Mutation Carrier Status Research Articles

Brisk walking pace offsets venous thromboembolism risk equivalent to established monogenic mutations.

Mendelian mutations in F2 and F5 genes are known risk factors for venous thromboembolism (VTE). This study aimed to explore the association between walking pace and VTE, compare its risk with Mendelian mutations, and identify if blood biomarkers mediate this effect. We followed 445,261 UK Biobank participants free of VTE at baseline. Walking pace was self-reported, and carrier status for F2 and F5 gene mutations was determined by rs1799963 and rs6025 genotypes. We used a Cox proportional hazard model to estimate walking pace's effect on VTE risk, bidirectional Mendelian randomization (MR) analysis to assess causality, and mediation analysis to explore blood biomarkers. Over a median follow-up of 12.8 years, 11,155 incident VTE cases were identified. The 10-year incidence rates for brisk and slow walking paces were 1.32% and 3.90%, respectively. For F5 carriers, the rates were 1.70% (brisk pace) and 3.62% (slow pace). Brisk walking pace reduced VTE risk in F5 carriers (2.65%) compared to non-carriers with a slow pace (3.66%). MR analysis confirmed a causal relationship from walking pace to VTE risk. Mediation analysis revealed that serum albumin and cystatin C mediated 8.7% to 11.7% of the effect of brisk walking pace on VTE risk. A slow walking pace is causally associated with increased VTE risk. A brisk walking pace mitigates VTE risk, particularly in individuals with F5 gene mutations, and this effect is partially mediated by serum albumin and cystatin C.

Evaluation of homeobox protein B13 (HOXB13) gene G84E mutation in patients with prostate cancer.

To comprehensively investigate the potential association between prostate cancer (PCa) and the G84E mutation within the Homeobox Protein B13 (HOXB13) gene among individuals of Turkish descent, our study aims to undertake a prospective examination. We evaluated 300 patients (150 diagnosed with prostate cancer, 150 controls) who presented in our clinic. Data collected were prospectively examined. DNA isolation was performed using an isolation kit. The HOXB13-G84E mutation (rs138213197) was analyzed in the obtained samples. Data encoding and statistical analysis were performed. The pathological allele for the G84E mutation was T. According to the findings, no mutations were detected in the control group, while the G84E mutation was detected in 17 patients in the patient group, all of whom had the TC genotype. The analysis showed that having the CC genotype reduced the risk of prostate cancer by 0.47 times (OR=0.47, CI=0.415-0.532). Our results did not support a trend toward family history or earlier-onset disease in comparisons between carriers and non-carriers of HOXB13 G84E mutation. Individuals with a positive family history exhibited a higher frequency of the G84E mutation. We concluded that HOXB13 gene mutation is indeed linked to PCa in Turkish men. However, we did not find a relationship between the HOXB13 gene G84E mutation carrier status and either early-onset PCa or familial PCa in Turkish men.

The risk of skin cancer in women who carry BRCA1 or BRCA2 mutations

BackgroundIt has not been clearly established if skin cancer or melanoma are manifestations of BRCA1 or BRCA2 mutation carrier status. Estimating the risk of skin cancer is an important step towards developing screening recommendations.MethodsWe report the findings of a prospective cohort study of 6,207 women from North America who carry BRCA1 or BRCA2 mutations. Women were followed from the date of baseline questionnaire to the diagnosis of skin cancer, to age 80 years, death from any cause, or the date of last follow-up.ResultsDuring the mean follow-up period of eight years, 3.7% of women with a BRCA1 mutation (133 of 3,623) and 3.8% of women with a BRCA2 mutation (99 of 2,584) reported a diagnosis of skin cancer (including both keratinocyte carcinomas and melanoma). The cumulative risk of all types of skin cancer from age 20 to 80 years was 14.1% for BRCA1 carriers and 10.7% for BRCA2 carriers. The cumulative risk of melanoma was 2.5% for BRCA1 carriers and 2.3% for BRCA2 carriers, compared to 1.5% for women in the general population in the United States. The strongest risk factor for skin cancer was a prior diagnosis of skin cancer.ConclusionThe risk of non-melanoma skin cancer in women who carry a mutation in BRCA1 or BRCA2 is similar to that of non-carrier women. The risk of melanoma appears to be slightly elevated. We suggest that a referral to a dermatologist or primary care provider for BRCA mutation carriers for annual skin examination and counselling regarding limiting UV exposure, the use of sunscreen and recognizing the early signs of melanoma might be warranted, but further studies are necessary.

