Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.

PURPOSE: Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS: We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS: Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION: The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.

CHEK2 Founder Variants and Thyroid Cancer Risk.

Background: Germline pathogenic variants in CHEK2 are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating CHEK2 variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444 + 1G>A) that is uncommon in other populations. In contrast, the predominant CHEK2 variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all CHEK2 pathogenic variants in two large U.S.-based commercial laboratory datasets. To further delineate the impact of common CHEK2 variants on thyroid cancer, we aimed to investigate the association of three CHEK2 founder variants (c.444 + 1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients. Methods: The presence of three CHEK2 founder variants was assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published genome-wide association study (GWAS) analyses, (2) 789 NMTC patients with germline exome sequencing (Oncology Research Information Exchange Network [ORIEN] Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios (ORs) calculated by comparison of all three groups with the Ohio State University GWAS control group. Results: The predominant Polish variant (c.444 + 1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The ORs (with 95% confidence intervals [CIs]) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The ORs (with CIs) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively. Conclusions: Our analyses of unselected patients with NMTC suggest that CHEK2 variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these CHEK2 variants.

Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline.

PURPOSE: To develop recommendations for germline mutation testing for patients with breast cancer. METHODS: An ASCO-Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS: Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS: BRCA1/2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing, regardless of family history. BRCA1/2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history.Additional information is available at www.asco.org/breast-cancer-guidelines.

Enhanced family history-based algorithms increase the identification of individuals meeting criteria for genetic testing of hereditary cancer syndromes but would not reduce disparities on their own.

OBJECTIVE: This study aimed to 1) investigate algorithm enhancements for identifying patients eligible for genetic testing of hereditary cancer syndromes using family history data from electronic health records (EHRs); and 2) assess their impact on relative differences across sex, race, ethnicity, and language preference. MATERIALS AND METHODS: The study used EHR data from a tertiary academic medical center. A baseline rule-base algorithm, relying on structured family history data (structured data; SD), was enhanced using a natural language processing (NLP) component and a relaxed criteria algorithm (partial match [PM]). The identification rates and differences were analyzed considering sex, race, ethnicity, and language preference. RESULTS: Among 120,007 patients aged 25-60, detection rate differences were found across all groups using the SD (all P < 0.001). Both enhancements increased identification rates; NLP led to a 1.9 % increase and the relaxed criteria algorithm (PM) led to an 18.5 % increase (both P < 0.001). Combining SD with NLP and PM yielded a 20.4 % increase (P < 0.001). Similar increases were observed within subgroups. Relative differences persisted across most categories for the enhanced algorithms, with disproportionately higher identification of patients who are White, Female, non-Hispanic, and whose preferred language is English. CONCLUSION: Algorithm enhancements increased identification rates for patients eligible for genetic testing of hereditary cancer syndromes, regardless of sex, race, ethnicity, and language preference. However, differences in identification rates persisted, emphasizing the need for additional strategies to reduce disparities such as addressing underlying biases in EHR family health information and selectively applying algorithm enhancements for disadvantaged populations. Systematic assessment of differences in algorithm performance across population subgroups should be incorporated into algorithm development processes.

Experiences of patients and family members with follow-up care, information needs and provider support after identification of Lynch Syndrome.

BACKGROUND: Lynch Syndrome is among the most common hereditary cancer syndromes and requires ongoing cancer surveillance, repeated screenings and potential risk-reducing surgeries. Despite the importance of continued surveillance, there is limited understanding of patient experiences after initial testing and counseling, the barriers or facilitators they experience adhering to recommendations, and how they want to receive information over time. METHODS: A cross-sectional, observational study was conducted among 127 probands and family members who had received genetic testing for Lynch Syndrome. We conducted semi-structured interviews to determine proband and family member experiences after receiving genetic testing results including their surveillance and screening practices, information needs, and interactions with health care providers. Both closed-ended and open-ended data were collected and analyzed. RESULTS: Both probands (96.9%) and family members (76.8%) received recommendations for follow-up screening and all probands (100%) and most family members (98.2%) who tested positive had completed at least one screening. Facilitators to screening included receiving screening procedure reminders and the ease of making screening and surveillance appointments. Insurance coverage to pay for screenings was a frequent concern especially for those under 50 years of age. Participants commented that their primary care providers were often not knowledgeable about Lynch Syndrome and surveillance recommendations; this presented a hardship in navigating ongoing surveillance and updated information. Participants preferred information from a knowledgeable health care provider or a trusted internet source over social media or support groups. CONCLUSIONS: Probands and family members receiving genetic testing for Lynch Syndrome generally adhered to initial screening and surveillance recommendations. However, factors such as insurance coverage and difficulty finding a knowledgeable healthcare provider presented barriers to receiving recommended follow-up care. There is an opportunity to improve care through better transitions in care, procedures to keep primary care providers informed of surveillance guidelines, and practices so that patients receive reminders and facilitated appointment setting for ongoing screening and surveillance at the time they are due.

