Cancer Risk Genes Research Articles

Gene-based burden tests of rare germline variants identify six cancer susceptibility genes.

Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.

Methylation, Gene Expression, and Risk Genotypes at the TERT-CLPTM1L Locus in Cervical Cancer.

The reverse transcriptase subunit of telomerase, TERT, is frequently activated in high-grade dysplasia and invasive cancers of the uterine cervix. Telomerase activation through hypomethylation of the TERT promoter holds promise as a biomarker for cervical cancer progression, however, specific CpG sites involved in cervical cancer risk remain to be fully defined. A recent genome-wide association study on cervical cancer identified genetic polymorphisms at 5p13.33 (close to TERT-CLPTM1L) but the underlying mechanisms are undetermined. We investigated 529 CpG sites within the TERT promoter region and 3 CpG islands nearby, and 21 CpG sites within CLPTM1L in 190 bisulfite-converted cervical tumor DNA samples from BioRAIDs (NCT02428842). We identified eight CpG sites within TERT intron 2 where methylation was significantly associated with the genotypes of cervical cancer risk variants rs27070 and rs459961 in cervical tumors after multiple testing correction (p < 9.4 × 10E-5). Hypermethylation at chr5:1289663 correlated with decreased TERT mRNA levels. In an independent series of 188 normal or dysplastic cervical tissues, rare alleles of rs27070 and rs459961 were associated with low basal CLPTM1L levels and with the absence of TERT mRNA in HPV-negative samples, consistent with their proposed role as protective variants for cervical cancer. HPV infection was associated with increased CLPTM1L and TERT levels. Collectively, our results provide a link between cervical cancer risk variants, methylation, and gene expression and implicate both TERT and CLPTM1L as genes modulated by genomic background and HPV infection during cervical cancer development.

Comprehensive analysis of the functional impact of single nucleotide variants of human CHEK2.

Loss of function mutations in the checkpoint kinase gene CHEK2 are associated with increased risk of breast and other cancers. Most of the 3,188 unique amino acid changes that can result from non-synonymous single nucleotide variants (SNVs) of CHEK2, however, have not been tested for their impact on the function of the CHEK2-enocded protein (CHK2). One successful approach to testing the function of variants has been to test for their ability to complement mutations in the yeast ortholog of CHEK2, RAD53. This approach has been used to provide functional information on over 100 CHEK2 SNVs and the results align with functional assays in human cells and known pathogenicity. Here we tested all but two of the 4,887 possible SNVs in the CHEK2 open reading frame for their ability to complement RAD53 mutants using a high throughput technique of deep mutational scanning (DMS). Among the non-synonymous changes, 770 were damaging to protein function while 2,417 were tolerated. The results correlate well with previous structure and function data and provide a first or additional functional assay for all the variants of uncertain significance identified in clinical databases. Combined, this approach can be used to help predict the pathogenicity of CHEK2 variants of uncertain significance that are found in susceptibility screening and could be applied to other cancer risk genes.

The Role of Health Literacy in Skin Cancer Preventative Behavior and Implications for Intervention: A Systematic Review.

Health literacy is essential for individuals to access, understand, and utilize information and services to inform health related decisions and actions. As one of the most diagnosed and preventable forms of cancer, skin cancer disease risk can be reduced through preventative behavior. Currently, there is no focused study looking specifically at health literacy and skin cancer. An understanding of how health literacy affects skin cancer-related preventive behaviors can improve current practices in skin cancer prevention. To systematically identify, synthesize, and summarize findings on the role of health literacy in skin cancers (including cutaneous squamous cell carcinoma, basal cell carcinoma, and melanoma), with a focus on preventive behaviors using studiesthat utilized quantifiablehealth literacy measurements. A literature search was performed by searching PubMed, Embase, PsycINFO, and CINAHL from inception until September 26, 2023 to identify cross-sectional, case-control, cohort, or randomized controlled studies that investigated the association between health literacy and skin cancer prevention and diagnosis. Health literacy levels varied across geographic regions, specific populations, and ethnicities. Most of the included studies found a positive association between higher health literacy and better skin cancer preventative behaviors. This included sun-protective behaviors such as: wearing sleeved shirts or shirts with collars, using gloves, covering head and face, limiting sun exposure, more sunscreen use, and less sunbathing or indoor tanning. Higher health literacy was associated with increased likelihood to engage in genetic testing and less family influence on health in one study which assessed determinants of interest in skin cancer genetic testing. Another study investigating family communication about skin cancer found that higher health literacy was associated with increased family communication regarding general cancer risk. One sun protection interventional education program was effective at increasing participants' knowledge, awareness of skin cancer risk, willingness to change sun protection, and use of sun protection, but results varied between ethnic groups. Skin cancer-related educational interventions can be effective in improving health literacy and potentially lessen the impact of skin cancer through positive behavior modification, early detection, and disease knowledge and awareness. Interventions need to be tailored to its target population to maximize effectiveness due to thevarying baseline of health literacy identified across different geographic and ethnic groups. Protocol Registration PROSPERO CRD42022340826.

