Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Next-generation universal hereditary cancer screening: implementation of an automated hereditary cancer screening program for patients with advanced cancer undergoing tumor sequencing in a large HMO.

Variants in hereditary cancer risk genes are frequently identified following tumor-based DNA sequencing and represent an opportunity to diagnose hereditary cancer. We implemented an automated hereditary cancer screening program in a large HMO for all patients who underwent tumor-based DNA sequencing to identify patients with hereditary cancer and determine if this approach augmented existing genetic counseling approaches driven by personal/family history criteria. Regular automated searches of a centralized tumor DNA variant database were performed for ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2, and/or PMS2 variants, and germline hereditary cancer gene panel testing was offered to patients with tumor variants who had never undergone germline testing. Patients completing germline testing due to their tumor DNA test results were considered part of the tumor DNA safety net. Patients previously completing germline testing via traditional genetic counseling and tumor DNA safety net were compared for demographics, tumor type, presence of germline pathogenic/likely pathogenic (P/LP) variant, and whether NCCN criteria were met for hereditary cancer genetic testing. Germline P/LP variants were common in both groups. Patients who received germline testing through traditional genetic counseling were more likely to have cardinal hereditary tumors than the tumor DNA safety net group. Patients identified with hereditary cancer through traditional genetic counseling were more likely to meet NCCN personal/family history criteria for germline testing than the tumor DNA safety net group (99% versus 34%). A universal tumor DNA safety net screen is an important diagnostic strategy which augments traditional genetic counseling approaches based on personal/family history.

Patient Satisfaction with Private Genetic Counselling for Familial Cancer in Western Australia: A Prospective Audit.

BACKGROUND: The rapid increase in demand for cancer genetic testing in Australia led to the establishment of private Familial Cancer Clinics (FCCs) as alternatives to public sector FCCs. Australian studies conducted in the public sector have shown high patient satisfaction with genetic counselling. No study has investigated patient satisfaction with genetic counselling in the private sector in Australia. Our aim was to assess patient satisfaction with genetic counselling for familial cancer within the private healthcare sector of Western Australia. MATERIALS AND METHODS: Questionnaires were given to all eligible patients after their first genetic counselling appointment, consisting of the 12-item Satisfaction with Genetic Counselling Scale and an added question regarding the perceived value for the financial cost. Outcomes assessed included instrumental satisfaction, affective satisfaction, procedural satisfaction and perceived value for financial cost. Participants scored the representative questions from one to four (unsatisfied - highly satisfied). RESULTS: Two hundred and twenty patients were given the questionnaire, 75 questionnaires were returned (response rate 34%),  and 73 were appropriately completed and analysed. Overall, seventy (96%) participants were highly satisfied with the genetic counsellor's explanation; seventy-four (98%) were highly satisfied/satisfied with the reassurance provided. Sixty-eight participants (93%) were highly satisfied/satisfied with the help received. Seventy-two (99%) participants had their expectations met and sixty-nine (95%) participants were highly satisfied with the service. Sixty-eight (93%) participants were highly satisfied/satisfied with the cost of private genetic counselling. Sixty-one (83.6%) proceeded to genetic testing. CONCLUSIONS: Private genetic counselling was considered highly satisfactory, and the cost considered acceptable by most participants.

Paediatric polyposis syndromes: burden of disease and current concepts.

PURPOSE OF REVIEW: Polyposis syndromes are rare but significant entities that often present during childhood and adolescence. Polyposis syndromes should remain high on the differential diagnoses for any child presenting with rectal bleeding, protein-losing enteropathy or intussusception in the setting of multiple polyps in the gastrointestinal tract. There are three primary paediatric polyposis syndromes: Juvenile polyposis syndrome (JPS), Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS). This review will cover recent guidelines for these conditions and advances in genetic testing. RECENT FINDINGS: The first set of paediatric guidelines were released in 2019 by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for FAP, JPS and PJS. Even with advances in genetic testing, a significant proportion of patients with polyposis syndromes have no identifiable genetic mutations. Recent research has shown that polyps behave differently in patients with and without disease-causing variants, emphasizing the role of genetic testing in the diagnosis and management of polyposis syndromes. SUMMARY: Polyposis syndromes in the paediatric population are growing due to increased recognition and advances in genetic testing. A timely diagnosis and surveillance of a paediatric polyposis syndrome are pivotal for the management of disease burden and early identification of cancers within the gastrointestinal tract and beyond. Paediatricians, paediatric gastroenterologists, paediatric oncologists and paediatric surgeons should be familiar with the presentation and comorbidities of polyposis syndromes in children and adolescents. Further research into genotype-phenotype correlations is needed to tailor the care for paediatric patients with polyposis syndromes.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Evolving Significance of Tumor-Normal Sequencing in Cancer Care.