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633-0.810). Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.

Investigation of interest in and timing preference for cancer predisposition testing and expanded carrier screening among women of reproductive age.

Objective: To examine cognitive, relational, and social predictors of interest in and timing preference for cancer predisposition testing (CPT) and expanded carrier screening (ECS) offered in routine gynecologic care for women of reproductive age. Methods: Women between 20 and 35 years old who were currently pregnant or had a prior pregnancy (N = 351) completed an online survey. Bivariate and multivariable analyses were used to identify significant predictors of women's interest in and timing preference for CPT and ECS. Results: Most respondents reported high interest in CPT and ECS and preferred to have them when planning for a pregnancy. Perceived importance of genetic information and negative attitude towards uncertainty predicted interest in CPT and ECS in multivariable models. Genetic knowledge predicted preference for CPT or ECS when planning for a pregnancy. Conclusion: Educational and decision support tools should be developed to enhance women's knowledge and awareness of CPT and ECS and to provide them with strategies to manage uncertainty. Innovation: We examined women's timing preference for CPT and ECS and the impact of partner support and trust with gynecologist. A context-specific attitudes toward uncertainty scale was used to investigate women's particular perceptions of uncertainty in genetic testing.

Predictors of Women's Intentions to Communicate Updated Genetic Test Results to Immediate and Extended Family Members.

INTRODUCTION: Many individuals who previously received negative genetic test results are eligible for updated testing. This study examined intention to communicate updated genetic test results to relatives in participants who previously received negative genetic test results. METHODS: Women with a personal or family history of breast or ovarian cancer who tested negative for BRCA1/2 before 2013 were enrolled between April 2018 and October 2019. Proportions were calculated to assess intention to communicate updated genetic test results to living immediate family, extended family, and all family. Potential predictors of intentions from the theory of planned behavior (attitudes, subjective norms, perceived behavioral control) were assessed. The three outcomes were analyzed using generalized linear models with a quasi-binomial probability distribution. RESULTS: 110 women completed the baseline assessment prior to updated testing. Participants intended to communicate genetic test results to 90% of immediate family, 51% of extended family, and 66% of all living relatives. Participants with higher subjective norms (aOR = 1.93, 95% CI: 1.08-3.57) had higher intentions to communicate genetic test results to extended family, while participants with more positive attitudes (aOR = 1.27, 95% CI: 1.01-1.60) had higher intentions to communicate to all family. Placing higher importance on genetic information was associated with higher intentions to communicate to immediate family (aOR = 1.40, 95% CI: 1.06-1.83). Lower subjective numeracy was associated with higher intentions to communicate to extended family (aOR = 0.50, 95% CI: 0.32-0.76). CONCLUSION: Attitudes and subjective norms were predictors of intention to communicate updated genetic information to at-risk biological relatives, and predictors may vary by degree of relationship.

A need to tailor surveillance based on family history: describing a highly penetrant familial paraganglioma kindred with an SDHD pathogenic variant.

Pathogenic variants (PVs) in the SDHD gene increase risk for paragangliomas (PGL)/pheochromocytomas, renal cell carcinomas, and gastrointestinal stromal tumors. Penetrance in individuals with SDHD PVs varies in reported research from 40-70%, and there is limited evidence of specific genotype risks. This study aims to characterize a multi-generational family with SDHD p.Trp43* PVs and potential genotype-phenotype considerations for surveillance. Individuals with a paternally inherited SDHD p.Trp43*(c.129G > A) PV were identified. Genetic, medical and family histories were abstracted, including clinical characteristics, tumor histories, and treatment approaches. Eleven individuals with the SDHD PV in the same kindred were diagnosed with 41 SDHx-related tumors across all family members. Eight individuals developed 27 head and neck PGL of varying origins, and seven individuals developed tumors outside of the head and neck region. Many individuals had multiple tumors, and age of first tumor diagnosis ranged from age 10 to age 45 years old. Individuals with SDHD p.Trp43* variants may have higher risks for SDHx related tumors than other SDHD variants. Prioritizing identification of at-risk individuals and initiating surveillance tailored to family history is recommended given the rate of multiple tumors found in one familial branch of individuals under 18 years old. Individuals with strong family histories of PGL at young ages with this PV will benefit from tailored surveillance recommendations.