MAPT Locus in Parkinson's Disease Patients of Ashkenazi Origin: A Stratified Analysis.

Introduction: MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.

Tau pathology is associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican descent at risk for autosomal‐dominant Alzheimer’s disease

AbstractBackgroundNeuropsychiatric symptoms are common in Alzheimer’s disease (AD), causing significant suffering and diminished quality of life for both individuals and caregivers. The goal of this study was to investigate the relationship between tau pathology in vivo and neuropsychiatric symptoms within a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant autosomal dominant AD (ADAD) caused by mutations in PSEN1 and APP genes (Figure 1).MethodParticipants from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) cohort were selected based on availability of demographic variables, mutation carrier status, tau PET scans (flortaucipir), and completion of the neuropsychiatric inventory (NPI). Linear regression models were used to investigate whether regional tau PET standard uptake value ratio (SUVR) predicted total score on the NPI. Models were adjusted for age, sex, and mutation carrier status. Participants were characterized as carriers if they possessed one of the following ADAD mutations: PSEN1 A431E, PSEN1 I180F, or APP V717I. Analyses were done with and without outliers. The 12‐item total NPI score was used for all analyses. The primary brain regions of interest (i.e., medial orbitofrontal, caudal anterior cingulate, rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were selected based on previous findings. Additional analyses were conducted only on individuals who were carriers of 1 of the ADAD mutations.ResultThe sample consisted of 31 participants (45% women, mean age±SD = 37.1±11.7 years, 71% ADAD mutation carriers [81% PSEN1 A431E, 16% PSEN1 I180F, and 3% APP V717I carriers]). A significant relationship was found between regional tau pathology and neuropsychiatric symptoms for all six brain regions (Table 1), all p’s < 0.01. Within all regression models, regional tau pathology explained between 24% to 49% of the variance in neuropsychiatric symptoms. Sub‐set analyses completed on the ADAD mutation carriers sample exhibited similar results (Table 2). No significant results were found for non‐carriers.ConclusionRegional tau pathology within six distinct brain regions is strongly associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant ADAD caused by mutations in PSEN1 and APP genes.

Tau pathology is associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican descent at risk for autosomal‐dominant Alzheimer’s disease

AbstractBackgroundNeuropsychiatric symptoms are common in Alzheimer’s disease (AD), causing significant suffering and diminished quality of life for both individuals and caregivers. The goal of this study was to investigate the relationship between tau pathology in vivo and neuropsychiatric symptoms within a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant autosomal dominant AD (ADAD) caused by mutations in PSEN1 and APP genes (Figure 1).MethodParticipants from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) cohort were selected based on availability of demographic variables, mutation carrier status, tau PET scans (flortaucipir), and completion of the neuropsychiatric inventory (NPI). Linear regression models were used to investigate whether regional tau PET standard uptake value ratio (SUVR) predicted total score on the NPI. Models were adjusted for age, sex, and mutation carrier status. Participants were characterized as carriers if they possessed one of the following ADAD mutations: PSEN1 A431E, PSEN1 I180F, or APP V717I. Analyses were done with and without outliers. The 12‐item total NPI score was used for all analyses. The primary brain regions of interest (i.e., medial orbitofrontal, caudal anterior cingulate, rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were selected based on previous findings. Additional analyses were conducted only on individuals who were carriers of 1 of the ADAD mutations.ResultThe sample consisted of 31 participants (45% women, mean age±SD = 37.1±11.7 years, 71% ADAD mutation carriers [81% PSEN1 A431E, 16% PSEN1 I180F, and 3% APP V717I carriers]). A significant relationship was found between regional tau pathology and neuropsychiatric symptoms for all six brain regions (Table 1), all p’s < 0.01. Within all regression models, regional tau pathology explained between 24% to 49% of the variance in neuropsychiatric symptoms. Sub‐set analyses completed on the ADAD mutation carriers sample exhibited similar results (Table 2). No significant results were found for non‐carriers.ConclusionRegional tau pathology within six distinct brain regions is strongly associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant ADAD caused by mutations in PSEN1 and APP genes.

