Monkeypox in Montréal: Epidemiology, Phylogenomics, and Public Health Response to a Large North American Outbreak.

BACKGROUND: Monkeypox, a viral zoonotic disease, is causing a global outbreak outside of endemic areas. OBJECTIVE: To characterize the outbreak of monkeypox in Montréal, the first large outbreak in North America. DESIGN: Epidemiologic and laboratory surveillance data and a phylogenomic analysis were used to describe and place the outbreak in a global context. SETTING: Montréal, Canada. PATIENTS: Probable or confirmed cases of monkeypox. MEASUREMENTS: Epidemiologic, clinical, and demographic data were aggregated. Whole-genome sequencing and phylogenetic analysis were performed for a set of outbreak sequences. The public health response and its evolution are described. RESULTS: Up to 18 October 2022, a total of 402 cases of monkeypox were reported mostly among men who have sex with men (MSM), most of which were suspected to be acquired through sexual contact. All monkeypox genomes nested within the B.1 lineage. Montréal Public Health worked closely with the affected communities to control the outbreak, becoming the first jurisdiction to offer 1 dose of the Modified Vaccinia Ankara-Bavarian Nordic vaccine as preexposure prophylaxis (PrEP) to those at risk in early June 2022. Two peaks of cases were seen in early June and July (43 and 44 cases per week, respectively) followed by a decline toward near resolution of the outbreak in October. Reasons for the biphasic peak are not fully elucidated but may represent the tempo of vaccination and/or several factors related to transmission dynamics and case ascertainment. LIMITATIONS: Clinical data are self-reported. Limited divergence among sequences limited genomic epidemiologic conclusions. CONCLUSION: A large outbreak of monkeypox occurred in Montréal, primarily among MSM. Successful control of the outbreak rested on early and sustained engagement with the affected communities and rapid offer of PrEP vaccination to at-risk persons. PRIMARY FUNDING SOURCE: None.

Clinical Considerations in the Selection of Preexposure Prophylaxis for HIV Prevention in Canada.

According to the Public Health Agency of Canada, approximately 62,050 people were living with HIV in Canada in 2018, and of those, 13% were undiagnosed. Currently, no single strategy provides complete protection or is universally effective across all demographic groups at risk for HIV. However, HIV preexposure prophylaxis (PrEP) is the newest HIV prevention strategy that shows promise. To date, two products have received an indication for PrEP by Health Canada: emtricitabine/tenofovir disoproxil fumarate (Truvada®; FTC/TDF) and emtricitabine/tenofovir alafenamide (Descovy®; FTC/TAF). Despite the high efficacy of these PrEP intervention methods, access to PrEP in Canada remains low. Identifying and addressing barriers to PrEP access, especially in high-risk groups, are necessary to reduce HIV transmission in Canada. While guidelines published by the Center for Disease Control and Prevention (CDC) include FTC/TAF information, the efficacy of FTC/TAF for PrEP has not yet been considered in Canada's clinical practice guidelines. Thus, the current paper reviews data regarding the use of FTC/TDF and FTC/TAF for PrEP, which may be useful for Canadian healthcare providers when counseling and implementing HIV prevention methods. The authors highlight these data in relation to various at-risk populations and review ongoing clinical trials investigating novel PrEP agents. Overall, FTC/TDF PrEP is effective for many populations, including men who have sex with men, transgender women, heterosexuals with partners living with HIV, and people who use drugs. While there is fewer data reported on the efficacy of FTC/TAF to date, recent clinical trials have demonstrated noninferiority of FTC/TAF in comparison to FTC/TDF. Notably, as studies have shown that FTC/TAF maintains renal function and bone mineral density to a greater extent than FTC/TDF, FTC/TAF may be a safer option for patients experiencing renal and/or bone dysfunction, for those at risk of renal and bone complications, and for those who develop FTC/TDF-related adverse events.

Mutational and splicing landscape in a cohort of 43,000 patients tested for hereditary cancer.

DNA germline genetic testing can identify individuals with cancer susceptibility. However, DNA sequencing alone is limited in its detection and classification of mRNA splicing variants, particularly those located far from coding sequences. Here we address the limitations of splicing variant identification and interpretation by pairing DNA and RNA sequencing and describe the mutational and splicing landscape in a clinical cohort of 43,524 individuals undergoing genetic testing for hereditary cancer predisposition.

Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients' family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

Atypical choroidal nevus in a subject with a germline PALB2 pathogenic variant.

Recent evidence suggests that PALB2 variants may increase risk for the development of uveal melanoma and uveal melanocytic neoplasms. Here we report a case of an atypical choroidal nevus in a patient with a personal history of cancer and pathogenic PALB2 germline variant. A 75-year-old white female presented with an elevated predominantly amelanotic choroidal lesion OS. On examination and ophthalmic imaging, the mass measured 8.8 mm × 6.5 mm × 1.5 mm. The mass showed predominantly medium to high reflectivity on diagnostic A-scan and acoustic hollowing on B-scan. OCT over the lesion showed no subretinal fluid. The patient has a personal history of breast cancer and gastric adenoma and a strong family history of cancer. The patient was found to have a pathogenic truncating variant in PALB2 (rs118203998 c.3549C > A, p.Y1183*). Together with our previous findings of pathogenic PALB2 variants in uveal melanoma patients, this new finding of an atypical choroidal nevus in a patient with a pathogenic PALB2 germline variant suggests that pathogenic PALB2 variants may be a risk factor for uveal melanocytic neoplasms. This finding warrants further assessment of the prevalence and progression of uveal melanocytic neoplasms in PALB2 pathogenic variant carriers.

Genetic evaluation of patients and families with concern for hereditary endocrine tumor syndromes.

Hereditary endocrine tumor syndromes are rare conditions with overlapping features. It is imperative that healthcare providers differentiate between these syndromes for proper patient care. Advances in genetic testing technologies have increased utilization of genetic counseling and testing in this field; however, few endocrine cancer genetics clinics exist. Two years ago, a genetic counselor (GC) specializing in endocrine cancer genetics was added to the multidisciplinary team of the James Neuroendocrine/Thyroid Clinic at The Ohio State University. Here, we report on this experience. In total, 358 patients were seen. The majority were referred by medical oncology (n = 204; 57%) for a personal history of disease (n = 249; 81%). The most common referral indications were pancreatic neuroendocrine tumors (n = 44; 17%), multiple primary tumors (n = 37; 14%), and pheochromocytoma/paraganglioma (n = 35; 14%). Most patients completed genetic testing after genetic counseling (n = 200; 65%). Targeted gene panel testing was the most common testing ordered (n = 98; 32%). Thirty-one patients (15.5%) had ≥ one likely pathogenic variant (LPV) or pathogenic variant (PV) identified. Approximately 37% (n = 11) did not meet genetic testing guidelines for the gene they tested positive for. The most common genes with LPV/PVs were the SDH genes (n = 8) and MEN1 (n = 7). Referral indications with the highest likelihood of LPV/PVs were paraganglioma, medullary thyroid carcinoma, and multiple primary tumors. We believe this data can provide valuable guidance to healthcare providers who see patients with endocrine neoplasia or who are seeking to establish hereditary endocrine cancer clinics.

How Have Multigene Panels Changed the Clinical Practice of Genetic Counseling and Testing.

Historically, genetic testing (and billing) for hereditary cancer risk was essentially performed gene by gene, with clinicians ordering testing only for the genes most likely to explain a patient's or family's cancer presentation, with laboratories typically charging $1,000 to $1,500 for each gene that was sequenced. Given the expense, only patients at high risk of having a hereditary syndrome were offered testing. With the introduction of next-generation sequencing technologies, however, laboratories are able to test for multiple genes at the same time with greater efficiency, significantly decreased costs, and relatively little increased expense when adding additional genes. This has drastically altered clinical practice so that clinicians now typically order testing for a panel of multiple genes for most patients. Although this approach has streamlined the diagnostic odyssey, it has introduced several problems, as well, including difficulties in choosing the appropriate panel test for a given patient, assessing the significance of identified genetic variants (including variants of uncertain significance [VUS]), and understanding the disease risks and management associated with pathogenic variants in a given gene. Many laboratories offer testing for genes that have limited data supporting their associated cancer risks, which then leads to an inability to set management guidelines based on that gene. In addition, testing larger numbers of genes increases the likelihood of finding one or more VUS, which introduce their own management issues. Thus, although panel testing has certainly moved clinical practice forward in many ways, it has also raised its own set of problems that increase the complexity of genetic counseling and highlight the need for education of community practitioners on the complexities and nuances of this testing. Whenever possible, testing should be performed by, or in consultation with, cancer genetics professionals.

