlighted ethical concepts of justice and beneficence. The lay groups' standpoint emphasized autonomy and patients' rights to choose what findings they receive, and that patients accept the consequences of any potential anxiety and uncertainty. The lay groups also felt that it was their responsibility to check genomic developments over time with their original test results and saw patient responsibility as an important part of patient choice.

Specialized chromosomes and their uses in Caenorhabditis elegans.

Research on Caenorhabditis elegans involves the use of a wide range of genetic and molecular tools consisting of chromosomal material captured and modified for specific purposes. These "specialized chromosomes" come in many forms ranging from relatively simple gene deletions to complex rearrangements involving endogenous chromosomes as well as transgenic constructs. In this chapter, we describe the specialized chromosomes that are available in C. elegans, their origins, practical considerations, and methods for generation and evaluation. We will summarize their uses for biological studies, and their contribution to our knowledge about chromosome biology.