Life’s Simple 7 Relates to Better Cognitive and Brain Health in Individuals with Autosomal Dominant Frontotemporal Dementia

AbstractBackgroundCardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.Method243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.ResultMutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)ConclusionBetter cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.

High Epstein-Barr virus capsid antigen IgG level associates with the carriership of CD8+ T cell somatic mutations in the STAT3 SH2 domain

High carrier prevalence of STAT3 SH2 domain somatic mutations was recently discovered in CD8+ T cells. We found these low-allele-fraction clones in 26% of donors, without difference between multiple sclerosis (MS) patients and controls. Here we tested whether anti-viral antibodies associate with the carriership of these mutant clones. We compared antibody responses against common viruses in mutation carriers vs. non-carriers. Plasma samples of 152 donors (92 MS patients, 60 controls) were analyzed for antibodies against cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6A and parvovirus B19. The mutation carrier status associated with EBV VCA IgG level (p = 0.005) and remained significant after logistic regression (p = 0.036). This association was contributed similarly by MS patients and controls. These results suggest that EBV contributes to the generation or growth of these clones. The pathogenic role of the STAT3 mutant clones in MS is presently unclear, but their detailed characterization warrants further study.

Efficacy of olaparib maintenance therapy in <i>BRCA1</i> germline mutations in familial pancreatic cancer patient

Pancreatic cancer (PaCa) is one of the most aggressive and unfavourable current oncological diseases. The vast majority of patients have unresectable or metastatic disease at diagnosis. Despite considerable achievements in the drug therapy of most malignant tumours, the immediate and long-term results of the treatment of PaCa still remain extremely unsatisfactory, as overall survival at 5 years does not exceed 10%. The high molecular genetic heterogeneity, which is characteristic of pancreatic adenocarcinomas, the low frequency of driver changes, the diagnostic difficulties, and the rapid progressive deterioration of the general health condition of most patients are just a few of the reasons for the lack of highly specific treatment. Understanding that about 10–15% of pancreatic tumours are a manifestation of genetically determined syndromes has changed the pharmaceutical treatment options for this cohort of patients. BRCA1/2 mutation carrier status is one of these reasons, while the relative risk of PaCa is 2.36 in BRCA1 mutation and 3.34 in BRCA2, respectively. The PARP inhibitor therapy experience and proven efficacy allowed to successfully use this group of drugs in the treatment of BRCA-mutated ovarian and breast cancers. The double-blind, placebo-controlled phase III POLO trial showed the benefit of olaparib as maintenance therapy in BRCA-mutated PaCa. This article presents a clinical case report of the use of olaparib in a patient with familial BRCA1-mutated metastatic PaCa.