Effectiveness of alcohol warning labels for at-risk groups and the general public: A policy-informing randomized experiment in Chile

ObjectiveThe World Health Organization recommends using health-risk warnings on alcoholic beverages. This study examines the impact of separate or combined warning labels for at-risk groups and the general population on alcohol purchase decisions. MethodsIn 2022, 7758 adults who consumed alcohol or were pregnant/lactating women (54.0 % female, mean age = 40.6 years) were presented with an online store's beverage section and randomly assigned to one of six warning labels in a between-subjects experimental design: no-warning, pregnant/lactating, drinking-driving, general cancer risk, combined warnings, and assorted warnings across bottles. The main outcome, the intention to purchase an alcoholic vs. non-alcoholic beverage, was examined with adjusted risk differences using logistic regressions. ResultsParticipants exposed to the general cancer risk warning decreased their alcoholic choices by 10.4 percentage points (pp.) (95 % CI [−0.139, −0.069], p < 0.001, OR = 0.561), while those in the pregnancy/lactation warning condition did it by 3.8 pp. (95 % CI [−0.071, −0.005], p = 0.025, OR = 0.806). The driving-drinking warning had no significant effect. Participants exposed to the combined warnings label, or the assorted warnings reduced alcohol purchase decisions by 6.1 pp. (95 % CI [−0.095, −0.028], p < 0.001, OR = 0.708) and 4.3 pp. (95 % CI [−0.076, −0.010], p = 0.011, OR = 0.782), respectively. Cancer warning outperformed other labels and was effective for subgroups such as pregnant/lactating women, young adults, and low-income individuals. ConclusionsGeneral cancer risk warnings are more effective at reducing alcohol purchase decisions compared to warning labels for specific groups or labels using multiple warnings. In addition to warning labels, other policies should be considered for addressing well-known alcohol-related risks (e.g., drinking and driving).

Биохимические показатели мышц судака из Рыбинского водохранилища и оценка риска их потребления

Fish, as a food component, is very beneficial for human health. It is rich in protein, valuable fatty acids, vitamins and minerals. However, when consuming it, there is a risk of toxic substances entering the human body that ac-cumulate in the tissues of aquatic organisms, for example, heavy metals. The purpose of the work is to determine the biochemical parameters in the muscles of pike perch from the reaches of the Rybinsk reservoir, which differ in anthropogenic load, and to assess the risks of human consumption of this species. The amount of water, dry matter, lipids, protein, minerals and carbohydrates in muscle tissue was determined using standard methods. To assess the threat to human health associated with the potential duration of exposure to heavy metals from walleye consumption, target and cumulative hazard ratios were calculated. The assessment of carcinogenic risk to human health was determined using the target and general cancer risk index. Calculated indicators were obtained based on data on the content of heavy metals in the muscles of pike perch, established earlier. In the muscles of pike perch specimens from the Sheksninsky and Volzhsky reaches, no significant differences between biochemical parameters were found. According to the ratio of protein and lipids in muscle tissue, the studied individuals belong to category A, and according to the amount of lipids – to fish with a low-fat content. The estimated dietary intakes for weekly intakes of heavy metals from pike perch meat was below the reference values. The target and total hazard coefficient turned out to be less than one, which indicates that there is no potential non-carcinogenic risk for humans when consuming pike perch meat. The target cancer risk indices for Cd, Pb, Al and Cr are within acceptable ranges. The total risk of developing cancer for these metals is more than 1 in 100,000.

