Amanda Gammon

Hamartomatous polyposis syndromes

Hamartomatous polyposis syndromes are a diverse group of inherited conditions grouped together because they exhibit hamartomatous rather than epithelial polyp histology. Each syndrome exhibits characteristic polyp histology, gastrointestinal polyp distribution, gastrointestinal cancer risks, extra-intestinal benign findings and often extra-intestinal cancer risks. Identifying individuals at risk for these syndromes and accurately defining the precise diagnosis are necessary for planning surveillance and management in order to prevent the benign and malignant complications. Characteristic syndrome features including gastrointestinal findings, pathology, genetics, and management options for the three most common hamartomatous polyposis syndromes, Peutz-Jeghers syndrome, PTEN hamartoma tumour syndrome, and juvenile polyposis will be presented in this review.

Classification of missense substitutions in the BRCA genes: A database dedicated to Ex-UVs†

Unclassified sequence variants (UVs) arising from clinical mutation screening of cancer susceptibility genes present a frustrating issue to clinical genetics services and the patients that they serve. We created an open‐access database holding missense substitutions from the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. The main inclusion criterion is that each variant should have been assessed in a published work that used the Bayesian integrated evaluation of unclassified BRCA gene variants. Transfer of data on these substitutions from the original publications to our database afforded an opportunity to analyze the missense substitutions under a single model and to remove inconsistencies that arose during the evolution of the integrated evaluation over the last decade. This analysis also afforded the opportunity to reclassify these missense substitutions according to the recently published IARC 5‐Class system. From an initial set of 248 missense substitutions, 31 were set aside due to nonnegligible probability to interfere with splicing. Of the remaining substitutions, 28 fell into one of the two pathogenic classes (IARC Class 4 or 5), 174 fell into one of the two nonpathogenic classes (IARC Class 1 or 2), and 15 remain in IARC Class 3, “Uncertain.” The database is available at http://brca.iarc.fr/LOVD. Hum Mutat 33:22–28, 2012.

Expanding Access to BRCA1/2 Genetic Counseling with Telephone Delivery: A Cluster Randomized Trial

BACKGROUND The growing demand for cancer genetic services underscores the need to consider approaches that enhance access and efficiency of genetic counseling. Telephone delivery of cancer genetic services may improve access to these services for individuals experiencing geographic (rural areas) and structural (travel time, transportation, childcare) barriers to access. METHODS This cluster-randomized clinical trial used population-based sampling of women at risk for BRCA1/2 mutations to compare telephone and in-person counseling for: 1) equivalency of testing uptake and 2) noninferiority of changes in psychosocial measures. Women 25 to 74 years of age with personal or family histories of breast or ovarian cancer and who were able to travel to one of 14 outreach clinics were invited to participate. Randomization was by family. Assessments were conducted at baseline one week after pretest and post-test counseling and at six months. Of the 988 women randomly assigned, 901 completed a follow-up assessment. Cluster bootstrap methods were used to estimate the 95% confidence interval (CI) for the difference between test uptake proportions, using a 10% equivalency margin. Differences in psychosocial outcomes for determining noninferiority were estimated using linear models together with one-sided 97.5% bootstrap CIs. RESULTS Uptake of BRCA1/2 testing was lower following telephone (21.8%) than in-person counseling (31.8%, difference = 10.2%, 95% CI = 3.9% to 16.3%; after imputation of missing data: difference = 9.2%, 95% CI = -0.1% to 24.6%). Telephone counseling fulfilled the criteria for noninferiority to in-person counseling for all measures. CONCLUSIONS BRCA1/2 telephone counseling, although leading to lower testing uptake, appears to be safe and as effective as in-person counseling with regard to minimizing adverse psychological reactions, promoting informed decision making, and delivering patient-centered communication for both rural and urban women.

A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes

As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC.