MP38-06 IMPACT OF THREE MEASURES OF INHERITED PROSTATE CANCER RISK ON UPGRADING DURING ACTIVE SURVEILLANCE FOR GRADE GROUP 1 PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP38-06 IMPACT OF THREE MEASURES OF INHERITED PROSTATE CANCER RISK ON UPGRADING DURING ACTIVE SURVEILLANCE FOR GRADE GROUP 1 PROSTATE CANCER Claire De La Calle, Julia Fountain, Sean Fletcher, Yuezhou Jing, Patricia Landis, Jun Wei, Zhuqing Shi, S. Lilly Zheng, Jianfeng Xu, William Isaacs, and Christian Pavlovich Claire De La CalleClaire De La Calle More articles by this author , Julia FountainJulia Fountain More articles by this author , Sean FletcherSean Fletcher More articles by this author , Yuezhou JingYuezhou Jing More articles by this author , Patricia LandisPatricia Landis More articles by this author , Jun WeiJun Wei More articles by this author , Zhuqing ShiZhuqing Shi More articles by this author , S. Lilly ZhengS. Lilly Zheng More articles by this author , Jianfeng XuJianfeng Xu More articles by this author , William IsaacsWilliam Isaacs More articles by this author , and Christian PavlovichChristian Pavlovich More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003276.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In this study, we sought to evaluate the impact of three measures of inherited risk (rare pathogenic mutation (RPM) carrier status, single nucleotide polymorphism (SNP) -based genetic risk score (GRS) and various definitions of family history (FH)) on upgrading during active surveillance (AS). METHODS: We identified 700 men enrolled in the Johns Hopkins AS registry from 1995 to 2018 with available sequencing data. All men had GG1 disease at diagnosis. A multivariable proportional hazards model was used to assess the association between RPM carrier status, GRS and FH and upgrading defined as the detection of Grade group (GG) ≥2 PCa on a surveillance biopsy, adjusting for age, PSA density, cancer volume metrics, and Eigen values (genetic background). RPM carrier status was defined as being a carrier of any one of the following gene mutations: BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, or HOXB13. GRS was defined as: low (<0.5), average (0.5 – 1.5), moderately high (1.5 – 3), and high (≥3). Various definitions of FH were used: any FH of PCa (FHP), any FH of cancer (FHC), high-risk FH of PCa (HR-FHP) and high-risk FH for any cancer (HR-FHC) based on National Comprehensive Cancer Network guidelines, and history of lethal PCa (L-FHP). RESULTS: Among the 700 AS patients, 34 were RPM carriers (4.9%), 31 had a high GRS (4.4%), 174 (24.9%) had a FHP, 36 (5.1%) had a HR-FHP, 517 (73.9%) had a FHC, 153 (21.9%) had a HR-FHC, and 35 (5.0%) had a L-FHP. Overall, 196 (28.0%) patients upgraded on surveillance. There was no significant difference in RPM status, GRS, or FH (using any of the FH definitions) between men who upgraded and men who did not (Table). In addition, men with high GRS and positive FH, and RPM carriers with a positive FH, did not experience more upgrading, regardless of the definition used for FH (Table). On multivariable analysis neither RPM carrier status, GRS or FH (using any of the FH definitions) nor any of the three measures of inherited risk combined were predictors of upgrading (p>0.05). CONCLUSIONS: In a large cohort of AS men with GG1 PCa, neither RPM carrier status, high GRS, positive FH nor combinations of the three predicted upgrading on AS, suggesting that such men can be safely monitored on AS. This study is limited by low number of RPM carriers and low number of men with high GRS. Source of Funding: Ralph T. and Esther L. Warburton Foundation and Dr. Hugh Judge Jewett Fellowship in Urologic Oncology. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e525 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Claire De La Calle More articles by this author Julia Fountain More articles by this author Sean Fletcher More articles by this author Yuezhou Jing More articles by this author Patricia Landis More articles by this author Jun Wei More articles by this author Zhuqing Shi More articles by this author S. Lilly Zheng More articles by this author Jianfeng Xu More articles by this author William Isaacs More articles by this author Christian Pavlovich More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract OT2-12-01: Clinical Application of LFSPRO: A Prospective Study

