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.

Priority of Risk (But Not Perceived Magnitude of Risk) Predicts Improved Sun-Protection Behavior Following Genetic Counseling for Familial Melanoma.

BACKGROUND: Understanding multiple components of risk perceptions is important because perceived risk predicts engagement in prevention behaviors. PURPOSE: To examine how multiple components of risk perceptions (perceived magnitude of and worry about risk, prioritization of the management of one's risk) changed following genetic counseling with or without test reporting, and to examine which of these components prospectively predicted improvements in sun-protection behavior 1 year later. METHODS: A prospective, nonrandomized study design was used. Participants were 114 unaffected members of melanoma-prone families who (i) underwent genetic testing for a CDKN2A/p16 mutation (n = 69) or (ii) were at comparably elevated risk based on family history and underwent genetic counseling but not testing (no-test controls, n = 45). Participants reported risk perception components and sun-protection behavior at baseline, immediately following counseling, and 1 month and 1 year after counseling. RESULTS: Factor analysis indicated three risk components. Carriers reported increased perceived magnitude and priority of risk, but not cancer worry. No-test controls showed no changes in any risk perception. Among noncarriers, priority of risk remained high at all assessments, whereas magnitude of risk and cancer worry decreased. Of the three risk components, greater priority of risk uniquely predicted improved self-reported sun protection 1 year post-counseling. CONCLUSIONS: Priority of risk (i) seems to be a component of risk perceptions distinguishable from magnitude of risk and cancer worry, (ii) may be an important predictor of daily prevention behavior, and (iii) remained elevated 1 year following genetic counseling only for participants who received a positive melanoma genetic test result.

Parent and child perspectives on family interactions related to melanoma risk and prevention after CDKN2A/p16 testing of minor children.

Predispositional genetic testing of children for adult-onset health risks is typically only used when prevention and screening measures have utility during childhood. Little is known about how children and their parents may use predispositional risk information, including whether it changes their interactions around risk-reducing prevention and screening behaviors. The current study examined perspectives on family interactions around skin cancer prevention and control practices through 1 year after test reporting and counseling among children who received melanoma predispositional genetic testing and their parents. Eighteen children (50% carriers, 56% male, mean age = 12.4 years) and 11 parents from 11 families participated in semi-structured interviews 1 month and 1 year after receiving the child's test result. Both parents (73%) and children (50%) reported making changes to family skin cancer prevention and control practices after receiving the test result. Parent- and child-reported discussions about melanoma prevention increased over time (36% parents and 61% children at 1 month, 73% parents and 67% at 1 year). One-quarter (27%) of parents and no children reported having conflicts about sun protection or screening 1 year after test reporting. A majority of parents (63%) reported treating their child differently at the 1-year follow-up, especially among carriers. Predispositional genetic testing for melanoma was associated with reported changes to plans for and discussions about sun protection, and high levels of parent-child collaboration to implement child sun protection. Future work could seek to identify child and parent factors and interactions that predict improved prevention and screening behaviors following pediatric predispositional genetic testing.

CDKN2A testing and genetic counseling promote reductions in objectively measured sun exposure one year later.

PURPOSE: This study investigated whether genetic counseling and test reporting for the highly penetrant CDKN2A melanoma predisposition gene promoted decreases in sun exposure. METHODS: A prospective, nonequivalent control group design compared unaffected participants (N = 128, Mage = 35.24, 52% men) from (1) families known to carry a CDKN2A pathogenic variant, who received counseling about management recommendations and a positive or negative genetic test result and (2) no-test control families known not to carry a CDKN2A pathogenic variant, who received equivalent counseling based on their comparable family history. Changes in daily ultraviolet radiation (UVR) exposure (J/m2), skin pigmentation (melanin index), and sunburns between baseline and one year following counseling were compared among carriers (n = 32), noncarriers (n = 46), and no-test control participants (n = 50). RESULTS: Both carriers and no-test control participants exhibited a decrease one year later in daily UVR dose (B = -0.52, -0.33, p < 0.01). Only carriers exhibited a significant decrease in skin pigmentation at the wrist one year later (B = -0.11, p < 0.001), and both carriers and no-test control participants reported fewer sunburns than noncarriers (p < 0.05). Facial pigmentation did not change for any group. Noncarriers did not change on any measure of UVR exposure. CONCLUSIONS: These findings support the clinical utility of disclosing CDKN2A test results and providing risk management education to high-risk individuals.