Susceptibility gene mutations in germline and tumors of patients with HER2-negative advanced breast cancer

Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2−) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17–0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.

Association between rare pathogenic variants in established cancer risk genes and the diagnosis of single and multiple common cancers: A UK Biobank study.

10505 Background: Much of our understanding of cancer risk attributable to rare pathogenic variants (RPV) is derived from family-based and case-only cohort studies, which may be limited by ascertainment bias. We sought to identify associations between RPVs and cancer diagnoses in a large population-based study. Methods: We conducted a case-control study using the UK Biobank. We performed gene-based aggregate testing to examine the relationship between RPVs (defined as pathogenic or likely pathogenic variants) in 96 genes implicated in cancer risk and the diagnosis of 11 common cancers using the combined optimal unified sequence kernel association test (SKAT-O). Odds ratios (OR) and 95% confidence intervals (CI) were then calculated using Firth logistic regression. Results were adjusted for age, sex and genetic ancestry. Bonferroni-adjusted p-values were used to determine statistical significance. Variant pathogenicity was determined by American College of Medical Genetics criteria. Results: We identified 24 genes in which RPVs were statistically significantly associated with at least one of 11 common cancers among 183,626 individuals. The presence of an RPV in one of these 24 genes was associated with increased odds of one cancer (OR 1.8; 95% CI: 1.7-2.0), and multiple cancers (OR 2.5; 95% CI: 2.2-2.9). Conclusions: This large population-based study identified 24 established cancer risk genes in which RPVs were associated with common cancers. We identified both known and novel associations between cancer and RPVs. Some associations—i.e. renal/pancreas and MEN1—may be due to ascertainment and/or misclassification bias. We also show that individuals with RPVs in cancer risk genes not only have higher odds of one cancer diagnosis, but also multiple cancers.[Table: see text]

Universal germline testing for cancer susceptibility and actionable noncancer disorders among 19,842 patients: Initial findings from the City of Hope INSPIRE study.

10594 Background: Germline testing can be essential for risk stratification and therapeutic decision making. However, guideline-based testing misses ~50% of people with inherited cancer risk. To address this gap, we launched the INSPIRE study, offering universal germline testing (31 non-cancer and 154 cancer genes) to consented patients affected and unaffected with cancer. Methos: In 2020, we initiated a scalable in person/remote consent model without formal pre-test counseling. Consenting patients opted-in for one, both, or neither germline test. Research staff placed orders. Results were reviewed by a genetic counselor. Pathogenic/likely pathogenic (P/LP) and increased risk allele (IRA) results were disclosed by phone and scheduled for a genetic consult. Variant of uncertain significance (VUS)/negative results were disclosed by letter with a genetic consult available on request. Descriptive statistics and chi-squared tests evaluated a priori hypotheses regarding potential factors impacting genetic testing uptake and actionability. Results: We approached 26,920 patients: 22,115 (82%) enrolled, 1,830 (7%) declined, 2,975 (11%) deferred a decision. Consented patients opted for testing for germline cancer (21,871/ 99%), non-cancer (21,731/98%), or neither (160/0.7%). We have returned results to 19,842 patients: mean age 62, 69% female; 72% white, 14% Asian, 5% Black, 9% other; 24% Hispanic. Most patients (15,578) had cancer, 13% with multiple primaries. Among the 19,842 patients, 4,456 (23%) had at least one P/LP/IRA variant; 3,971 (20%) in a cancer risk gene and 589 (3%) in a non-cancer gene. Variant proportion by category was 1,466 (30%) high-penetrance, 847 (18%) moderate-penetrance, 1,127 (23%) low-penetrance, 1,282 (28%) recessive, and 34 (0.7%) preliminary evidence. Penetrance prevalence differed by sex: high penetrance variants were more common in females (33% vs. 27%; p=&lt;0.001) and moderate penetrance variants were more common in males (21% vs. 17%; p=0.003). 16,883 (85%) individuals carry at least one VUS. Conclusions: A scalable model to increase germline genetic testing among unselected cancer and unaffected patients across &gt;20 sites was highly feasible. A significant proportion of patients had actionable findings in cancer and non-cancer genes. Next steps include analyses to establish variant prevalence across groups, a longitudinal assessment of psychological outcomes and an evaluation of the impact of result disclosure on cost, patient care, and outcomes.