Increasing Skin Cancer Prevention in Young Adults: the Cumulative Impact of Personalized UV Photography and MC1R Genetic Testing.

Skin cancer has become increasingly common among young adults; however, this population does not consistently adhere to recommended methods for preventing the disease. Interventions in college settings have relied on appearance-focused appeals and have not been able to examine the cumulative effect of multiple behavior change and skin cancer risk communication strategies. The goal of the current study was to examine the unique and combined impacts of personalized ultraviolet (UV) radiation photographs, genetic testing for skin cancer risk, and general skin cancer prevention education. Participants were randomly assigned to one of four conditions: (1) skin cancer prevention education, (2) education + UV photo, (3) education + genetic testing, and (4) education + UV photo + genetic testing. Self-reported sun protection, tanning, and sunburn were assessed at baseline, immediately post-intervention, and 1 month post-intervention. The findings indicated benefits of the interventions to skin cancer prevention behaviors in the overall sample; however, the combined (UV photo + genetic testing) intervention had the most consistent positive effects on behaviors. Intervention effects were distinct across seasons. These results suggest that interventions containing multiple skin cancer risk communication strategies hold promise in benefitting health-promoting behavior changes in an at-risk, young adult population.Trial Registration Number: NCT03979872; Registered 6/5/2019.

Barriers to family history collection among Spanish-speaking primary care patients: a BRIDGE qualitative study.

Objectives: Family history is an important tool for assessing disease risk, and tailoring recommendations for screening and genetic services referral. This study explored barriers to family history collection with Spanish-speaking patients. Methods: This qualitative study was conducted in two US healthcare systems. We conducted semi-structured interviews with medical assistants, physicians, and interpreters with experience collecting family history for Spanish-speaking patients. Results: The most common patient-level barrier was the perception that some Spanish-speaking patients had limited knowledge of family history. Interpersonal communication barriers related to dialectical differences and decisions about using formal interpreters vs. Spanish-speaking staff. Organizational barriers included time pressures related to using interpreters, and ad hoc workflow adaptations for Spanish-speaking patients that might leave gaps in family history collection. Conclusions: This study identified multi-level barriers to family history collection with Spanish-speaking patients in primary care. Findings suggest that a key priority to enhance communication would be to standardize processes for working with interpreters. Innovation: To improve communication with and care provided to Spanish-speaking patients, there is a need to increase healthcare provider awareness about implicit bias, to address ad hoc workflow adjustments within practice settings, to evaluate the need for professional interpreter services, and to improve digital tools to facilitate family history collection.

'I had a bigger cancer risk than I thought ': The experience of receiving personalized risk information as part of a skin cancer prevention intervention in the college setting.

BACKGROUND: Diagnoses of both melanoma and nonmelanoma skin cancers are becoming increasingly common among young adults. Interventions in this population are a priority because they do not consistently follow skin cancer prevention recommendations. OBJECTIVES: The goal of the current study was to examine college students' perspectives on and experience with receiving a skin cancer prevention intervention that provided personalized skin cancer risk feedback in the form of an ultraviolet (UV) photograph, the results of genetic testing for common skin cancer risk variants, and/or general skin cancer prevention education. METHODS: Qualitative interviews were conducted with 38 college students who received a skin cancer prevention intervention. The interview covered students' feelings about their personal skin cancer risk information, the impact of the intervention on their skin cancer risk perceptions, actions or intentions to act with regard to their sun protection practices and feedback for improvement of the intervention content or delivery. RESULTS: Participants reported that different intervention components contributed to increased awareness of their sun protection behaviours, shifts in cognitions about and motivation to implement sun protection strategies and reported changes to their skin cancer prevention strategies. CONCLUSION: Our findings indicate that college students are interested in and responsive to these types of multicomponent skin cancer preventive interventions. Further, students demonstrate some motivation and intentionality toward changing their skin cancer risk behaviour in the short term. PATIENT OR PUBLIC CONTRIBUTION: Participants involved in this study were members of the public (undergraduate students) who were involved in a skin cancer prevention intervention, then participated in semistructured interviews, which provided the data analysed for this study.

Association of Disparities in Family History and Family Cancer History in the Electronic Health Record With Sex, Race, Hispanic or Latino Ethnicity, and Language Preference in 2 Large US Health Care Systems.

