A Randomized Trial Comparing the Effectiveness of Pre-test Genetic Counseling Using an Artificial Intelligence Automated Chatbot and Traditional In-person Genetic Counseling in Women Newly Diagnosed with Breast Cancer.

BACKGROUND: Alternative service delivery models are critically needed to address the increasing demand for genetics services and limited supply of genetics experts available to provide pre-test counseling. METHODS: We conducted a prospective randomized controlled trial of women with stage 0-III breast cancer not meeting National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Patients were randomized to pre-test counseling with a Chatbot or a certified genetic counselor (GC). Participants completed a questionnaire assessing their knowledge of breast cancer genetics and a survey assessing satisfaction with their decision regarding pre-test counseling. RESULTS: A total of 39 patients were enrolled and 37 were randomized to genetic counseling with an automated Chatbot or a GC; 19 were randomized to Chatbot and 18 to traditional genetic counseling, and 13 (38.2%) had a family member with breast cancer but did not meet NCCN criteria. All patients opted to undergo genetic testing. Testing revealed six pathogenic variants in five patients (13.5%): CHEK2 (n = 2), MSH3 (n = 1), MUTYH (n = 1), and BRCA1 and HOXB13 (n = 1). No patients had a delay in time-to-treatment due to genetic testing turnaround time, nor did any patients undergo additional risk reducing surgery. There was no significant difference in median knowledge score between Chatbot and traditional counseling (11 vs. 12, p = 0.09) or in median patient satisfaction score (30 vs. 30, p = 0.19). CONCLUSION: Satisfaction and comprehension in patients with breast cancer undergoing pre-test genetic counseling using an automated Chatbot is comparable to in-person genetic testing. Utilization of this technology can offer improved access to care and a much-needed alternative for pre-test counseling.

Are population level familial risks and germline genetics meeting each other?

Large amounts of germline sequencing data have recently become available and we sought to compare these results with population-based family history data. Family studies are able to describe aggregation of any defined cancers in families. The Swedish Family-Cancer Database is the largest of its kind in the world, covering the Swedish families through nearly a century with all cancers in family members since the start of national cancer registration in 1958. The database allows estimation of familial risks, ages of cancer onset and the proportion of familial cancer in different family constellations. Here, we review the proportion of familial cancer for all common cancers and specify them based on the number of affected individuals. With the exception of a few cancers, age of onset of familial cancer is not different from all cancers combined. The highest proportions of familial cancer were found for prostate (26.4%), breast (17.5%) and colorectal (15.7%) cancers, but the proportions of high-risk families with multiple affected individuals were only 2.8%, 1% and 0.9%, respectively. A large sequencing study on female breast cancer found that BRCA1 and BRCA2 mutations could account for 2% of the cases (subtracting the proportions in healthy individuals) and that all germline mutations accounted for 5.6% of the cases. Early age of onset was a distinct feature of only BRCA mutations. In heritable colorectal cancer, Lynch syndrome genes dominate. Large studies on penetrance in Lynch syndrome have shown an approximately linear increase in risk from 40-50 years up to age 80 years. Interesting novel data revealed a strong modification of familial risk by unknown factors. High-risk germline genetics of prostate cancer is characterized by BRCA and other DNA repair genes. HOXB13 encodes a transcription factor which contributes to germline risk of prostate cancer. A strong interaction was shown with a polymorphism in the CIP2A gene. The emerging germline landscape of common cancers can be reasonably accommodated by family data on these cancers as to high-risk proportions and age of onset.

A genome-wide positioning systems network algorithm for in silico drug repurposing.

Recent advances in DNA/RNA sequencing have made it possible to identify new targets rapidly and to repurpose approved drugs for treating heterogeneous diseases by the 'precise' targeting of individualized disease modules. In this study, we develop a Genome-wide Positioning Systems network (GPSnet) algorithm for drug repurposing by specifically targeting disease modules derived from individual patient's DNA and RNA sequencing profiles mapped to the human protein-protein interactome network. We investigate whole-exome sequencing and transcriptome profiles from ~5,000 patients across 15 cancer types from The Cancer Genome Atlas. We show that GPSnet-predicted disease modules can predict drug responses and prioritize new indications for 140 approved drugs. Importantly, we experimentally validate that an approved cardiac arrhythmia and heart failure drug, ouabain, shows potential antitumor activities in lung adenocarcinoma by uniquely targeting a HIF1α/LEO1-mediated cell metabolism pathway. In summary, GPSnet offers a network-based, in silico drug repurposing framework for more efficacious therapeutic selections.

