ß-Hydroxybutyrate suppresses colorectal cancer.

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body ß-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.

The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals.

BACKGROUND: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. METHODS: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. RESULTS: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst. CONCLUSIONS: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.

APC and P53 mutations synergise to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with the majority of cases initiated by inactivation of the APC tumour suppressor. This results in the constitutive activation of canonical WNT pathway transcriptional effector ß-catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM which antagonises WNT-FZD receptor-ligand interactions. Here, we sought to evaluate the effects of NOTUM activity on CRC as a function of driver mutation landscape. DESIGN: Mouse and human colon organoids engineered with combinations of CRC driver mutations were used for Notum genetic gain-of-function and loss-of-function studies. In vitro assays, in vivo endoscope-guided orthotopic organoid implantation assays and transcriptomic profiling were employed to characterise the effects of Notum activity. Small molecule inhibitors of Notum activity were used in preclinical therapeutic proof-of-principle studies targeting oncogenic Notum activity. RESULTS: NOTUM retains tumour suppressive activity in APC-null adenomas despite constitutive ß-catenin activity. Strikingly, on progression to adenocarcinoma with P53 loss, NOTUM becomes an obligate oncogene. These phenotypes are Wnt-independent, resulting from differential activity of NOTUM on glypican 1 and 4 in early-stage versus late-stage disease, respectively. Ultimately, preclinical mouse models and human organoid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonisation of distal organs. CONCLUSIONS: Our findings that a single agent targeting the extracellular enzyme NOTUM is effective in treating highly aggressive, metastatic adenocarcinomas in preclinical mouse models and human organoids make NOTUM and its glypican targets therapeutic vulnerabilities in advanced CRC.

Outcomes of upper endoscopy screening in Lynch syndrome: a meta-analysis.

BACKGROUND AND AIMS: Lynch syndrome (LS) predisposes affected individuals to a high lifetime risk of malignancies, including colorectal, endometrial, gastric, and duodenal cancers. The role of upper GI (UGI) cancer screening in LS has been uncertain, but recent studies have evaluated its utility. METHODS: Databases were queried through December 2021 to identify studies that examined upper endoscopy screening in LS using EGD. Mantel-Haenszel pooled odds ratios and 95% confidence intervals (CIs) for outcomes were constructed using a random-effects model to identify pooled odds of endoscopic findings in persons with LS. Event rates for detection of gastric and duodenal cancers, high-risk lesions, and clinically actionable findings were calculated. Statistical heterogeneity was assessed using the I2 statistic. RESULTS: Nine studies were identified with 2356 LS patients undergoing approximately 7838 EGDs. In total, 47 LS-associated UGI cancers (18 gastric and 29 duodenal cancers), 237 high-risk lesions, and 335 clinically actionable findings were identified. The pooled event rate for detection of any UGI cancer, high-risk lesions, and clinically actionable findings during screening were .9% (95% CI, .3-2.1; I2 = 89%), 4.2% (95% CI, 1.6-10.9; I2 = 98%), and 6.2% (95% CI, 2.2-16.5; I2 = 99%), respectively. There was no difference between LS-associated gene and gastric or duodenal cancer detection. CONCLUSIONS: In LS, there is evidence that endoscopic screening detects UGI cancers, precancerous lesions, and other clinically actionable findings that favor its use as a part of cancer risk management in LS.

The Approach to Performance of Quality Upper Endoscopy in Lynch Syndrome (QUELS): An International Expert Statement.

Strong evidence demonstrates the protective benefit of frequent colonoscopy surveillance for colorectal cancer prevention in Lynch Syndrome (LS) and is endorsed by many guidelines. Until recently, the evidence supporting the utility of upper endoscopy [esophagogastroduodenoscopy (EGD)] for upper gastrointestinal (UGI) cancer surveillance was limited. Over the last 3 years, multiple studies have demonstrated that EGD surveillance in LS is associated with the detection of both precancerous lesions and early-stage UGI cancers. On the basis of the emerging favorable evidence derived from EGD surveillance programs, the 2022 National Comprehensive Cancer Network (NCCN) Guidelines for LS recommend UGI surveillance with EGD starting between age 30 and 40 years with repeat EGDs every 2 to 4 years, preferably in conjunction with colonoscopy, in all patients with a germline pathogenic variant (PV) in MLH1, MSH2, EPCAM, and MSH6 and, because of the lack of data, consideration in PMS2. Standardization of the approach to performing EGD surveillance in LS and reporting clinically actionable findings is requisite for both improving quality and understanding the cost efficiency and outcomes of patients undergoing EGD as a surveillance tool. Accordingly, the primary objective of this Quality of Upper Endoscopy in Lynch Syndrome (QUELS) statement is to articulate a framework for standardizing the approach to performing and reporting EGD findings in patients with LS by introducing emerging quality metrics. The recommendations presented herein were developed from available evidence and consensus-based expert opinion and provide a practical approach for clinicians applying EGD surveillance in accordance with the most recent and existing LS guidelines.