Importance: Clinical decision support (CDS) algorithms are increasingly being implemented in health care systems to identify patients for specialty care. However, systematic differences in missingness of electronic health record (EHR) data may lead to disparities in identification by CDS algorithms. Objective: To examine the availability and comprehensiveness of cancer family history information (FHI) in patients' EHRs by sex, race, Hispanic or Latino ethnicity, and language preference in 2 large health care systems in 2021. Design, Setting, and Participants: This retrospective EHR quality improvement study used EHR data from 2 health care systems: University of Utah Health (UHealth) and NYU Langone Health (NYULH). Participants included patients aged 25 to 60 years who had a primary care appointment in the previous 3 years. Data were collected or abstracted from the EHR from December 10, 2020, to October 31, 2021, and analyzed from June 15 to October 31, 2021. Exposures: Prior collection of cancer FHI in primary care settings. Main Outcomes and Measures: Availability was defined as having any FHI and any cancer FHI in the EHR and was examined at the patient level. Comprehensiveness was defined as whether a cancer family history observation in the EHR specified the type of cancer diagnosed in a family member, the relationship of the family member to the patient, and the age at onset for the family member and was examined at the observation level. Results: Among 144 484 patients in the UHealth system, 53.6% were women; 74.4% were non-Hispanic or non-Latino and 67.6% were White; and 83.0% had an English language preference. Among 377 621 patients in the NYULH system, 55.3% were women; 63.2% were non-Hispanic or non-Latino, and 55.3% were White; and 89.9% had an English language preference. Patients from historically medically undeserved groups-specifically, Black vs White patients (UHealth: 17.3% [95% CI, 16.1%-18.6%] vs 42.8% [95% CI, 42.5%-43.1%]; NYULH: 24.4% [95% CI, 24.0%-24.8%] vs 33.8% [95% CI, 33.6%-34.0%]), Hispanic or Latino vs non-Hispanic or non-Latino patients (UHealth: 27.2% [95% CI, 26.5%-27.8%] vs 40.2% [95% CI, 39.9%-40.5%]; NYULH: 24.4% [95% CI, 24.1%-24.7%] vs 31.6% [95% CI, 31.4%-31.8%]), Spanish-speaking vs English-speaking patients (UHealth: 18.4% [95% CI, 17.2%-19.1%] vs 40.0% [95% CI, 39.7%-40.3%]; NYULH: 15.1% [95% CI, 14.6%-15.6%] vs 31.1% [95% CI, 30.9%-31.2%), and men vs women (UHealth: 30.8% [95% CI, 30.4%-31.2%] vs 43.0% [95% CI, 42.6%-43.3%]; NYULH: 23.1% [95% CI, 22.9%-23.3%] vs 34.9% [95% CI, 34.7%-35.1%])-had significantly lower availability and comprehensiveness of cancer FHI (P < .001). Conclusions and Relevance: These findings suggest that systematic differences in the availability and comprehensiveness of FHI in the EHR may introduce informative presence bias as inputs to CDS algorithms. The observed differences may also exacerbate disparities for medically underserved groups. System-, clinician-, and patient-level efforts are needed to improve the collection of FHI.

Correction: Identifying Patients Who Meet Criteria for Genetic Testing of Hereditary Cancers Based on Structured and Unstructured Family Health History Data in the Electronic Health Record: Natural Language Processing Approach.

[This corrects the article DOI: 10.2196/37842.].

Identifying Patients Who Meet Criteria for Genetic Testing of Hereditary Cancers Based on Structured and Unstructured Family Health History Data in the Electronic Health Record: Natural Language Processing Approach.

BACKGROUND: Family health history has been recognized as an essential factor for cancer risk assessment and is an integral part of many cancer screening guidelines, including genetic testing for personalized clinical management strategies. However, manually identifying eligible candidates for genetic testing is labor intensive. OBJECTIVE: The aim of this study was to develop a natural language processing (NLP) pipeline and assess its contribution to identifying patients who meet genetic testing criteria for hereditary cancers based on family health history data in the electronic health record (EHR). We compared an algorithm that uses structured data alone with structured data augmented using NLP. METHODS: Algorithms were developed based on the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing for hereditary breast, ovarian, pancreatic, and colorectal cancers. The NLP-augmented algorithm uses both structured family health history data and the associated unstructured free-text comments. The algorithms were compared with a reference standard of 100 patients with a family health history in the EHR. RESULTS: Regarding identifying the reference standard patients meeting the NCCN criteria, the NLP-augmented algorithm compared with the structured data algorithm yielded a significantly higher recall of 0.95 (95% CI 0.9-0.99) versus 0.29 (95% CI 0.19-0.40) and a precision of 0.99 (95% CI 0.96-1.00) versus 0.81 (95% CI 0.65-0.95). On the whole data set, the NLP-augmented algorithm extracted 33.6% more entities, resulting in 53.8% more patients meeting the NCCN criteria. CONCLUSIONS: Compared with the structured data algorithm, the NLP-augmented algorithm based on both structured and unstructured family health history data in the EHR increased the number of patients identified as meeting the NCCN criteria for genetic testing for hereditary breast or ovarian and colorectal cancers.

