Identifying Mediators of Intervention Effects Within a Randomized Controlled Trial to Motivate Cancer Genetic Risk Assessment Among Breast and Ovarian Cancer Survivors.

BACKGROUND: A theory-guided Tailored Counseling and Navigation (TCN) intervention successfully increased cancer genetic risk assessment (CGRA) uptake among cancer survivors at increased risk of hereditary breast and ovarian cancer (HBOC). Understanding the pathways by which interventions motivate behavior change is important for identifying the intervention's active components. PURPOSE: We examined whether the TCN intervention exerted effects on CGRA uptake through hypothesized theoretical mediators. METHODS: Cancer survivors at elevated risk for HBOC were recruited from three statewide cancer registries and were randomly assigned to three arms: TCN (n = 212), Targeted Print (TP, n = 216), and Usual Care (UC, n = 213). Theoretical mediators from the Extended Parallel Process Model, Health Action Planning Approach, and Ottawa Decision Support Framework were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. Generalized structural equation modeling was used for mediation analysis. RESULTS: The TCN effects were most strongly mediated by behavioral intention alone (ß = 0.49 and 0.31) and by serial mediation through self-efficacy and intention (ß = 0.041 and 0.10) when compared with UC and TP, respectively. In addition, compared with UC, the TCN also increased CGRA through increased perceived susceptibility, knowledge of HBOC, and response efficacy. CONCLUSIONS: Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove barriers to CGRA. System-level and policy interventions are needed to further expand access.

It is recommended that cancer survivors at increased risk for heredity seek cancer genetic risk assessment (CGRA), which includes cancer genetic counseling and genetic testing. A Tailored Counseling and Navigation (TCN) intervention successfully increased CGRA uptake among women with a history of cancer who enrolled in a randomized controlled trial. Understanding reasons for TCN's effectiveness can guide future interventions that use risk messages and behavior change techniques. We conducted mediation analyses, which enabled identification of the TCN's active components. Eligible breast and ovarian cancer survivors (n = 641) were recruited from three statewide cancer registries and were assigned to three groups: TCN, Targeted Print, and Usual Care. Mediator variables drawn from behavioral and risk communication theories were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. The strongest mediator was intention to obtain a CGRA, followed by self-efficacy, perceived risk, knowledge of hereditary breast and ovarian cancer, and perceived CGRA benefits. Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove CGRA barriers. System-level and policy interventions are needed to further expand access.

Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement.

BACKGROUND: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. METHODS: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. RESULTS: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC. CONCLUSIONS: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. LAY SUMMARY: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.

Use of Family History and Genetic Testing to Determine Risk of Colorectal Cancer.

Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5% to 10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes; this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality.

Estimating the number of potential family members eligible for BRCA1 and BRCA2 mutation testing in a "Traceback" approach.

U.S. guidelines recommend BRCA1/2 mutation testing for women diagnosed with high-grade ovarian cancer (HGOC) to increase recognition of carriers, but most remain unidentified and at risk. Accordingly, an approach termed "Traceback" has been proposed in which probands are retrospectively identified by testing archived pathology specimens, and family members are traced to provide genetic counseling and testing. We used population-based data to estimate the number of family members who might be contacted through such a program. We used incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the number of women diagnosed with HGOC from 2005 to 2016, and census data to estimate the number of spouses, offspring, and siblings (both sexes). Using overall survival for HGOC from SEER and all-cause mortality rates from the Centers for Diseases Control and Prevention, we estimated the number of patients, spouses, offspring, and siblings of HGOC cases living in 2017. Due to the high mortality rate of HGOC, consent from living probands may be possible in only 42% of the cases; consent to test pathology specimens would need to be sought from next of kin for the remainder. In 2017, an estimated 406,919 living next of kin (spouses, siblings, offspring) would be available for potential consent. Testing archived ovarian cancer pathology specimens may enable the identification of BRCA1/2 mutation carriers, but consent from next of kin would be required in in 58% of cases. Although Traceback offers the possibility of identifying unaffected BRCA1/2 mutation carriers, pilot feasibility studies that include assessment of methods to secure consent are needed.

Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. While population-wide screening recommendations for PDAC in asymptomatic individuals are not achievable due to its relatively low incidence, pancreatic cancer surveillance programs are recommended for patients with germline causative variants in PDAC susceptibility genes or a strong family history. In this study, we sought to determine the prevalence and significance of germline alterations in major genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. We performed a systematic review of PubMed publications reporting germline variants identified in these genes in PDAC patients. Overall, the retrieved articles included 1493 PDAC patients. A high proportion of these patients (n = 1225/1493, 82%) were found to harbor alterations in genes (ATM, BRCA1, BRCA2, PALB2) involved in the homologous recombination repair (HRR) pathway. Specifically, the remaining PDAC patients were reported to carry alterations in genes playing a role in other cancer pathways (CDKN2A, STK11, TP53; n = 181/1493, 12.1%) or in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2; n = 87/1493, 5.8%). Our findings highlight the importance of germline genetic characterization in PDAC patients for better personalized targeted therapies, clinical management, and surveillance.

The role of admixture in the rare variant contribution to inflammatory bowel disease.

BACKGROUND: Identification of rare variants involved in complex, polygenic diseases like Crohn's disease (CD) has accelerated with the introduction of whole exome/genome sequencing association studies. Rare variants can be used in both diagnostic and therapeutic assessments; however, since they are likely to be restricted to specific ancestry groups, their contributions to risk assessment need to be evaluated outside the discovery population. Prior studies implied that the three known rare variants in NOD2 are absent in West African and Asian populations and only contribute in African Americans via admixture. METHODS: Whole genome sequencing (WGS) data from 3418 African American individuals, 1774 inflammatory bowel disease (IBD) cases, and 1644 controls were used to assess odds ratios and allele frequencies (AF), as well as haplotype-specific ancestral origins of European-derived CD variants discovered in a large exome-wide association study. Local and global ancestry was performed to assess the contribution of admixture to IBD contrasting European and African American cohorts. RESULTS: Twenty-five rare variants associated with CD in European discovery cohorts are typically five-fold lower frequency in African Americans. Correspondingly, where comparisons could be made, the rare variants were found to have a predicted four-fold reduced burden for IBD in African Americans, when compared to European individuals. Almost all of the rare CD European variants were found on European haplotypes in the African American cohort, implying that they contribute to disease risk in African Americans primarily due to recent admixture. In addition, proportion of European ancestry correlates the number of rare CD European variants each African American individual carry, as well as their polygenic risk of disease. Similar findings were observed for 23 mutations affecting 10 other common complex diseases for which the rare variants were discovered in European cohorts. CONCLUSIONS: European-derived Crohn's disease rare variants are even more rare in African Americans and contribute to disease risk mainly due to admixture, which needs to be accounted for when performing cross-ancestry genetic assessments.

The First Exploratory Personalized Medicine Approach to Improve Bariatric Surgery Outcomes Utilizing Psychosocial and Genetic Risk Assessments: Encouraging Clinical Research.

It is predicted that by 2030, globally, an estimated 2.16 billion adults will be overweight, and 1.12 billion will be obese. This study examined genetic data regarding Reward Deficiency Syndrome (RDS) to evaluate their usefulness in counselling patients undergoing bariatric surgery and gathered preliminary data on the potential use in predicting short term (6-month) weight loss outcomes. Methods: Patients undergoing bariatric surgery (n = 34) were examined for Genetic Addiction Risk Severity (GARS) [measures the presence of risk alleles associated with RDS]; as well as their psychosocial traits (questionnaires). BMI changes and sociodemographic data were abstracted from Electronic Health Records. Results: Subjects showed ∆BMI (M = 10.0 ± 1.05 kg/m2) and a mean % excess weight loss (56 ± 13.8%). In addition, 76% of subjects had GARS scores above seven. The homozygote risk alleles for MAO (rs768062321) and DRD1 (rs4532) showed a 38% and 47% prevalence among the subjects. Of the 11 risk alleles identified by GARS, the DRD4 risk allele (rs1800955), was significantly correlated with change in weight and BMI six months post-surgery. We identified correlations with individual risk alleles and psychosocial trait scores. The COMT risk allele (rs4680) showed a negative correlation with EEI scores (r = -0.4983, p < 0.05) and PSQI scores (r = -0.5482, p < 0.05). The GABRB3 risk allele (rs764926719) correlated positively with EEI (r = 0.6161, p < 0.01) and FCQ scores (r = 0.6373, p < 0.01). The OPRM1 risk allele showed a positive correlation with the DERS score (r = 0.5228, p < 0.05). We also identified correlations between DERS and BMI change (r = 0.61; p < 0.01). Conclusions: These data support the potential benefit of a personalized medicinal approach inclusive of genetic testing and psychosocial trait questionnaires when counselling patients with obesity considering bariatric surgery. Future research will explore epigenetic factors that contribute to outcomes of bariatric surgery.