Randomized Noninferiority Trial of Telephone Delivery of BRCA1/2 Genetic Counseling Compared With In-Person Counseling: 1-Year Follow-Up

PURPOSE The ongoing integration of cancer genomic testing into routine clinical care has led to increased demand for cancer genetic services. To meet this demand, there is an urgent need to enhance the accessibility and reach of such services, while ensuring comparable care delivery outcomes. This randomized trial compared 1-year outcomes for telephone genetic counseling with in-person counseling among women at risk of hereditary breast and/or ovarian cancer living in geographically diverse areas. PATIENTS AND METHODS Using population-based sampling, women at increased risk of hereditary breast and/or ovarian cancer were randomly assigned to in-person (n = 495) or telephone genetic counseling (n = 493). One-sided 97.5% CIs were used to estimate the noninferiority effects of telephone counseling on 1-year psychosocial, decision-making, and quality-of-life outcomes. Differences in test-uptake proportions for determining equivalency of a 10% prespecified margin were evaluated by 95% CIs. RESULTS At the 1-year follow-up, telephone counseling was noninferior to in-person counseling for all psychosocial and informed decision-making outcomes: anxiety (difference [d], 0.08; upper bound 97.5% CI, 0.45), cancer-specific distress (d, 0.66; upper bound 97.5% CI, 2.28), perceived personal control (d, -0.01; lower bound 97.5% CI, -0.06), and decisional conflict (d, -0.12; upper bound 97.5% CI, 2.03). Test uptake was lower for telephone counseling (27.9%) than in-person counseling (37.3%), with the difference of 9.4% (95% CI, 2.2% to 16.8%). Uptake was appreciably higher for rural compared with urban dwellers in both counseling arms. CONCLUSION Although telephone counseling led to lower testing uptake, our findings suggest that telephone counseling can be effectively used to increase reach and access without long-term adverse psychosocial consequences. Further work is needed to determine long-term adherence to risk management guidelines and effective strategies to boost utilization of primary and secondary preventive strategies.

Awareness and Preferences Regarding BRCA1/2 Genetic Counseling and Testing Among Latinas and Non-Latina White Women at Increased Risk for Hereditary Breast and Ovarian Cancer

This study was an investigation of awareness, cognitions, and psychosocial and educational needs related to genetic counseling and testing among Latinas and non-Latina whites at increased risk for having a BRCA1/2 mutation. Sixty-three Latina and eighty-four non-Latina white women completed telephone surveys employing a mixture of quantitative and qualitative questions assessing awareness, benefits, risks, barriers, and genetic counseling communication preferences regarding BRCA1/2 testing. Among participants who had not previously had genetic counseling/testing, 56.9% of Latinas (29/51) and 34.8% of non-Latina white participants (24/69) were unaware of the availability of BRCA1/2 testing. In multivariate logistic regression analysis, Latina ethnicity was the only statistically significant independent factor associated with lack of awareness (OR = 0.42; 95% CI = 0.19–0.35). No appreciable differences were noted between ethnic groups regarding perceived benefits of BRCA1/2 testing or desired genetic counseling topics. These findings underscore the importance of increasing awareness of cancer genetic counseling and genetic testing among both Latina and non-Latina white populations.

Serrated polyposis: colonic phenotype, extracolonic features, and familial risk in a large cohort.