Abstract Background: Individuals with Li-Fraumeni Syndrome (LFS) have increased risk of developing cancers of several types, such as early-onset breast cancer, soft-tissue/bone sarcoma, leukemia, brain tumors, and more, throughout their lifetime. LFS is primarily caused by autosomal dominant germline mutations in the TP53 tumor suppressor gene. It is difficult to identify TP53 mutation carriers because of the overlap in the occurrence of multiple cancer types in LFS with other inherited cancer syndromes. In order to improve the accuracy of risk assessment for these families, the LFSPRO risk model was created to predict the likelihood of a proband having LFS based off detailed patient and family history information, as well as predict cancer-specific risks for patients who have already been identified as having LFS. Specific Aims: The primary aim of this study is to evaluate the concordance of LFSPRO and clinical criteria in predicting TP53 mutation status in patients undergoing germline TP53 testing. Trial Design: After receiving standard genetic counseling, patients identified as concerning for a potential TP53 mutation by a MD Anderson genetic counselor (GC) are run through LFSPRO. LFSPRO TP53 mutation carrier risk, whether the patient meets Chompret and/or Classic criteria, decision to test, and genetic test results are collected. Select GCs are then asked to complete a survey regarding their experience with LFSPRO. Eligibility Criteria: Through standard genetic counseling practice, MD Anderson GCs identify patients with a clinical suspicion for a TP53 germline mutation. All patients identified are run through LFSPRO. Out of these identified patients, select GCs that participated in the initial genetic counseling session are asked to complete a survey over their experience using the LFSPRO. Statistical methods: We will evaluate the concordance in the prediction of TP53 mutation carrier status between LFSPRO and current clinical criteria as compared to the outcome of genetic testing results. We will cross-tabulate the predicted TP53-mutation status (positive vs. negative) with the carrier status in a 2 × 2 table and calculate the sensitivity and specificity of each prediction tool separately (LFSPRO, clinical criteria), with 95% confidence interval. Accrual: Currently, 72 patients have been run through LFSPRO. Select GCs have completed the survey regarding their experience with LFSPRO on 20 of these patients. Data collection began in December 2021 and is currently ongoing. Funding: This research is supported by the Cancer Research and Prevention Institute of Texas. Contact: Jacynda Woodman-Ross, MS, CGC, The University of Texas MD Anderson Cancer Center, jawoodman@mdanderson.org Citation Format: Jacynda Woodman-Ross, Elissa Dodd-Eaton, Jessica Corredor, Sierra O. Green, Nam H. Nguyen, Nathaniel Hernandez, Courtney D. DiNardo, Wenyi Wang, Banu K. Arun. Clinical Application of LFSPRO: A Prospective Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-12-01.

TERT Mutations in Non-Small Cell Lung Cancer: Clinicopathologic Features and Prognostic Implications.

The associations between the clinical characteristics of non-small cell lung cancer (NSCLC) and mutations in telomerase reverse transcriptase (TERT) gene remain unclear. In this study, we used next-generation sequencing (NGS) to investigate the incidence rate and clinical correlates of TERT mutations in patients with NSCLC. In total, 283 tumor samples from patients with NSCLC were tested using an NGS panel from September 2017 to May 2020. The genetic testing results and clinical data of all patients were collected. TERT mutations were found in 30 patients, which were significantly associated with age, smoking history, sex, and metastasis (P < 0.05). Survival analyses showed that patients who carried TERT mutations had a poorer prognosis. Of the 30 TERT-mutation carriers, 17 harbored epidermal growth factor receptor (EGFR) mutations, which were significantly associated with sex, histopathology type, and metastasis (P < 0.05; overall survival [OS], 21 months; 95% confidence interval [CI], 8.153-33.847 months). Three TERT mutation patients harbored Kirsten rat sarcoma virus (KRAS) mutations, which were significantly associated with metastasis risk (P < 0.05), KRAS mutations carriers had a worse prognosis, with an OS of 10 months (95% CI, 8.153-33.847 months). Multivariate Cox regression analyses showed that age, cancer stage, and TERT mutation carrier status were independent risk factors for NSCLC, and the TERT mutation was 2.731 times higher than that without TERT mutation (95% CI, 1.689-4.418, P < 0.001). TERT mutations were present in 11% of patients with NSCLC. TERT mutations were associated with age, smoking history, sex, and distant metastasis. Co-mutations in TERT and EGFR/KRAS indicated a poor prognosis. The co-mutations of TERT and EGFR differed according to sex, histopathology type, and metastasis, whereas TERT and KRAS co-mutations were only associated with patient metastasis. Age, cancer stage, and TERT mutation carrier status were independent risk factors for poor prognosis in patients with NSCLC.