Smoking and pathogenic germline variants in patients with lung cancer.

8040 Background: Few studies have investigated the correlation of smoking history with pathogenic germline variants (PGVs) in patients diagnosed with lung cancer. With emerging opportunities for PGVs in DNA damage-repair (DDR) genes to inform precision therapies, we investigated the prevalence of PGVs in patients with lung cancer, stratified by smoking status. Methods: Germline genetic testing (GGT) (Invitae Corp.) and insurance claims (Komodo Healthcare MapTM) data were reviewed for 14,317 patients with an ICD code for lung cancer from 2015-2023 and hereditary cancer GGT of ≥ 10 genes. PGV rates were assessed overall, in DDR genes and in lung cancer related genes. Smoking history was defined by ICD codes. Number of genes tested varied per ordering clinician preference. Clinically actionable PGVs were defined as those associated with clinical management recommendations or trial eligibility per current standard of care guidelines. Chi-square tests were used with significance set to p &lt; 0.05. Results: The cohort was predominantly female (70.9%), white (65.7%), and over half had a history of smoking (57.1%). PGVs in 73 known cancer-risk genes were identified in 1,804/14,317 (12.6%) patients. Frequencies of PGV were 12.6% (1,026/8,175) in patients with smoking history compared to 12.7% (778/6,142) in those with no reported smoking history. There was no statistically significant difference in DDR gene, TP53, or EGFR PGV rates for patients with or without smoking history (p &gt; 0.05). Mean (SD) age of lung cancer diagnosis was significantly younger for patients with a history of smoking and DDR PGVs (61 (11)) compared to those with negative results (62 (12), p = 0.005). There was no significant difference in age of diagnosis between patients with no smoking history and DDR PGVs (60 (12)) and those with negative results (59 (13), p = 0.888). PGV rates by clinician-reported ancestry: Black/African-American, 9%; Asian or Pacific Islander, 11%; Hispanic, 12%; White, 13%. Among genes with &gt; 1,000 patients tested, PGVs were most common in BRCA2 (2.2%), CHEK2 (2.0%), ATM (1.6%), SPINK1 (1.6%), and BRCA1 (1.2%). Conclusions: In 14,317 patients with lung cancer, 12.6% had PGVs. There was no significant difference in enrichment of PGVs in DDR genes when patients were stratified by reported smoking history, suggesting the enrichment of these genes is independently associated with lung cancer. The age of onset for patients with DDR gene PGVs varied with smoking history, suggesting that risk conferred by these PGVs could be additive to smoking risk. These data reinforce prior studies supporting consideration of GGT for all patients with lung cancer, independent of age or reported smoking history.

Risk of secondary leukemias in patients with germline PALB2 pathogenic variants after chemotherapy exposure.

10598 Background: Pathogenic variants in germline cancer-predisposing genes (e.g. BRCA1/2, PALB2) confer an increased risk for solid tumors but not de novomyeloid malignancies. Many of these genes are related to DNA repair pathways. It is not known whether exposure to genotoxic therapy increases the risk of secondary hematologic malignancies. Here, we report the incidence of hematologic malignancy after a solid tumor diagnosis among patients with a germline PALB2 pathogenic variant. Methods: Patients were identified at the Massachusetts General Hospital Center for Cancer Risk Assessment among individuals seeking counseling and/or testing for hereditary cancer risk genes. Analyses were conducted using R version 4.2.2 “tidyverse” and “gtsummary” packages. Results: Of the 176 charts reviewed, 102 (57%) had a history of malignancy, of which 68 (66%) received genotoxic chemotherapy. The median follow-up after chemotherapy was 59mo (IQR =17,109). The most common malignancy and chemotherapy were breast cancer (n=76, 75%) and doxorubicin, cyclophosphamide, and paclitaxel (n = 21, 31%). We compared patient outcomes by receipt of chemotherapy or not. There was no difference in race, age at cancer diagnosis, surgery rate, treatment with hormone therapy, or secondary malignancy between the two groups (p &gt; 0.05). There was higher incidence of radiation treatment in those receiving genotoxic therapy compared to those who did not (65% vs 41%, p = 0.024), but no difference Gray or in follow up after radiation. Mortality in the genotoxic therapy group was 15% (n=10) vs. 9% (n=2) in the no genotoxic therapy group (p =0.33). Two subjects developed a hematologic malignancy (one case each of CLL and CML); both had prior chemotherapy and radiation exposure (Table). Conclusions: Cancer survivors with a germline PALB2 pathogenic variant and subsequent exposure to genotoxic therapy appear to have low risk of secondary hematologic malignancy. Although two subjects in the chemotherapy group developed leukemias, given the cases seen it is unlikely that these relate to the treatment exposure. Given the small sample size and retrospective nature of this study, more investigation is necessary to fully quantify the risk of therapy-related myeloid neoplasm in patients with germline PALB2 pathogenic variants. [Table: see text]

