Marjan Champine

Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management

Colorectal cancer (CRC) is the fourth most common cancer amongst men and women. Between 3 and 6% of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and several hamartomatous polyposis conditions. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This narrative review examines the hereditary colorectal cancer and polyposis syndromes, their genetic basis, clinical management, and evidence supporting cancer screening.

Genetic basis of Cowden syndrome and its implications for clinical practice and risk management

Cowden syndrome (CS) is an often difficult to recognize hereditary cancer predisposition syndrome caused by mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In addition to conferring increased cancer risks, CS also predisposes individuals to developing hamartomatous growths in many areas of the body. Due to the rarity of CS, estimates vary on the penetrance of certain phenotypic features, such as macrocephaly and skin findings (trichilemmomas, mucocutaneous papules), as well as the conferred lifetime cancer risks. To address this variability, separate clinical diagnostic criteria and PTEN testing guidelines have been created to assist clinicians in the diagnosis of CS. As knowledge of CS increases, making larger studies of affected patients possible, these criteria continue to be refined. Similarly, the management guidelines for cancer screening and risk reduction in patients with CS continue to be updated. This review will summarize the current literature on CS to assist clinicians in staying abreast of recent advances in CS knowledge, diagnostic approaches, and management.

Genetic test reporting of CDKN2A provides informational and motivational benefits for managing melanoma risk

A CDKN2A/p16 mutation confers 28%-67% lifetime melanoma risk, a risk that may be moderated by ultraviolet radiation exposure. The aim of this study was to test whether melanoma genetic counseling and test disclosure conferred unique informational, motivational, or emotional benefits compared to family history-based counseling. Participants included were 114 unaffected members of melanoma-prone families, ages 16-69, 51.8% men, 65.8% with minor children or grandchildren. Carriers (n = 28) and noncarriers (n = 41) from families with a CDKN2A mutation were compared to no-test controls (n = 45) from melanoma-prone families without an identifiable CDKN2A mutation. All participants received equivalent counseling about melanoma risk and management; only CDKN2A participants received genetic test results. Using newly developed inventories, participants rated perceived costs and benefits for managing their own and their childrens or grandchildrens melanoma risk 1 month and 1 year after counseling. Propensity scores controlled for baseline family differences. Compared to no-test controls, participants who received test results (carriers and noncarriers) reported feeling significantly more informed and prepared to manage their risk, and carriers reported greater motivation to reduce sun exposure. All groups reported low negative emotions about melanoma risk. Parents reported high levels of preparedness to manage childrens risk regardless of group. Carrier parents reported greater (but moderate) worry about their childrens risk than no-test control parents. Women, older, and more educated respondents reported greater informational and motivational benefits regardless of group. Genetic test results were perceived as more informative and motivating for personal sun protection efforts than equivalent counseling based on family history alone.

Genetic Counseling and Testing for Hereditary Melanoma: An Updated Guide for Dermatologists

Melanoma is a multifactorial disease with environmental exposure, phenotype, and in rare cases, cancer predisposition genes each contributing to an individuals risk. Approximately 10% of melanomas occur in familial clusters, and germline mutations in CDKN2A account for 20-40% of families at high risk for this cancer. Dermatologists play a key role in identifying patients who may have an inherited risk for melanoma and in offering them appropriate genetic counseling and testing services. Identifying high-risk families permits patients and their at-risk relatives to benefit from tailored screening recommendations and risk reducing strategies. Incorporating risk assessment and appropriate pre- and post-test counseling into routine clinical practice can be challenging; therefore, partnerships with genetic counseling resources are necessary. Genetic counselors are trained to assess cancer risk, provide personalized risk assessment and management recommendations, and counsel patients regarding the ethical and psychosocial implications of genetic testing. This review will provide an updated guide for dermatologists regarding factors to consider in melanoma risk assessment including environmental exposure, phenotype, and genetic status. We will also discuss the process and potential outcomes of genetic testing for hereditary melanoma in high-risk families.

Leptomeningeal dissemination of a low-grade lumbar paraganglioma: case report

Leptomeningeal dissemination of paraganglioma is rare, with only 2 prior cases in the literature. The authors present the case of a metastatic low-grade lumbar paraganglioma via leptomeningeal dissemination. This report emphasizes the utility of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA) PET scanning for diagnosis, as well as the combination of radiation therapy and alkylating chemotherapeutic agents for the treatment of this rare phenomenon. The patient was a 61-year-old woman who presented with low-back pain and was found to have an isolated L-3 intrathecal tumor on MRI. Sixteen months after gross-total en bloc resection of the paraganglioma, the patient again became symptomatic with new neurological symptoms. MRI findings revealed enhancing leptomeningeal nodules throughout the spine. 18F-FDOPA PET/CT scanning was used to confirm the diagnosis of disseminated paraganglioma. Intrathecal thiotepa, radiation therapy, and systemic therapy with capecitabine and temozolomide have been used sequentially over a 2-year period, with each able to stabilize tumor growth for several months. The authors also summarize the 2 other reports of leptomeningeal dissemination of paragangliomas in the literature and compare the course and management of the 3 cases.

Inherited Gene Mutations in Melanoma

The future of melanoma prevention and early diagnosis lies in personalized medicine. Patient-tailored management should target processes of initiation, uncontrolled proliferation, and invasion of melanocytes to abort progressive and incurable disease. Our growing knowledge of the somatic mutations in melanogenesis and the hereditary melanoma susceptibility genes is enabling clinicians to manipulate the neoplastic genotypes and develop effective treatments and raise the potential for a cure. Genomic analyses using high-throughput sequencing and comparative genomic hybridization have been instrumental in identifying these key molecules in melanomagenic pathways.