Impact of the 2018 ACR Supplemental Screening Recommendations on MRI Eligibility in Breast Cancer Survivors.

The 2018 American College of Radiology (ACR) recommendations for breast cancer screening in women at higher-than-average risk include new recommendations for supplemental breast MRI for patients with a personal history of breast cancer (PHBC) who either carry a hereditary cancer gene mutation, have dense breast tissue, or were diagnosed before age 50. In comparison, prior guidelines only recommended supplemental MRI for women with PHBC who carried a hereditary cancer gene mutation. In this study, we sought to quantify the increase in number of breast cancer patients for whom supplemental breast MRI would now be recommended. Data were extracted from the electronic health record of patients presenting for screening or diagnostic mammograms at an urban academic medical center between July 20, 2020 and July 19, 2021. Data extracted including patient reported PHBC, age at time of breast cancer diagnosis, and hereditary cancer gene mutation carrier status. We report descriptive statistics evaluating the rate of eligibility for supplemental Breast MRI in a retrospective population given the new ACR guidelines. Of the 2950 patients with a self-reported PHBC who presented for breast cancer screening in a year between July 2020 and 2021, 1805 (61%) of patients met criteria for supplemental breast MRI according to the 2018 guidelines compared to only 3.6% using pre-2018 guidelines. Measuring the impact of the 2018 ACR supplemental MRI recommendations using real-world data at a single urban academic medical center demonstrated a 15-fold increase in potential eligibility for supplemental breast MRI in patients with a PHBC.

Determining concordance of LFSPRO TP53 germline carrier risk predictions to standard genetic counseling practice.

10593 Background: Li-Fraumeni Syndrome (LFS) is a hereditary cancer syndrome associated with a germline mutation in the TP53 tumor suppressor gene and an increased risk of developing a spectrum of cancers throughout a carrier’s lifetime. Early cancer detection in patients with TP53 mutations can dramatically improve cancer survival rates. However, it can be difficult to identify patients at risk of LFS due to the overlap of the multiple cancer types with other inherited cancer syndromes. Risk prediction modeling has been widely accepted by the clinical community, however, currently there is not an available tool to assist in risk prediction of LFS during genetic counseling sessions. LFSPRO is a statistical model that has previously been validated on large research cohorts in predicting the likelihood of a proband having LFS based off detailed patient and family history information. To improve the clinical utility of LFSPRO, a user-friendly interface is still needed. Additionally, we aim to evaluate concordance between LFSPRO’s abilities in predicting the likelihood of a proband having LFS and currently established clinical testing criteria. Methods: We developed a Shiny App to create a user-friendly interface for genetic counselors (GCs) to run LFSPRO. Determining concordance of LFSPRO to standard germline testing criteria and the clinical utility of the LFSPRO Shiny App is underway by GCs within the Department of Clinical Cancer Genetics at MD Anderson Cancer Center through prospective data collection and completion of user surveys. Following a standard genetic counseling session, individuals identified as concerning for a potential germline TP53 mutation are evaluated with LFSPRO to compare performance of the model to established TP53 testing guidelines. Concordance is then evaluated in prediction of TP53 mutation carrier status from LFSPRO, current clinical criteria and clinical judgment. Data collection began 12/21/2021 and is currently ongoing. Results: Close collaboration with GCs and clinicians on the development of the LFSPRO Shiny App has achieved automated de-identified input data, clear pedigree drawing, important demographic data, interpretable risk results and risk visualizations to be used at the GC's discretion. To date, 29 individual’s family data have been run through LFSPRO. Of these, 11 have not currently completed TP53 testing and concordance cannot be determined. Of the 18 remaining, 14 individuals’ LFSPRO results were concordant with current clinical criteria. Further data collection is needed to appropriately analyze concordance. Conclusions: The LFSPRO Shiny App aims to provide an additional tool for GCs and clinical providers to assess patient risk for LFS. This ongoing study will help establish the clinical utility of LFSPRO in a single institution’s genetic counseling practice with the potential to be applied to other patient care settings in the future.