First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants.

BACKGROUND: Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV. METHODS: Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty. RESULTS: Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL. CONCLUSION: This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.

Summary of the experiences, knowledge, medical management, and family communication of monoallelic MUTYH carriers.

Germline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer- and polyposis-focused panels, as well as on broader pan-cancer panels. With up to 1%-2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross-sectional self-report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals.

Comparing telemedicine and in-person gastrointestinal cancer genetic appointment outcomes during the COVID-19 pandemic.

BACKGROUND: The study purpose is to compare outcomes associated with completion of genetic testing between telemedicine and in-person gastrointestinal cancer risk assessment appointments during the COVID-19 pandemic. METHODS: Data was collected on patients with scheduled appointments between July 2020 and June 2021 in a gastrointestinal cancer risk evaluation program (GI-CREP) that utilized both telemedicine and in-person visits throughout the COVID-19 pandemic, and a survey was administered. RESULTS: A total of 293 patients had a GI-CREP appointment scheduled and completion rates of in-person versus telemedicine appointments were similar. Individuals diagnosed with cancer and those with Medicaid insurance had lower rates of appointment completion. Although telehealth was the preferred visit modality, there were no differences in recommending genetic testing nor in the consent rate for genetic testing between in-person and telemedicine visits. However, of patients who consented for genetic testing, more than three times more patients seen via telemedicine did not complete genetic testing compared to those seen in-person (18.3% versus 5.2%, p = 0.008). Furthermore, telemedicine visits had a longer turnaround time for genetic test reporting (32 days versus 13 days, p < 0.001). CONCLUSIONS: Compared to in-person GI-CREP appointments, telemedicine was associated with lower rates of genetic testing completion, and longer turnaround time for results.

Colorectal Neoplasia in CDH1 Pathogenic Variant Carriers: A Multicenter Analysis.

INTRODUCTION: Germline variants in CDH1 are associated with elevated risks of diffuse gastric cancer and lobular breast cancer. It is uncertain whether there is an increased risk of colorectal neoplasia. METHODS: This was a retrospective analysis of colonoscopy outcomes in patients with germline CDH1 pathogenic/likely pathogenic variants. RESULTS: Eighty-five patients were included with a mean age of 46.9 years. Initial colonoscopy found adenomatous polyps in 30 patients (35.3%), including advanced adenomas in 9 (10.6%). No colorectal cancers were identified on index or subsequent colonoscopies (when available). DISCUSSION: CDH1 carriers have colorectal neoplasia identified at similar rates as in the general population. Despite potential difficulties after gastrectomy, colorectal cancer screening remains important in this population.

An updated counseling framework for moderate-penetrance colorectal cancer susceptibility genes.

PURPOSE: With the recent guideline change for individuals at average risk for colorectal cancer (CRC) to initiate colonoscopy at the age of 45 years, there is a need to provide an updated counseling framework for individuals with variants in moderate-penetrance CRC susceptibility genes. METHODS: Population age-specific incidence rates for CRC were obtained from the 2014-2018 US Surveillance, Epidemiology, and End Results Program cancer statistics. Average-risk multipliers derived from a systematic meta-analysis were used to calculate the 5-year and cumulative lifetime risks for specific genetic variants associated with a moderate risk for CRC: NM_007194.4(CHEK2):c.1100del (p.Thr367fs), NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr), NM_000038.6(APC):c.3920T>A (p.Ile1307Lys) and monoallelic MUTYH. RESULTS: When an individual at average risk would initiate colonoscopy at age 45 years, a CRC risk of 0.39% is reached. For CHEK2 1100delC, CHEK2 I157T, and APC I1307K heterozygotes, this same level of risk is reached (or nearly reached) by age 40 to 45 years. For individuals with a monoallelic MUTYH variant, the CRC risk is 0.46% by age 45 to 49 years, similar to individuals at average risk. CONCLUSION: These updated calculations support recommendations to initiate earlier colonoscopy surveillance for CHEK2 and APC I1307K germline variant heterozygotes. However, earlier surveillance is not indicated for individuals with monoallelic MUTYH germline variants in the absence of family history.

Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia.