Abstract 6133: Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study

Abstract Background: Individuals in Tijuana have been identified as having multicultural and racial diversity. In Baja, California, Mexico, the prevalence and composition of cancer-predisposing germline variants in gynecologic cancers in Tijuana patients have not been evaluated. Aim and Methods: We aimed to evaluate the prevalence of pathogenic variants (PV) using a panel of 84 cancer-predisposing genes in breast, endometrial, and ovarian cancer from the General Hospital of Tijuana during the period of October 2021-October 2023, who were contacted and invited to participate in the evaluation. Pre- and post-test genetic counseling was given, and a questionnaire on personal, gyneco-obstetric, demographic, and lifestyle variables was conducted. Peripheral blood samples were obtained from all patients, and Next-generation sequencing (NGS) was performed on the Illumina commercial platform (Illumina, SD, USA). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG). Data was collected and descriptive statistics was applied to describe the characteristics of the population. Results: A total of 51 patients were included in our cohort; 98.0% (50/51) were females and 2% (1/51) were males. Among study participants (mean age ±standard deviation: 46.1 ± 10.9), 49% reported a personal history of cancer (25/51). Diagnosis of breast cancer was present in 80.3% of the patients (41/51), 9% (5/51) with ovarian cancer, and 3.9% (2/51) with endometrial cancer. Twenty-five percent of participants (13/51) harbor a PV or likely pathogenic (LP) variant distributed among four cancer-risk genes (BRCA1, BRCA2, ATM, and TP53). The distribution by gene in the patients with a PV was: BRCA1 in 61% (8/13), BRCA2 in 23% (3/13), TP53 in 8% (1/13), and ATM in 8% (1/13). Whereas 39.2% (20/51) had variants of uncertain clinical significance in genes with ambiguous or non-well-established risk association for cancer (BARD1, AXIN2, GPC3, NF2, CEBPA, MSH3, ALK, DIS3L2, CDC73, BAP1, RAD51D, NF1, MSH2, BLM, NBN, BRCA2, BARD1, RUNX1, RECQL4, EGFR, PALB2, CASR, and POLD1), and 35.2% (18/51) had negative results for both; PV and VUS. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of the gynecological cancer population in Tijuana, Mexico, consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary cancer and implement appropriate preventative programs. Disparities in access to testing have a significant impact on affected populations, due in part to underrepresentation in surveys of regional cancer etiology and in genomic variant databases. Citation Format: Jorge Alberto Guadarrama-Orozco, Paula Leal-Anaya, Eva Guerrero-Santillan. Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6133.

Abstract 7056: The role of aggressive prostate cancer risk gene ANO7 in prostate metabolism