Patient Decisions to Receive Secondary Pharmacogenomic Findings and Development of a Multidisciplinary Practice Model to Integrate Results Into Patient Care.

Whole exome sequencing (WES) has the potential of identifying secondary findings that are predictive of poor pharmacotherapy outcomes. The purpose of this study was to investigate patients' wishes regarding the reporting of secondary pharmacogenomic findings. WES results (n = 106 patients) were retrospectively reviewed to determine the number of patients electing to receive secondary pharmacogenomic results. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The percent of patients with a predicted phenotype associated with a gene-based CPIC dosing recommendation was determined. Ninety-nine patients (93.4%) elected to receive secondary pharmacogenomic findings. For each gene-drug pair analyzed, the number of patients with an actionable phenotype ranged from two (2%) to 43 patients (43.4%). Combining all gene-drug pairs, 84 unique patients (84.8%) had an actionable phenotype. A prospective multidisciplinary practice model was developed for integrating secondary pharmacogenomic findings into clinical practice. Our model highlights a unique collaboration between physician-geneticists, pharmacists, and genetic counselors.

Frequency of germline PTEN mutations in differentiated thyroid cancer.

BACKGROUND: Differentiated thyroid cancer (DTC) is seen in 3%-10% of individuals carrying a germline PTEN mutation. Patients with PTEN mutations are at risk for additional neoplasms as are their affected offspring. However, the frequency of PTEN mutations among DTC cases has not been systematically analyzed. The objective of this study was to determine the frequency of PTEN mutations in an unselected group of patients with DTC and to identify whether additional clinical features might indicate the need for referral for genetic counseling and possible testing. METHODS: We collected personal medical and family history information, head circumference data, and blood from 259 consecutively identified clinic-based patients with DTC, unselected for personal or family history. Individuals were categorized for diagnostic criteria for Cowden syndrome (CS) using the 2009 National Comprehensive Cancer Network (NCCN) guidelines and underwent germline PTEN mutation analysis. RESULTS: Two of the 259 patients (0.8%), with both follicular thyroid carcinoma and macrocephaly, were found to carry a germline mutation in the PTEN gene. The PTEN mutation frequency in unselected cases of follicular thyroid carcinoma was 4.8%. CONCLUSION: The frequency of germline pathogenic PTEN mutations in an unselected series of patients with DTC is relatively low, but it is enriched by considering follicular histology and macrocephaly. These results suggest that by adding head circumference to the clinical assessment, thyroid cancer specialists can more effectively identify patients needing referral for cancer genetic services.

A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands.

Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score-the Cleveland Clinic (CC) score-resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.

ATP modulates PTEN subcellular localization in multiple cancer cell lines.

The tumour suppressor gene PTEN plays an important somatic role in both hereditary and sporadic breast carcinogenesis. While the role of PTEN's lipid phosphatase activity, as a negative regulator of the cytoplasmic phosphatidylinositol-3-kinase/Akt pathway is well known, it is now well established that PTEN exists and functions in the nucleus. Multiple mechanisms of regulating PTEN's subcellular localization have been reported. However none are ubiquitous across multiple cancer cell lines and tissue types. We show here that adenosine triphosphate (ATP) regulates PTEN subcellular localization in a variety of different cancer cell lines, including those derived from breast, colon and thyroid carcinomas. Cells deficient in ATP show an increased level of nuclear PTEN protein. This increase in PTEN is reversed when cells are supplemented with ATP, ADP or AMP. In contrast, the addition of the non-hydrolyzable analogue ATPgammaS, did not reverse nuclear PTEN protein levels in all the cell types tested. To our knowledge, this is the first report that describes a regulation of PTEN subcellular localization that is not specific to one cell line or tissue type, but appears to be common across a variety of cell lineages.

Interview.