Familial Predisposition and Genetic Risk Factors Associated with Pancreatic Cancer.

Pancreatic cancer (PC) is a highly lethal cancer and projected to be the second leading cause of cancer death by 2030. Multigene panel testing has facilitated the identification of germline variants associated with an increased risk of PC. Precision treatment has led to improved outcomes for patients with these findings. Because of these improved outcomes as well as the implications for at-risk family members who may benefit from additional cancer screening, the NCCN recommends universal genetic testing for newly diagnosed PC patients. This review describes the most common heritable conditions associated with PC and those who may benefit from screening.

Clinical Performance of a Gene-Based Machine Learning Classifier in Assessing Risk of Developing OUD in Subjects Taking Oral Opioids: A Prospective Observational Study.

OBJECTIVE: To reduce the incidence of Opioid Use Disorder (OUD), multiple guidelines recommend assessing the risk of OUD prior to prescribing oral opioids. Although subjective risk assessments are available to help classify subjects at risk for OUD, we are aware of no clinically validated objective risk assessment tools. An objective risk assessment based on genetics may help inform shared decision-making prior to prescribing short-duration oral opioids. METHODS: A multicenter, observational cohort of adults exposed to prescription oral opioids for 4-30 days was conducted to determine the performance of an OUD classifier derived from machine learning (ML). From this cohort, the demographics of the U.S. adult opioid-prescribed population were used to create a blinded, random, representative group of subjects (n=385) for analysis to accurately estimate the performance characteristics in the intended use population. Genotyping was performed via a qualitative SNP microarray on DNA extracted from buccal samples. RESULTS: In the study subjects, the classifier demonstrated 82.5% sensitivity (95% confidence intervals: 76.1%-87.8%) and 79.9% specificity (73.7-85.2%), with no statistically significant differences in clinical performance observed based on gender, age, length of follow-up from opioid exposure, race, or ethnicity. CONCLUSION: This study demonstrates an ML classifier may provide additional objective information regarding a patient's risk of developing OUD. This information may enable subjects and healthcare providers to make more informed decisions when considering the use of oral opioids.

Feasibility of genetic testing for cancer risk assessment programme in Nigeria.

BACKGROUND: A high frequency of BRCA mutations has been established in Nigerian breast cancer (BC) patients. Recently, patients' and first-degree relatives' interest have been raised on cancer genetic risk assessment through our awareness activities in Nigeria. This led to the emergence of nurse-led cancer genetic counselling (CGC) and testing aimed at providing standard-of-care for individuals at increased risk of hereditary breast and ovarian cancers. METHODS: In June 2018, CGC and testing of patients with BC and ovarian cancer (OC) commenced in collaboration with Color Genomics Inc. for a 30-panel gene testing. Previously trained nurses in CGC at the University College Hospital, Ibadan offered genetic counselling (GC) to willing patients with BC and gynaecological cancer in four out-patient oncology clinics and departments for the pilot study. Consultation consisted of CGC, patient's history, pedigree and sample collection for genetic testing (GT). RESULTS: Forty-seven patients - 40 with BC, five with OC and two with endometrial cancer received GC, and all chose to undergo GT. The average age at testing was 48.2 ± 12.1 years. Eight women reported a known family cancer history and there were more perceived benefits than barriers to GT with the patients experiencing the desire for none of their relative to have cancer. Results revealed no mutations in 27 (57.4%), 16 (4.0%) variants of unknown significance and 4 (8.5%) pathogenic mutations. CONCLUSION: Personalised cancer care utilises GC and testing for cancer risk assessment towards prevention and early detection in high risk women. The study indicates the necessity of expanded cancer genetic services for integration into patient care and cancer prevention.

