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PURPOSE PTEN Hamartoma Tumor syndrome (PHTS) includes patients with Cowden syndrome or other syndromes with germline mutation of the PTEN tumor suppressor gene. The risk for breast, colorectal, and endometrial cancer and polyposis is increased, creating clinical overlap with hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and adenomatous polyposis syndromes (APS). We reviewed our series of patients with PHTS to determine how often testing criteria for these syndromes were met and how often other-gene testing was ordered before testing PTEN. PATIENTS AND METHODS Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation. Mutations were identified by mutation scanning/multiplex ligation-dependent probe amplification analysis and confirmed by sequencing/quantitative polymerase chain reaction. Patients were excluded if they were adopted, were

Introduction. DNA variants of uncertain significance (VUS) are common outcomes of clinical genetic testing for susceptibility to cancer. A statistically rigorous model that provides a pathogenicity score for each variant has been developed to aid in the clinical management of patients undergoing genetic testing. Methods. The information in this article is derived from multiple publications on VUS in BRCA genes, distilled for communicating with clinicians who may encounter VUS in their practice. Results. The posterior probability scores for BRCA1 or BRCA2 VUS, calculated from a multifactorial likelihood model, are explained, and links for looking up specific VUS are provided. The International Agency on Cancer Research (IARC) of the World Health Organization has proposed a simple five-tier system for clinical management that is not widely known to clinicians. Classes 1 and 2 in this system are managed as neutral variants, classes 4 and 5 are managed as pathogenic variants, and class 3 variants still have insufficient evidence to move to either end of this scale and, thus, cannot be used in medical management. Conclusions. Development of models that integrate multiple independent lines of evidence has allowed classification of a growing number of VUS in the BRCA1 and BRCA2 genes. The pathogenicity score that is generated by this model maps to the IARC system for clinical management, which will assist clinicians in the medical management of those patients who obtain a VUS result upon testing.

Learning Objectives After completing this couse, the reader will be able to: Apply presymptomatic gene testing to family members with familial renal cancer in order to facilitate earlier diagnosis and treatment for this population.Use genetic testing for timely detection of familial renal cancer in carriers to enable earlier use and increased efficacy of VEGF and mTOR pathway inhibiting drugs. CME This article is available for continuing medical education credit at CME.TheOncologist.com. We discuss recent advances in the diagnosis and management of renal cell cancer (RCC) given the enhanced molecular genetics knowledge in this area. A number of hereditary renal cancer syndromes have been described, including von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary leiomyomatosis/RCC syndrome, and hereditary papillary renal cancer. Early molecular diagnosis now facilitates the management and prevention of RCC in families. Recommendations for screening in families are discussed.

This article presents the case of an adult patient with tuberous sclerosis complex who presented with large right benign and left malignant Leydig cell tumors. The tumors were examined to determine if they showed the classic hallmarks of TSC1/TSC2 involvement.

Genetic syndromes with dermatologic findings and multisystemic involvement (e.g., visceral cancer predisposition) are underrecognized. Patients may have incomplete penetrance and variable expressivity; some patients may solely exhibit subtle skin signs, which create a diagnostic challenge for physicians. Interdisciplinary diagnostic knowledge is required for the early diagnosis and monitoring of patients with these syndromes. Cutaneous changes in the face—one of the most highly exposed areas—can be easily noticed by patients themselves, their families and friends, and physicians; these changes may serve as early indicators of genetic syndromes with malignancies. In this article, we present examples of genetic syndromes with malignancies for which a thorough faciocutaneous examination is helpful in establishing a diagnosis. These examples include lentiginosis-related syndromes (e.g., Peutz-Jeghers syndrome, Carney complex), photosensitivity-related syndromes (Bloom syndrome, Rothmund-Thomson syndrome), and hamartoma-related syndromes (Cowden syndrome, multiple endocrine neoplasia syndrome, tuberous sclerosis complex, Gardner syndrome, Muir-Torre syndrome). The characteristics of these faciocutaneous clues are summarized and discussed. Objective evaluation of these faciocutaneous clues in combination with other clinical information (e.g., family history, histopathological findings, combination with other concomitant faciocutaneous lesions) is emphasized to narrow the diagnosis. The list of genetic syndromes with faciocutaneous manifestations is still expanding. Increased awareness of faciocutaneous markers can alert physicians to underlying syndromes and malignancies, render earlier screening and detection of associated medical issues, and allow for genetic counseling of family members.

Recent studies implicate single nucleotide polymorphisms (SNPs) within the 8q24 region as a risk factor for prostate cancer (PCa). New developments suggest that 8q24 encodes regulators of the nearby MYC gene, a known oncogene. In order to better understand the implications of SNPs in this region, we performed meta-analyses, stratified by race, of seven SNPs and one microsatellite marker previously identified as risk loci on the 8q24 region of the genome. In addition, we reviewed the literature examining the possible associations between these polymorphisms and clinicopathological features of PCa. The results of the meta-analyses indicate that rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737 are significantly associated with a higher risk for PCa for at least one race, whereas the variants rs13254738 and rs7000448 are not. The degree of association and frequency of the causative allele varied among men of different races. Though several studies have demonstrated an association between certain 8q24 SNPs and clinicopathological features of the disease, review of this topic revealed conflicting results.

This article presents the case of an 8-year-old boy with a TSC2 1801A>G mutation who has five facial features of tuberous sclerosis complex.