Charis Eng is the Chairman and founding Director of the Genomic Medicine Institute of the Cleveland Clinic Foundation, founding Director and attending clinical cancer geneticist of the institute's clinical component, the Center for Personalized Genetic Healthcare, and Professor and Vice Chairman of the Department of Genetics at Case Western Reserve University School of Medicine. She holds a joint appointment as Professor of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine and is a full member of Cleveland Clinic's Taussig Cancer Center and of the CASE Comprehensive Cancer Center. Dr Eng was recently honored with the Sondra J and Stephen P Hardis Endowed Chair in Cancer Genomic Medicine. She continues to hold an honorary appointment at the University of Cambridge. Dr Eng's research interests may be broadly characterized as clinical cancer genetics translational research. Her work on RET testing in multiple endocrine neoplasia type 2 and the characterization of the widening clinical spectra of PTEN gene mutations have been acknowledged as the paradigm for the practice of clinical cancer genetics.

Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma.

BACKGROUND: A 43-year-old woman presented to a cancer genetics clinic for a genetic risk assessment because of her personal history of multiple neoplasias. At 37 years of age, she was diagnosed with multifocal papillary thyroid cancer, and within a year was further diagnosed with a paraganglioma of the left common carotid artery. Two years later, she was diagnosed with a paraganglioma of the right carotid body. All three tumors were treated with surgical resection. There was no family history of malignancy. Past medical history includes uterine leiomyoma and fibrocystic breast disease. Physical examination revealed macrocephaly and papillomatous papules. INVESTIGATIONS: CT scan of the neck and thorax, 24-hour urine collection for measurement of metanephrines and catecholamines, MRI of the neck, thorax, and abdomen, metaiodobenzylguanidine scan, germline mutation analysis of PTEN, SDHB, SDHC and SDHD. DIAGNOSIS: Cowden syndrome due to a germline mutation of PTEN, and pheochromocytoma-paraganglioma syndrome due to a germline mutation of SDHC. MANAGEMENT: Clinical surveillance for breast, endometrial, thyroid, and renal cell carcinoma risks associated with Cowden syndrome according to the National Comprehensive Cancer Network guidelines, annual MRI of the neck, thorax, abdomen and pelvis, annual metabolic screening, and where available, annual 18-fluorodopamine PET scanning, predictive genetic testing of both PTEN and SDHC for the patient's daughter and parents.

Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers.

Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the association between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1-3, 4-5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72-1.12), 0.75 (95% CI 0.47-1.19) and 0.31 (95% CI 0.13-0.71; p-trend = 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee consumption is unlikely to be harmful and that high levels of consumption may in fact be related to reduced breast cancer risk.

Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.

CONTEXT: Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery. OBJECTIVE: To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results. DESIGN, SETTING, AND PATIENTS: Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed. MAIN OUTCOME MEASURES: Molecular, clinical, and histopathological findings in patients with unexplained polyposis. RESULTS: Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen. CONCLUSIONS: Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.

Phytoestrogen exposure elevates PTEN levels.

Epidemiological data suggest that consumption of phytoestrogens can be protective against the development of breast cancer. It may be logical to postulate that phytoestrogens may regulate proteins that control cellular division, such as the tumor suppressor PTEN. Germline, and more significantly, somatic PTEN mutations have been observed in a broad range of human cancers, especially those of the breast. Active PTEN results in decreased phosphorylation of Akt and MAPK, the up-regulation of p27 and down-regulation of cyclin D1 protein levels resulting in decreased proliferation and an increase in apoptosis. We hypothesized that phytoestrogen exposure regulates PTEN protein expression in the breast cancer cell line, MCF-7. When MCF-7 cells were stimulated with resveratrol, quercetin or genistein, there was an increase in PTEN protein levels. Concomitantly, phytoestrogen stimulation resulted in decreased Akt phosphorylation and an increase in p27 protein levels, indicating active PTEN lipid phosphatase activity. In contrast, we found that MAPK phosphorylation and cyclin D1 levels, which are regulated by PTEN's protein phosphatase activity, were not altered. Using semi-quantitative RT-PCR, we found that mRNA levels were slightly increased in cells stimulated by phytoestrogens, suggesting that the mechanism for increased PTEN protein expression is dependent upon transcription. Concurrently, our data provide evidence that a mechanism for phytoestrogens' protective nature is partially through increased PTEN expression. More importantly, it provides a novel target for the regulation of PTEN expression and suggests that dietary changes may be adjunctive to traditional preventive and therapeutic strategies against breast cancer.