Inherited predisposition to pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the US by 2030. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of PDAC. Precision treatment, informed by germline genetic testing and molecular tumor analysis, can optimize therapeutic regimens and outcomes for those diagnosed with PDAC. As a result, the National Comprehensive Cancer Network currently recommends genetic testing for all newly diagnosed PDAC patients given the clinical implications for treatment but also for the identification of at-risk family members who can benefit from pancreatic cancer screening and other cancer prevention strategies. This article reviews inherited risk factors for the development of PDAC and current screening strategies for the early detection of PDAC in high-risk populations.

Relationship Between Hereditary Cancer Syndromes and Oncotype DX Recurrence Score.

BACKGROUND: Oncotype DX (ODX) is a genomic assay of tumor tissue that is utilized to predict the likelihood of recurrence and benefit of chemotherapy in breast cancer patients. Five to 10% of breast cancers are hereditary, and hereditary syndromes may not be uncovered through family history alone. We hypothesized that high ODX recurrence score (RS) may signal a potential hereditary cancer risk. PATIENTS AND METHODS: We performed a retrospective analysis of data from hormone receptor-positive breast cancer patients who had undergone ODX and germline genetic testing. The chi-square test and Fisher exact test were used to examine univariable association between RS and germline mutation status. Multivariable logistic regression was utilized to examine if there was an association of RS with germline mutation status. RESULTS: In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). In the multivariable logistic regression model predicting germline mutation status, RS level remained significantly associated with germline mutation, in particular BRCA1 or BRCA2. The mean RS for those with non-BRCA1/2 germline mutations versus those without germline mutations was not significant (P = .38). CONCLUSION: High RS is associated with germline mutation status. Breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. If confirmed prospectively, oncologists may consider referring patients with high RS for genetic risk assessment and counseling to inform management plans, as well as counseling of family members.

[Complex assessment of the contribution of genetic factors to the risk of ischemic stroke]. / Kompleksnaia otsenka vklada geneticheskikh faktorov v razvitie ishemicheskogo insul'ta.

AIM: To develop a method of the complex assessment of genetic risk for ischemic stroke (IS) and evaluate its effectiveness. MATERIAL AND METHODS: Genotyping of 182 patients with atherothrombotic and cardioembolic subtypes of IS and 360 healthy individuals of 48 single nucleotide polymorphic loci (SNP) associated with the risk of II and its subtypes was performed. RESULTS AND CONCLUSION: In each group of SNPs, composite indicators of genetic risk of IS in groups of patients and healthy controls were identified. Differences between the calculated values of the genetic risk in these groups were significant (p <0,05). The quality of the binary classification validated by ROC-analysis confirmed the predictive potential of the proposed method of risk calculation for determining the genetic predisposition to the development of IS.

Clinical Assessment and Diagnosis of Germline Predisposition to Hematopoietic Malignancies: The University of Chicago Experience.