Chimeric antigen receptor (CAR) T cells have radically improved the treatment of B cell-derived malignancies by targeting CD19. The success has not yet expanded to treat acute myeloid leukemia (AML). We developed a Sequentially Tumor-Selected Antibody and Antigen Retrieval (STAR) system to rapidly isolate multiple nanobodies (Nbs) that preferentially bind AML cells and empower CAR T cells with anti-AML efficacy. STAR-isolated Nb157 specifically bound CD13, which is highly expressed in AML cells, and CD13 CAR T cells potently eliminated AML in vitro and in vivo. CAR T cells bispecific for CD13 and TIM3, which are upregulated in AML leukemia stem cells, eradicated patient-derived AML, with much reduced toxicity to human bone marrow stem cells and peripheral myeloid cells in mouse models, highlighting a promising approach for developing effective AML CAR T cell therapy.

Patterns of germline and somatic testing after universal tumor screening for Lynch syndrome: A clinical practice survey of active members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer.

Clinical guidelines recommend universal tumor screening (UTS) of colorectal and endometrial cancers for Lynch syndrome (LS). There are limited guidelines for how to integrate germline testing and somatic tumor testing after a mismatch repair deficient (dMMR) tumor is identified. We sought to characterize current practice patterns and barriers to preferred practice among clinical providers in high-risk cancer programs. A clinical practice survey was sent to 423 active members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) with a follow-up survey sent to 103 clinician responders. The survey outlined clinical vignettes and asked respondents their preferred next test. The survey intended to assess: (1) the role of patient age and family history in risk assessment and (2) barriers to preferred genetic testing. Genetic test options included targeted germline testing based on dMMR expression, germline testing for LS, germline testing with a multigene cancer panel including LS, or paired tumor/germline testing including LS. In October 2020, 117 of 423 (28%) members completed the initial survey including 103 (88%) currently active clinicians. In April 2021, a follow-up survey was sent to active clinicians, with 45 (44%) completing this second survey. After selecting their preferred next germline or paired tumor/germline tumor test based on the clinical vignette, 39% of respondents reported wanting to make a different choice for the initial genetic test without any testing barriers. The proportion of respondents choosing a different initial genetic test was dependent on the proband's age at diagnosis and specified family history. The reported barriers included patient's lack of insurance coverage, patient unable/unwilling to self-pay for proposed testing, and inadequate tumor tissue. Responders reported insurance, financial constraints, and limited tumor tissue as influencing preferred genetic testing in high-risk clinics, thus resulting in possible under-diagnosis of LS and impacting potential surveillance and cascade testing of at-risk relatives.

Chemoprevention of Colorectal Cancer.

Although colorectal cancer (CRC) screening has reduced the incidence of and mortality from CRC, chemoprevention strategies have the potential to further reduce CRC incidence and mortality. Chemoprevention agents might be used for average-risk as well as high-risk groups, and to prevent CRC recurrence after therapy. CRC chemoprevention agents that have been studied include aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, statins, agents that target metabolic pathways, and vitamins and minerals. We review the prospect of chemoprevention of CRC, results from preclinical and human studies, challenges, and future directions.

COVID-19 related pancreatic cancer surveillance disruptions amongst high-risk individuals.

BACKGROUND: COVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain. METHODS: Analysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals. RESULTS: Amongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed. CONCLUSIONS: COVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling.

Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth.

TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.

Abnormal Pretreatment Liver Function Tests Are Associated with Discontinuation of Peptide Receptor Radionuclide Therapy in a U.S.-Based Neuroendocrine Tumor Cohort.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is effective for treating midgut neuroendocrine tumors (NETs); however, incorporation of PRRT into routine practice in the U.S. is not well studied. Herein we analyze the first year of PRRT implementation to determine tolerance of PRRT and factors that increase risk of PRRT discontinuation. MATERIALS AND METHODS: Medical records were reviewed and data were abstracted on all patients with NETs scheduled for PRRT during the first year of PRRT implementation at a U.S. NET referral center (August 2018 through July 2019). Logistic regression was used to identify factors associated with PRRT discontinuation. RESULTS: Fifty-five patients (56% male) were scheduled for PRRT over the study period. The most common primary NET location was small bowel (47%), followed by pancreas (26%), and 84% of the NETs were World Health Organization grade 1 or 2. The cohort was heavily pretreated with somatostatin analog (SSA) therapy (98%), non-SSA systemic therapy (64%), primary tumor resection (73%), and liver-directed therapy (55%). At the time of analysis, 52 patients completed at least one PRRT treatment. Toxicities including bone marrow suppression and liver function test (LFT) abnormalities were comparable to prior publications. Eleven patients (21%) prematurely discontinued PRRT because of toxicity or an adverse event. Pretreatment LFT abnormality was associated with increased risk of PRRT cancellation (odds ratio: 12; 95% confidence interval: 2.59-55.54; p < .001). CONCLUSION: PRRT can be administered to a diverse NET population at a U.S. NET referral center. Baseline liver function test abnormality increases the likelihood of PRRT discontinuation. IMPLICATIONS FOR PRACTICE: Peptide receptor radionuclide therapy (PRRT) can be successfully implemented at a U.S. neuroendocrine tumor (NET) referral center in a NET population that is diverse in tumor location, grade, and prior treatment history. Toxicity and adverse effects of PRRT are comparable to prior reports; however, 21% of individuals prematurely discontinued PRRT. Patients with baseline liver function test abnormalities were more likely to discontinue PRRT than patients with normal liver function tests, which should be taken into consideration when selecting treatment options for NETs.