Molecular tests assist at various stages of cancer patient management, including providing diagnosis, predicting prognosis, identifying therapeutic targets, and determining hereditary cancer risk. The current testing paradigm involves germline testing in a subset of patients determined to be at high risk for having a hereditary cancer syndrome, and tumor-only sequencing for treatment decisions in advanced cancer patients. A major limitation of tumor-only sequencing is its inability to distinguish germline versus somatic mutations. Tumor-normal sequencing has emerged as a comprehensive analysis for both hereditary cancer predisposition and somatic profiling. Here, we review recent studies involving tumor-normal sequencing, discuss its benefits in clinical care, challenges for its implementation, and novel insights it has provided regarding tumor biology and germline contribution to cancer.

High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers.

INTRODUCTION: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. MATERIALS AND METHODS: Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. RESULTS: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). CONCLUSIONS: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

Breast cancer risk assessment in patients who test negative for a hereditary cancer syndrome.

BACKGROUND: The majority of women who undergo genetic testing due to a significant family history of breast cancer will receive a negative result. The purpose of this study was to calculate the lifetime risk of breast cancer in women undergoing genetic counseling who received an uninformative genetic test result. METHODS: A retrospective chart review of mutation-negative women presenting to a cancer risk assessment clinic was performed. Lifetime risks of breast cancer were calculated using the Claus, Gail, and Tyrer-Cuzick risk assessment models. RESULTS: Approximately half (51%) of the women were classified as high-risk by at least one risk assessment model. The Tyrer-Cuzick model identified the highest proportion (43.2%) of patients as high-risk. Four percent (n = 4) of the sample was considered high-risk by all three models. CONCLUSIONS: More than half (51%) of women who underwent genetic counseling and received an uninformative negative genetic test result had a significantly elevated risk for the development of breast cancer. It is, therefore, imperative that women do not conclude that a negative genetic test result represents a lack of risk.

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG).

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

Understanding mechanisms of cancer initiation and development supports the need for an implementation of primary and secondary cancer prevention.

The burden of cancer is increasing worldwide, with a continuous rise of the annual total cases. Although mortality rates due to cancer are declining in developed countries, the total number of cancer deaths continues to rise due to the increase in the number of aged people. Three main causes of cancer have been described, represented by environmental factors, hereditary factors and random factors related to defects originated during cell replication. The frequency of cancers is very different for the various tissues and there is great debate on the extent of the specific contribution of environmental factors and random factors (due to "bad luck") to cancer development. However, there is consensus that about 50% of all cases of cancer are related to environment and are preventable. Although a part of cancers is related to intrinsic mechanisms non preventable of genetic instability, it is evident that implementation of primary and secondary prevention measures is the only affordable strategy to meet from a medical and economic point of view the tremendous pressure created on healthcare structures by the increased cancer burden. It is time to bypass the paradox of disease prevention: celebrated in principle, resisted in practice.

Hereditary Cancer Syndromes and Risk Assessment: ACOG COMMITTEE OPINION SUMMARY, Number 793.

A hereditary cancer syndrome is a genetic predisposition to certain types of cancer, often with onset at an early age, caused by inherited pathogenic variants in one or more genes. Most hereditary cancer syndromes exhibit autosomal dominant inheritance. The most common hereditary cancer syndromes related to women's cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer. A hereditary cancer risk assessment is the key to identifying patients and families who may be at increased risk of developing certain types of cancer. Assessments should be performed by obstetrician-gynecologists or other obstetric-gynecologic care providers and should be updated regularly. An assessment includes information on personal and family history, including pathology, imaging reports, and evaluation of other medical risk factors for cancer. If a hereditary cancer risk assessment suggests an increased risk of a hereditary cancer syndrome, referral to a specialist in cancer genetics or a health care provider with expertise in genetics is recommended for expanded gathering of family history information, risk assessment, education, and counseling, which may lead to genetic testing and tailored cancer screening or risk reduction measures, or both. Currently, genetic testing is guided by personal history, family history, pedigree analysis and, in some cases, risk models that may include pathology reports and confirmation of cancer diagnoses with medical records, death certificates, or both. Counseling before and after genetic testing is an important part of the process to discuss rationale for any genetic testing, disclose results, define other cancer risks, identify educational needs, and secure referrals if necessary for ongoing management. This revision includes updates related to hereditary breast and ovarian cancer, cascade testing, and referrals to genetics specialists.

Hereditary Cancer Syndromes and Risk Assessment: ACOG COMMITTEE OPINION, Number 793.

A hereditary cancer syndrome is a genetic predisposition to certain types of cancer, often with onset at an early age, caused by inherited pathogenic variants in one or more genes. Most hereditary cancer syndromes exhibit autosomal dominant inheritance. The most common hereditary cancer syndromes related to women's cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer. A hereditary cancer risk assessment is the key to identifying patients and families who may be at increased risk of developing certain types of cancer. Assessments should be performed by obstetrician-gynecologists or other obstetric-gynecologic care providers and should be updated regularly. An assessment includes information on personal and family history, including pathology, imaging reports, and evaluation of other medical risk factors for cancer. If a hereditary cancer risk assessment suggests an increased risk of a hereditary cancer syndrome, referral to a specialist in cancer genetics or a health care provider with expertise in genetics is recommended for expanded gathering of family history information, risk assessment, education, and counseling, which may lead to genetic testing and tailored cancer screening or risk reduction measures, or both. Currently, genetic testing is guided by personal history, family history, pedigree analysis and, in some cases, risk models that may include pathology reports and confirmation of cancer diagnoses with medical records, death certificates, or both. Counseling before and after genetic testing is an important part of the process to discuss rationale for any genetic testing, disclose results, define other cancer risks, identify educational needs, and secure referrals if necessary for ongoing management. This revision includes updates related to hereditary breast and ovarian cancer, cascade testing, and referrals to genetics specialists.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019.

Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.

Proposed outcomes measures for state public health genomic programs.

PURPOSE: To assess the implementation of evidence-based genomic medicine and its population-level impact on health outcomes and to promote public health genetics interventions, in 2015 the Roundtable on Genomics and Precision Health of the National Academies of Sciences, Engineering, and Medicine formed an action collaborative, the Genomics and Public Health Action Collaborative (GPHAC). This group engaged key stakeholders from public/population health agencies, along with experts in the fields of health disparities, health literacy, implementation science, medical genetics, and patient advocacy. METHODS: In this paper, we present the efforts to identify performance objectives and outcome metrics. Specific attention is placed on measures related to hereditary breast ovarian cancer (HBOC) syndrome and Lynch syndrome (LS), two conditions with existing evidence-based genomic applications that can have immediate impact on morbidity and mortality. RESULTS: Our assessment revealed few existing outcome measures. Therefore, using an implementation research framework, 38 outcome measures were crafted. CONCLUSION: Evidence-based public health requires outcome metrics, yet few exist for genomics. Therefore, we have proposed performance objectives that states might use and provided examples of a few state-level activities already under way, which are designed to collect outcome measures for HBOC and LS.

Breast Cancer: Genetics and Risk Assessment.

As health care providers, we play a crucial role in the assessment of a patient's risk for hereditary breast cancer syndromes. The panorama of genetic assessment and testing has evolved dramatically since the identification of the BRCA genes. Next-generation sequencing technology has facilitated the development of multigene panels, but 1 consequence has been an increased identification of pathogenic variants at odds with a family history as well as variants of uncertain significance for which treatment guidelines are not defined. Progress in this field requires close collaboration between patients and clinicians with a thorough understanding in cancer genetics.

Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.

Patients' Attitudes Towards Disclosure of Genetic Test Results to Family Members: The Impact of Patients' Sociodemographic Background and Counseling Experience.

Many factors predict the intention to disclose genetic information to relatives. The article examines the impact of patients' socio-demographic factors on their intention to disclose genetic testing results to their relatives. Data were collected in eight genetic clinics in Israel. Patients were requested to fill in a questionnaire after counseling. A convenience sample of 564 participants who visited these clinics was collected for a response rate of 85 %. Of them, 282 participants came for susceptibility testing for hereditary cancers (cancer group), and 282 for genetic screening tests (prenatal group). In the cancer group, being secular and having more years of education correlated positively with the intention to disclose test results to relatives. In the prenatal group, being married and female correlated positively with the intention to disclose. In the cancer group, being religious and with less years of education correlated positively with the view that the clinician should deliver the results to the family. In the prenatal group, being male and unmarried correlated positively with this belief. In both groups, being of young age correlated with the perception that genetic information is private. Varied sociodemographic factors affect the intention to inform family members. Thus, knowing the social background of patients will shed light on people's attitudes to genetic information and will help clinicians provide effective counseling in discussions with patients about the implications of test results for relatives.

Management of women at high risk of hereditary breast cancer in the Veneto Regional Program for Prevention.

INTRODUCTION: Today it is well-known that high risk of genetic breast cancer concerns a very limited part of the population: no more than 2-3 women are affected every thousand and this condition as a whole accounts for no more than 3%-5% of all breast cancers. OBJECTIVES AND METHODS: Following the directions contained in the 2014-2018 National Prevention Plan, Veneto's 2014-2018 Regional Program of Prevention (PRP), approved by Regional Council Resolution (DGR) No. 749 of 14.5.2015, consolidation of a pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma is thus proposed. The principal activities of this policy will be the following: creation of a regional working group, survey of currently existing pathways for the identification of women at risk of hereditary breast cancer and adoption of the same, approval and consolidation of a structured regional pathway for women at high risk of hereditary breast and/or ovarian cancer, from paths of oncogenetic consultation and genetic testing to management of disease risk. Subsequent to the recognition of the pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma, the Veneto region undertakes to develop a co-ordinated program of information and training on this pathway directed at the population and healthcare workers. CONCLUSIONS: It is firmly hoped that with the inclusion of a program for the management of women at high risk of hereditary breast cancer within the Veneto PRP this topic may become more defined and structured in terms of sustainability, integration with the existing regional networks (mammography network, Breast Unit), contrasting inequality, monitoring and evaluation, in this way pursuing the objectives of a reduction of cause-specific mortality and improvement of quality of life.