Interest in Cancer Predisposition Testing and Carrier Screening Offered as Part of Routine Healthcare Among an Ethnically Diverse Sample of Young Women.

Sequencing technologies can inform individuals' risks for multiple conditions, supporting population-level screening approaches. Prior research examining interest in genetic testing has not generally examined the context of population-based approaches offered in routine healthcare or among ethnically diverse populations. Cancer predisposition testing and carrier screening could be offered broadly to women of reproductive age. This study therefore examined interest in these tests when offered as part of routine care, and predictors of interest, among an ethnically diverse sample of women aged 20-35. We conducted an online English-language survey of 450 women; 39% identified as Latina. We examined predictors of interest for two outcomes, interest in testing in the next year and level of interest, in multivariable logistic regression models and stratified analyses by Latina ethnicity. More than half of respondents reported being interested in cancer predisposition testing (55%) and carrier screening (56%) in the next year; this did not differ by ethnicity. About 26% reported being very interested in cancer predisposition testing and 27% in carrier screening. Latina respondents (32%) were more likely to be very interested in cancer predisposition testing than non-Latina respondents (22%; p < 0.03). In multivariable models, having higher worry about genetic risks, higher genetic knowledge, and higher perceived importance of genetic information were associated with higher interest across multiple models. Predictors of interest were generally similar by ethnicity. Our findings show substantial interest in both cancer predisposition testing and carrier screening among young women as part of routine healthcare with similar interest between Latina and non-Latina women. Efforts to broadly offer such testing could be important in improving access to genetic information. It will be critical to develop tools to help healthcare providers communicate about genetic testing and to address the needs of those who have less prior knowledge about genetics to support informed decision making.

Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders.

Although most non-melanoma skin cancers are felt to be sporadic in origin, these tumors do play a role in several cancer predisposition syndromes. The manifestations of skin cancers in these hereditary populations can include diagnosis at extremely early ages and/or multiple primary cancers, as well as tumors at less common sites. Awareness of baseline skin cancer risks for these individuals is important, particularly in the setting of treatments that may compromise the immune system and further increase risk of cutaneous malignancies. Additionally, diagnosis of these disorders and management of non-cutaneous manifestations of these diseases have profound implications for both the patient and their family. This review highlights the current literature on the diagnosis, features, and non-melanoma skin cancer risks associated with lesser-known cancer predisposition syndromes, including bone marrow failure disorders, genomic instability disorders, and base excision repair disorders.

Considerations for Germline Testing in Melanoma: Updates in Behavioral Change and Pancreatic Surveillance for Carriers of CDKN2A Pathogenic Variants.

The largest proportion of hereditary melanoma cases are due to pathogenic variants (PVs) in the CDKN2A/p16 gene, which account for 20%-40% of familial melanomas and confer up to a 30%-70% lifetime risk for melanoma in individuals with these variants. In addition, PVs in the CDKN2A gene also increase risk for pancreatic cancer (~5-24% lifetime risk). Individuals with PVs in the CDKN2A gene also tend to have an earlier onset of cancer. Despite these known risks, uptake of germline testing has been limited in the past, largely due to perceptions of limited benefit for patients. Prevention recommendations have been developed for individuals with CDKN2A PVs as well the providers who care for them. On the patient level, behavioral modifications regarding melanoma prevention such as wearing sunscreen, limiting prolonged sun exposure and practicing general sun safety can help reduce risks. Germline testing can provide motivation for some individuals to adhere to these lifestyle changes. On the provider level, pancreatic cancer surveillance for individuals with CDKN2A PVs has been increasingly endorsed by expert consensus, although the efficacy of these surveillance methods remains under study. This review summarizes the updated surveillance guidelines for individuals with CDKN2A PVs and explores the impact of genetic counseling and testing in influencing behavioral changes in these individuals.