Health communication roles in Latino, Pacific Islander, and Caucasian Families: A qualitative investigation.

Family communication about health is critical for the dissemination of information that may improve health management of all family members. Communication about health issues, attitudes, and behaviors in families is associated with life expectancy as well as quality of life for family members. This study addresses family communication about health by examining individual roles for family health communication and factors related to these roles, among families of three different racial/ethnic groups: Caucasians, Latinos, and Pacific Islanders. Data were collected from 60 participants recruited as 30 family dyads, 10 from each group, through qualitative semistructured interviews. Interviews were conducted with each participant separately and then together in a dyadic interview. Two coders independently coded interview transcripts using NVivo 11. Results identified the family health communication roles of collector, disseminator, health educator, and researcher. We also identified several factors related to these roles using the lens of family systems theory-the presence of chronic conditions in the family, previous experience, medical education, and family hierarchy. Findings demonstrate many similarities and relatively few differences in the family health communication roles and the related factors among the families of different race/ethnicity. Conclusions highlight implications for future research and intervention development.

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 children's or grandchildren's 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 children's risk regardless of group. Carrier parents reported greater (but moderate) worry about their children's 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 Test Reporting and Counseling for Melanoma Risk in Minors May Improve Sun Protection Without Inducing Distress.

Genetic testing of minors is advised only for conditions in which benefits of early intervention outweigh potential psychological harms. This study investigated whether genetic counseling and test reporting for the CDKN2A/p16 mutation, which confers highly elevated melanoma risk, improved sun protection without inducing distress. Eighteen minors (Mage = 12.4, SD = 1.9) from melanoma-prone families completed measures of protective behavior and distress at baseline, 1 week (distress only), 1 month, and 1 year following test disclosure. Participants and their mothers were individually interviewed on the psychological and behavioral impact of genetic testing 1 month and 1 year post-disclosure. Carriers (n = 9) and noncarriers (n = 9) reported significantly fewer sunburns and a greater proportion reported sun protection adherence between baseline and 1 year post-disclosure; results did not vary by mutation status. Anxiety symptoms remained low post-disclosure, while depressive symptoms and cancer worry decreased. Child and parent interviews corroborated these findings. Mothers indicated that genetic testing was beneficial (100%) because it promoted risk awareness (90.9%) and sun protection (81.8%) without making their children scared (89.9%); several noted their child's greater independent practice of sun protection (45.4%). In this small initial study, minors undergoing CDKN2A/p16 genetic testing reported behavioral improvements and consistently low distress, suggesting such testing may be safely implemented early in life, allowing greater opportunity for risk-reducing lifestyle changes.

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.

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.

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 enhances understanding of risk information and acceptance of prevention recommendations compared to family history-based counseling alone.

It is unknown whether or why genetic test reporting confers benefits in the understanding and management of cancer risk beyond what patients learn from counseling based on family history. A prospective nonexperimental control group study compared participants from melanoma-prone families who underwent CDKN2A/p16 (p16) genetic testing (27 carriers, 38 noncarriers) to participants from equivalently melanoma-prone families known not to carry a deleterious p16 mutation (31 no-test controls). All participants received equivalent counseling concerning elevated lifetime melanoma risk and corresponding recommendations for prevention and screening. Both immediately and 1 month after counseling, participants receiving a genetic test result reported greater understanding of their risk, decreased derogation of the risk information, and greater personal applicability of prevention recommendations than no-test controls. Decreased derogation of risk information after test reporting predicted further increases in understanding of melanoma risk and applicability of prevention recommendations 1 month later. Results suggest unique benefits of genetic test reporting in promoting understanding and acceptance of information about hereditary cancer risk and its management.