Sex Differences in Attitudes Toward Marriage and Childbearing Based on the Assumption of Being BRCA1/2 Mutation Carriers Among Young People.

PurposeThis study investigated changes in attitudes toward marriage and childbearing assuming a BRCA1/2 mutation carrier status among healthy, unmarried individuals in Korea.MethodsA nationally representative sample of healthy, unmarried individuals aged 20–39 years was surveyed. A questionnaire on marriage and childbearing intentions was administered to the participants before and after providing them with information on BRCA1/2 mutation carriers’ breast and ovarian cancer risks and their autosomal dominant inheritance pattern. The participants were asked about their attitudes toward childbearing through preimplantation genetic diagnosis (PGD).ResultsOf the participants who initially wanted to marry, the assumption that they or their partners had BRCA1/2 mutation caused 25.3% to no longer want to get married and 36.2% to change their attitude from wanting to bear children to no longer wanting them. Females were more likely than males to change their attitudes toward marriage and childbearing. The participants who had negative attitudes toward genetic testing were more likely to change their attitudes regarding marriage and childbearing than those who were favorable toward both disclosure and testing. More than 50% of the participants who did not want children were willing to bear children through PGD when it was assumed that they were BRCA mutation carriers.ConclusionOn the assumption of being carriers, general, young, and healthy females were more likely than males to negatively change their attitudes toward marriage and childbearing. Public education on the implications of living with mutation carriers and reproductive options may be required.

Histopathological characterization of carcinoma breast with BRCA1/2 sequence variation in a Tertiary Care Center in Kerala, South India

Background: Hereditary breast cancers constitute around 5%–10% of all breast cancers. The most commonly mutated genes in hereditary breast and ovarian cancer syndrome are the BRCA1 and BRCA2 genes. There has not been any research into the histopathological features of BRCA1/2 mutations in breast cancer in Kerala. The goal of this work was to use next-generation sequencing to look into the range of BRCA1/2 genetic variants and to discover characteristic histopathologic features associated with BRCA1/2 sequence variations. Methods: Fifty female patients diagnosed with carcinoma breast were screened for BRCA1/2 variants by next-generation sequencing. Patients were selected irrespective of age or family history of breast or ovarian cancer. The histopathological features of BRCA1/2 associated breast cancer cases were also studied. Results: We identified sequence variants in BRCA1 and BRCA2 genes in 6 women (6/50, 12%). The sequence variants included two deleterious mutations and five variants of uncertain significance. It was observed that most of the patients with BRCA1/2 sequence variants presented with aggressive tumor characteristics. Statistical significance was noted in BRCA1/2 carriers with tumors of higher histologic grade (P = 0.048). Conclusion: Morphological and immunohistochemical features of BRCA1/2-associated breast cancer may be valuable to predict mutation carrier status for appropriate therapeutic decision-making.