Endoscopic Ultrasound Has Limited Utility in Diagnosis of Gastric Cancer in Carriers of CDH1 Mutations.

A total of 1%-3% of gastric cancers are related to hereditary syndromes, including hereditary diffuse gastric cancer syndrome (HDGC), which is characterized by pathogenic variants of the CDH1 gene and a high risk of lifetime incidence of both diffuse gastric cancer (DGC) and lobular breast cancer.1,2 HDGC is suspected in families with DGC or lobular breast cancer, especially when either is diagnosed before 50 years of age or when present in multiple family members.3 As individuals with HDGC have up to a 70% lifetime risk of DGC, prophylactic total gastrectomy is recommended.1,2 For patients who defer surgery, annual endoscopic surveillance via the Cambridge protocol is recommended, comprising biopsies of any lesions and a minimum of 30 random biopsies from the antrum, transitional zone, body, fundus, and cardia.1.

Upper Gastrointestinal Cancer Risk and Surveillance Outcomes in Li-Fraumeni Syndrome.

INTRODUCTION: To assess the upper gastrointestinal (UGI) cancer risk and surveillance outcomes in Li-Fraumeni syndrome (LFS). METHODS: Analysis of the International Agency for Research on Cancer database and a single-center adult LFS cohort. RESULTS: UGI cancer was present in 7.2% of families and 3.9% of individuals with a pathogenic/likely pathogenic TP53 mutation in International Agency for Research on Cancer; 29% occurred before age 30. Our institutional cohort had 35 individuals (31% of the LFS cohort) with 48 cumulative upper endoscopies; 3 (8.5%) individuals had concerning UGI findings. DISCUSSION: UGI cancer is observed in LFS. Upper endoscopy should be part of a comprehensive LFS surveillance program.

Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer.

PURPOSE: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied. METHODS: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers. RESULTS: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers. CONCLUSION: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.

Associations of sociodemographic and clinical factors with gastrointestinal cancer risk assessment appointment completion.

Cancer risk assessment services are important for patient care; effective use requires appropriate provider referral, accurate scheduling processes, and completed attendance at booked appointments. Sociodemographic and clinical factors associated with gastrointestinal cancer (GIC)-specific risk assessment appointments remain unstudied; therefore, we aimed to identify factors associated with appointment completion in a GIC risk assessment program at a tertiary academic center. Retrospective chart review was conducted on all patients scheduled for an appointment in the Gastrointestinal Cancer Risk Evaluation Program (GI-CREP) between January 2016 and December 2017. Data collected included demographic and clinical factors. Chi-square and Wilcoxon's rank-sum tests compared variables among patients based on the study outcome of whether a GI-CREP appointment was completed; marginal standardization was used to predict the standardized percentage of patients that had appointment completion. A total of 676 patients had a scheduled GI-CREP appointment; 32 individuals were excluded due to incomplete information or scheduling error, resulting in 644 patients available for final analysis. Our study population was predominantly female (61%), White (77%), and married (64%), had private healthcare insurance (76%), and lacked a personal history of cancer (60%). Referrals internal to the healthcare system were most common (77%), with gastroenterologists as the most frequent referring provider (42%). Seventy-five percent of scheduled individuals had appointment completion, while 25% of individuals did not. Independent predictors for an incomplete GI-CREP appointment included Medicaid insurance (OR 2.45, 95% CI 1.21-4.28, p = .01), self-identified Black race (OR 1.97, 95% CI: 1.20-3.25, p = .008), and personal history of cancer (OR 1.60, 95% CI 1.11-2.31, p = .01). These data highlight existing disparities in GIC risk assessment appointment completion associated with race, health insurance coverage, and medical status. Further studies of these areas are necessary to ensure equitable access to important GIC risk assessment services.