With the increasing use of clinical genomics to guide cancer treatment and management, there is a rise in the identification of germline cancer predisposition syndromes and a critical need for patients with germline findings to be referred for surveillance and care. The University of Chicago Hematopoietic Malignancies Cancer Risk Team has established a unique approach to patient care for individuals with hereditary hematologic malignancies through close communication and coordination between our pediatric and adult programs. Dedicated program members, including physicians, nurses, genetic counselors, and clinical research assistants, screen individuals for cancer predisposition at initial diagnosis through survivorship, in addition to testing individuals with an established family history of a cancer predisposition syndrome. Sample procurement, such as a skin biopsy at the time of bone marrow aspirate/biopsy in individuals with a positive screen, has facilitated timely identification of clinical germline findings or has served as a pipeline for translational research. Our integrated translational research program has led to the identification of novel syndromes in collaboration with other investigators, which have been incorporated iteratively into our clinical pipeline. Individuals are referred for clinical assessment based on personal and family history, identification of variants in susceptibility genes via molecular tumor testing, and during evaluation for matched related allogeneic stem cell transplantation. Upon referral, genetic counseling incorporates education with mindfulness of the psychosocial issues surrounding germline testing at different ages. The training and role of genetic counselors continues to grow, with the discovery of new predisposition syndromes, in the age of improved molecular diagnostics and new models for service delivery, such as telemedicine. With the identification of new syndromes that may predispose individuals to hematologic malignancies, surveillance guidelines will continue to evolve and may differ between children and adults. Thus, utilizing a collaborative approach between the pediatric and adult oncology programs facilitates care within families and optimizes the diagnosis and care of individuals with cancer predisposition syndromes.

Breast Cancer Genetic Counseling: A Surgeon's Perspective.

As surgeons who care for patients with breast cancer, the possibility of a cancer diagnosis being related to a hereditary predisposition is always a consideration. Not only are we as surgeons always trying to identify these patients and families but also we are often asked about a potential hereditary component by the patients and their family members. It is therefore critical that we accurately assess patients to determine who may benefit from genetic testing. Importantly, the potential benefit for identifying a hereditary breast cancer extends beyond the patient to other family members and the risk may not be only for the development of breast cancers, but for other cancers as well. This review was written from the perspective of a surgeon with additional training in cancer genetics in an effort to provide a unique perspective on the issue and feel that a review of some of the more practical considerations is important.

Securing and Documenting Cancer Family History in the Age of the Electronic Medical Record.

Family health history is one of the least expensive, most useful, and most underused methods available to conduct assessments of the genetic aspect of a condition or to target the need for a genetic evaluation. This article introduces to the surgical oncologist the reason and process of collecting family history information. As medical records shift from paper to electronic formats, pedigree drawings are not readily available within the electronic health records. International efforts are underway to develop searchable, updatable, and interoperable formats that can collect family history information to inform clinical decision support for genetic risk assessment.

An epidemiologic-based survey of public attitudes towards predictive genetic testing in Russia.

Many new genetic tests for common multifactorial disorders are becoming available to individuals, including direct-to-consumer genotyping services. Typically, studies of public attitudes reveal a high level of interest for individual genotyping. In a Russian urban population, 85% of 2000 respondents answered positively to a question about their own willingness to undergo predictive genetic testing for preventable health conditions. Gender, age and health status significantly influenced response. Multivariate discriminant analyses revealed that wanting to know about probable future diseases, readiness to improve lifestyles and an interest in learning about individual genome characteristics are the most important predictors for wanting to be tested. Along with the high level of interest, highly overestimated expectations were encountered in many studies. With the low predictive abilities of currently available genetic tests for common disorders, proper interpretation of the data and genetic counseling are essential. There is a need for prospective validation of genetic panels for risk assessments, and for efforts to measure the effects of genetic information disclosure and how this information might contribute to lifestyle changes.

Public interest and expectations concerning commercial genotyping and genetic risk assessment.

In contrast to the modest progress made in the interpretation and clinical application of genomic data, genotyping technologies have experienced great progress. Genotyping costs are progressively decreasing making individual genotyping more commonly available. Financial availability of individual genome analysis and the strong desire of many people to know about their individual genomic characteristics, promotes the marketing of genetic tests of variable predictive value directly to the public. A survey of 2000 Russian respondents revealed very positive attitudes and beliefs towards these genetic developments: 85% of surveyed individuals would like to have their genetic risk for avoidable diseases estimated, and 89% responded stating that they would try to change their lifestyle by giving up bad habits, following a recommended diet or taking medications if a high risk of disease was identified. It is believed that with time, validated genetic information will find its rightful place in medicine, by supplementing phenotypic clinical data with validated genetic interpretations.