BACKGROUND: Serrated polyposis is a poorly understood and likely underdiagnosed condition. Little is known regarding the colorectal cancer risk, extracolonic phenotype, and cause of serrated polyposis. OBJECTIVE: The aim of this study is to describe the clinical and family history features of a large cohort of individuals with serrated polyposis. DESIGN: This is a retrospective cohort study from 2 prospectively collected registries. PATIENTS: Patients meeting the updated 2010 World Health Organization criteria for serrated polyposis were included. MAIN OUTCOME MEASURES: We report descriptive statistics for clinical and family history factors. RESULTS: A total of 52 individuals met criteria for serrated polyposis. Of these, one had Lynch syndrome and was not included in the statistical analyses. Median age at serrated polyposis diagnosis was 51 years (range, 18–77). Twenty-four (47%) patients were male, and 25 (49%) had a history of smoking. Two hundred sixty-eight lower endoscopic procedures were performed; 42 (82%) patients had colorectal adenomas, 8 (16%) had a personal history of colorectal cancer (only 1 was diagnosed during follow-up), 12 (24%) had extracolonic tumors (4 had more than 1 primary tumor), and 19 (37%) reported a family history of colorectal cancer. Esophagogastroduodenoscopy in 30 individuals revealed only 1 (3%) with unexplained gastroduodenal polyps. No association was found between colorectal cancer diagnosis and sex, age at serrated polyposis diagnosis, extracolonic tumor, history of adenoma, or smoking status. LIMITATIONS: This was a retrospective study with no comparison groups. CONCLUSIONS: Gastroduodenal polyps are uncommon and likely not associated with serrated polyposis. Although extracolonic tumors were common in our cohort, it is still unclear whether these are associated with serrated polyposis. Our data, along with previous studies, support an association between serrated polyposis and smoking. Further work is still needed to clarify the effect of smoking on polyp development/progression in serrated polyposis.

Multigene testing of moderate-risk genes: be mindful of the missense

Background Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established. Methods We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold. Results Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5. Conclusions Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

Patient outcomes associated with group and individual genetic counseling formats

Identifying new methods to deliver cancer genetic counseling (GC) are needed to meet the growing interest in BRCA1/2 testing. The goal of this pilot feasibility study was designed to test the initial acceptability of group GC on selected patient outcomes (satisfaction, distress, perceived control) in a breast/ovarian cancer genetics clinic setting. Sixty-five participants at increased risk for hereditary breast/ovarian cancer (HBOC) agreed to participate in self-selected individual or group GC appointments. Forty-nine participants completed all study questionnaires and were included in the analyses. There were significant improvements for participants in both the individual and group GC formats with regard to perceived personal control, general psychological distress and cancer-specific psychological distress scores. Participants in both the individual and group formats reported high satisfaction scores on the Genetic Counseling Satisfaction Scale. Study results suggest that group GC may be feasible and acceptable to high-risk women.

Interest and Informational Preferences Regarding Genomic Testing for Modest Increases in Colorectal Cancer Risk

Background/Aims: This study explored the interest in genomic testing for modest changes in colorectal cancer risk and preferences for receiving genomic risk communications among individuals with intermediate disease risk due to a family history of colorectal cancer. Methods: Surveys were conducted on 272 men and women at intermediate risk for colorectal cancer enrolled in a randomized trial comparing a remote personalized risk communication intervention (TeleCARE) aimed at promoting colonoscopy to a generic print control condition. Guided by Leventhals Common Sense Model of Self-Regulation, we examined demographic and psychosocial factors possibly associated with interest in SNP testing. Descriptive statistics and logistic regression models were used to identify factors associated with interest in SNP testing and preferences for receiving genomic risk communications. Results: Three-fourths of participants expressed interest in SNP testing for colorectal cancer risk. Testing interest did not markedly change across behavior modifier scenarios. Participants preferred to receive genomic risk communications from a variety of sources: printed materials (69.5%), oncologists (54.8%), primary-care physicians (58.4%), and the web (58.1%). Overall, persons who were unmarried (p = 0.029), younger (p = 0.003) and with greater cancer-related fear (p = 0.019) were more likely to express interest in predictive genomic testing for colorectal cancer risk. In a stratified analysis, cancer-related fear was associated with the interest in predictive genomic testing in the intervention group (p = 0.017), but not the control group. Conclusions: Individuals with intermediate familial risk for colorectal cancer are highly interested in genomic testing for modest increases in disease risk, specifically unmarried persons, younger age groups and those with greater cancer fear.