Concurrent germline BRCA1, BRCA2, and CHEK2 pathogenic variants in hereditary breast cancer: a case series.

BACKGROUND: Concurrent germline (g) pathogenic variants related to hereditary breast cancer represent a rare occurrence. While double heterozygosity in gBRCA1 and gBRCA2 has been reported in the past, herein we describe the first case of three known concurrent pathogenic variants identified in a family with a strong history of breast cancer. Case presentation The proband is a 55-year-old female diagnosed with synchronous bilateral breast cancers. She underwent a multi-gene panel testing indicating the presence of 3 concurrent heterozygous germline deleterious variants in BRCA1 (c.181T > G), BRCA2 (c.4398_4402delACATT), and CHEK2 (1100delC). The patient's two daughters (34 and 29 years-old) were found to be transheterozygous for inherited pathogenic variants in BRCA1 (c.181T > G) and CHEK2 (1100delC) genes. CONCLUSION: The cancer risk and phenotypic manifestations associated with transheterozygous or multiple concurrent deleterious germline variants in hereditary breast cancer requires further investigation. A personalized approach to counseling, screening, and risk reduction should be undertaken for these individuals.

Impact of Previous Genetic Counseling and Objective Numeracy on Accurate Interpretation of a Pharmacogenetics Test Report.

INTRODUCTION: Pharmacogenetic (PGx) testing can be useful for providing information about a patient's drug response by increasing drug efficacy and decreasing the incidence of adverse drug events. While PGx tests were previously only offered to patients under healthcare provider supervision, they are now available as direct to consumer (DTC) tests. This study aimed to assess how accurately individuals from the general population were able to interpret a sample PGx test report and if accuracy differed based on individuals' numeracy or prior genetic counseling (GC). METHODS: We surveyed 293 individuals from the general population, ascertained through ResearchMatch. The survey included questions about PGx test interpretation, numeracy, and genetic literacy. RESULTS: In our cohort, numeracy level impacted PGx result interpretation, with those of high numeracy performing statistically significantly better on both the table format and graphical format (p value = 0.002 and p value <0.001, respectively) and genetic knowledge questions (p value <0.001) than those with low/average numeracy. In addition, previous GC did not impact test interpretation or genetic knowledge, but the number of individuals with prior GC was small (n = 26). DISCUSSION/CONCLUSION: We found that numeracy had a significant impact on correct interpretation of PGx test reports. Because many individuals in the USA have low numeracy levels, it is extremely important that patients do not make their own medication management decision based on the test results and that they consult with their physicians about their PGx testing. The importance of consultation and discussion with providers about results should be emphasized on the test report.

Stromal Platelet-Derived Growth Factor Receptor-ß Signaling Promotes Breast Cancer Metastasis in the Brain.

Platelet-derived growth factor receptor-beta (PDGFRß) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRß and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRß tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRß (PDGFRßD849V) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRßD849V also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRßD849V was observed within a subset of astrocytes, and aged mice expressing PDGFRßD849V exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRßD849V in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRß signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRß paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients.See related article by Wyss and colleagues, p. 594.

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Metastatic breast cancer patient perceptions of somatic tumor genomic testing.

BACKGROUND: To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. METHODS: In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar's test of agreement. RESULTS: There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04). CONCLUSIONS: This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention. CLINICAL TRIAL INFORMATION: NCT01987726, registered November 13, 2013.

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.

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.

Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

PURPOSE: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations. DESIGN: Retrospective case series from academic referral centers. PARTICIPANTS: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene. METHODS: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping. MAIN OUTCOME MEASURES: Clinical characterization of UM patients with germline alterations in known cancer genes. RESULTS: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively). CONCLUSIONS: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.

Predictors of risk-reducing surgery intentions following genetic counseling for hereditary breast and ovarian cancer.

Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are increasingly used to reduce breast and ovarian cancer risk following BRCA1/BRCA2 testing. However, little is known about how genetic counseling influences decisions about these surgeries. Although previous studies have examined intentions prior to counseling, few have examined RRM and RRSO intentions in the critical window between genetic counseling and test result disclosure. Previous research has indicated that intentions at this time point predict subsequent uptake of surgery, suggesting that much decision-making has taken place prior to result disclosure. This period may be a critical time to better understand the drivers of prophylactic surgery intentions. The aim of this study was to examine predictors of RRM and RRSO intentions. We hypothesized that variables from the Health Belief Model would predict intentions, and we also examined the role of affective factors. Participants were 187 women, age 21-75, who received genetic counseling for hereditary breast and ovarian cancer. We utilized multiple logistic regression to identify independent predictors of intentions. 49.2% and 61.3% of participants reported intentions for RRM and RRSO, respectively. Variables associated with RRM intentions include: newly diagnosed with breast cancer (OR = 3.63, 95% CI = 1.20-11.04), perceived breast cancer risk (OR = 1.46, 95% CI = 1.17-1.81), perceived pros (OR = 1.79, 95% CI = 1.38-2.32) and cons of RRM (OR = 0.81, 95% CI = 0.65-0.996), and decision conflict (OR = 0.80, 95% CI = 0.66-0.98). Variables associated with RRSO intentions include: proband status (OR = 0.28, 95% CI = 0.09-0.89), perceived pros (OR = 1.35, 95% CI = 1.11-1.63) and cons of RRSO (OR = 0.72, 95% CI = 0.59-0.89), and ambiguity aversion (OR = 0.79, 95% CI = 0.65-0.95). These data provide support for the role of genetic counseling in fostering informed decisions about risk management, and suggest that the role of uncertainty should be explored further.

Current prostate cancer genetic testing capabilities and considerations.

With the advent of next-generation sequencing technologies, genetic testing of prostate cancer patients is now typically done using multi-gene panels. These vary from targeted disease-specific panels to comprehensive (pan-cancer) panels, with advantages and disadvantages for each. This paper reviews a number of issues raised in choosing the best panels and labs to use, and issues presented by the increasing availability of direct-to-consumer testing.

PTEN Hamartoma Tumor Syndrome: A Clinical Overview.

The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a grouping of related genetic disorders that has been linked to germline mutations in the PTEN gene. These disorders include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, adult Lhermitte-Duclos disease, and autism spectrum disorders associated with macrocephaly. The majority of the clinical information available on PHTS, however, is related to individuals diagnosed with CS. There is still much to be learned about this disorder, since diagnostic criteria for CS were only established in 1996, before the identification of the PTEN gene, and were based primarily on features seen in cases reported in the existing literature. More recently, however, data from several large series of patients have shown that a number of the clinical features associated with PTEN mutations are either more or less common than previously reported. In addition, we now know that only about 30-35% of patients meeting clinical diagnostic criteria for Cowden syndrome actually have a detectable PTEN mutation. Thus, our understanding of PTEN-related diseases and their management has evolved significantly over time. The United States National Comprehensive Cancer Network (NCCN) has produced and regularly updates practice guidelines which include clinical diagnostic criteria as well as guidelines for PTEN testing and management of patients with mutations. This review will summarize the overall literature on PHTS as well as recent findings which are broadening our understanding of this set of disorders.

The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families.

Beyond breast and ovarian cancers, mutations in the BRCA1 and BRCA2 genes increase risks for pancreatic and prostate cancers and contribute to the prevalence of these cancers. Mutations in a number of other genes have also been shown to increase the risk for these cancers as well. Genetic testing is playing an increasingly important role in the treatment of patients with pancreatic and prostate cancer and is now recommended for all patients with pancreatic or metastatic prostate cancer, as well as patients with high Gleason grade prostate cancer and a remarkable family history. Identification of an inherited mutation can direct evaluation of the patient for other cancer risks as well as identification and management of disease in at-risk relatives. Growing evidence suggests improved responses to PARP inhibitors and other therapies in patients with mutations in the BRCA and other DNA repair genes. Although more work must be done to clarify the prevalence and penetrance of mutations in genes other than BRCA1 and BRCA2 in patients with pancreatic and prostate cancer, in most cases, testing is now being done with a panel of multiple genes. Because of the complexities in panel testing and the increased likelihood of finding variants of uncertain significance, pre- and post-test genetic counseling are essential.