Cortical microstructural changes in autosomal dominant Alzheimer’s disease

AbstractBackgroundAutosomal dominant Alzheimer's Disease (ADAD) is an important area of study to understand the pathogenesis of AD. Previous studies suggested that mutations in the genes coding for amyloid precursor protein cause early deposition of amyloid‐β peptide (Aβ), resulting in an amyloid‐induced inflammatory response and cortical microstructural changes during the cognitively asymptomatic phase, several years before clinical onset. The aim of this work was to investigate the cortical microstructural changes in an ADAD population, using novel diffusion tensor imaging (DTI) metrics that are correlated with specific neuropathology and disruption of cortical minicolumns.MethodA total of 270 individuals from families with known mutations in the PSEN1, PSEN2, and APP genes (168 mutation carriers and 102 non‐carriers) from the Dominantly Inherited Alzheimer’s Network (DIAN) were included in the study. 3DT1 and DTI scans at baseline were used to calculate the cortical grey matter fraction, cortical thickness, mean diffusivity (MD), and three novel cortical diffusivity measures, namely: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD), and the principal diffusion component parallel with the minicolumns (ParlPD). A multivariate General Linear model (GLM) was used to investigate cross‐sectional differences. Mutation carrier status was added as a fixed factor, and “sex” and “age” as covariates. Differences across the clinical spectrum are evaluated with box‐plots of metrics grouped by clinical dementia rating (CDR) Figure 1.ResultDifferences in cortical diffusivity measures were found between mutation carriers and non‐carriers. The GLM results revealed a significant main effect of mutation carrier status (p&lt;0.05) as well as age (p&lt;0.001) and sex (p&lt;0.001). Between‐subjects effects revealed that PerpPD (p&lt;0.0001), ParlPD (p&lt;0.0001), and MD (p&lt;0.0001) were significantly higher in the mutation carrier group. As expected, the cortical grey matter fraction (p&lt;0.005) and cortical thickness (p&lt;0.01) were significantly lower in the mutation carrier group.ConclusionIn autosomal dominant (inherited) Alzheimer’s disease, differences emerge in several novel cortical diffusivity measures, years before the expected diagnosis based on parental age of onset. These findings support using cortical diffusivity measures as a surrogate of cortical microstructure quality for identification of the early stages of AD.

Lifetime risk of rheumatoid arthritis-associated interstitial lung disease in MUC5B mutation carriers

ObjectivesTo estimate lifetime risk of developing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with respect to the strongest known risk factor for pulmonary fibrosis, a MUC5B promoter variant.MethodsFinnGen is a collection...

Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.

Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established. We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p < .005 was considered significant based on Bonferroni correction. Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p < .005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62-6.69), 3.23 (2.23-4.56), 2.95 (2.01-4.22), 1.94 (1.43-2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%). Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.

Investigation of Hereditary Cancer Predisposition Genes of Patients with Colorectal Cancer: Single-centre Experience.

To investigate the genetic causes of colorectal cancers (CRCs); and to determine the genotype-phenotype correlation. Descriptive study. Department of Medical Genetics, Diskapi Yildirim Beyazit Training and Research, Hospital, Ankara, Turkey, between January 2018 and January 2020. 59 cancer susceptibility genes of 41 patients, included in the study and diagnosed with CRC, were examined using next generation sequencing (NGS) technique. Statistical analysis of the possible relationships among the mutation carrier status of the patients and the parameters of gender, age at diagnosis, and family cancer history, were performed. The mean age at diagnosis of all CRC patients was 48.7 years (range 28-74). Mutations in MLH1, MSH6, CHEK2, PMS2 and MUTYH genes were detected in 10 patients (24.4%). The mean age at diagnosis of CRC was 46.2 years in those who carried the mutation, while it was 49.5 years in those without. Carriers and non-mutation carriers, when compared in terms of age at diagnosis, gender, family cancer history, no significant difference was observed. Genes that may cause susceptibility to cancer may play a role in the etiopathogenesis of the CRC. NGS-based multigene panels allow these genes to be detected in the patient and to identify an inherited cancer syndrome. Key Words: Colorectal cancer, Lynch syndrome, Hereditary cancer, Gene, Next generation sequencing.