Abstract Prostate cancer (PCa), the most common male cancer worldwide, causes about 10% of cancer related deaths in Europe. It has a wide spectrum of clinical behavior that ranges from decades of indolence to rapid metastatic progression and lethality. However, the molecular mechanisms involved in aggressive PCa progression are still poorly understood. In PCa the expression of anoctamin 7 (ANO7) has been shown to diminish as the cancer progresses. We have previously linked single-nucleotide polymorphisms in the ANO7 gene to the risk of aggressive prostate cancer and shown that in homozygous carriers of rs77559646, the variant leads to a total loss of ANO7 protein. ANO7 is a prostate-specific gene and is highly expressed in the luminal cells of the human prostate. ANO7 belongs to a family of calcium-activated chloride channels and select members of the anoctamin family have phospholipid scramblase activity. To uncover the cellular functions of ANO7 has proven challenging because ANO7 is not expressed in commercially available cell lines. To study the cellular functions of ANO7, we have generated stable prostate cell lines overexpressing ANO7 using lentiviral transduction. To gain information into what pathways ANO7 is affecting, we performed RNA-sequencing and gene set enrichment analysis. Interestingly, we found enrichment and downregulation of mitochondrial genes participating in oxidative phosphorylation in ANO7 cells. We assessed the mitochondrial function by measuring the oxidative phosphorylation capability of the cells and showed that the basal and maximal respiratory capacity of ANO7 overexpressing cells is indeed reduced. We also analyzed which of the three major mitochondrial fuels (glucose, glutamine and fatty acids) are not used as efficiently for oxidative phosphorylation in ANO7 overexpressing cells. The result proves that ANO7 cells are not utilizing glucose as effectively as control cells. Furthermore, the glycolysis stress assay showed that glycolytic capacity is increased in ANO7 overexpressing cells. In addition, a targeted metabolite screening revealed that aspartate is decreased in ANO7 cells, which again points towards perturbed mitochondrial function as aspartate is produced from a tricarboxylic acid cycle intermediate. By inhibiting the uptake of extracellular aspartate, we measured slower proliferation of ANO7 expressing cells, while inhibiting aspartate had no effect on control cells. Interestingly, preliminary results also suggest ANO7's involvement in regulation of phospholipid acyl chain length and saturation, offering insights into altered signaling observed in ANO7 cells. Taken together, this study shows for the first time that ANO7 rewires prostate mitochondrial functions and thus cellular metabolism, which could explain why it is beneficial for cancer cells to lose ANO7 expression. Citation Format: Christoffer Löf, Nasrin Sultana, Neha Goel, Gudrun Wahlström, Johanna Schleutker. The role of aggressive prostate cancer risk gene ANO7 in prostate metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7056.

Abstract B043: Feasibility of a traceback approach to facilitate genetic testing in the Genetic Risk Analysis in Ovarian Cancer (GRACE) study

Abstract Current guidelines state that genetic testing is clinically indicated for all individuals diagnosed with ovarian cancer (OC). Individuals with a prior diagnosis of OC who have not received genetic testing represent missed opportunities to identify individuals and their families with inherited variants that put them at a higher risk for cancer. The Genetic Risk Analysis in Ovarian Cancer (GRACE) study aims to address this significant healthcare gap using a “traceback testing” approach to identify individuals with a prior diagnosis of OC and to offer genetic risk information to them and their family members. Tumor registry data at two integrated health care systems (Kaiser Permanente Northwest and Colorado) identified cases of OC diagnosed 1998-2020 with no prior genetic testing or testing limited to BRCA1/2. The study aimed to provide genetic risk information to OC survivors as well as family members of patients who were deceased by leveraging stored pathology specimens for germline testing. Comprehensive genetic testing using a panel of 60 cancer risk genes was offered; genetic testing of the familial variant was offered to first- and second-degree relatives if a pathogenic or likely pathogenic variant was detected. A total of 317 eligible OC survivors were identified from tumor registry and medical record review; 79 (25%) consented for testing. Sixteen (21%) were found to carry a pathogenic or likely pathogenic variant in a cancer risk gene. Genes with pathogenic variants included BRCA1/2, BARD1, PMS2, DICER1, MUTYH, APC, and SDHB. Of 73 relatives eligible for cascade testing, 24 consented (≈ 33% uptake) and 9 were found to carry the familial variant. The uptake of testing by OC survivors and their relatives reflects a strong interest in genetic risk information. However, practical barriers must be addressed to provide genetic risk information to relatives of individuals who are deceased. The GRACE study can inform broad implementation of future traceback programs, providing information to prevent and mitigate the burden of ovarian and other hereditary cancers. Citation Format: Larissa L. White, Yolanda K. Prado, Ana A. Reyes, Jamilyn M. Zepp, Jennifer Sawyer, Mahesh Maiyani, Rachel Zucker, Sarah Vertrees, Alan F. Rope, Sheila Weinmann, Mika Caruncho, Sandra Soo-Jin Lee, Nora B. Henrikson, Heather Spencer Feigelson, Jessica Ezzell Hunter. Feasibility of a traceback approach to facilitate genetic testing in the Genetic Risk Analysis in Ovarian Cancer (GRACE) study [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B043.

CD38 gene polymorphism rs1130169 contribution to the increased gene expression and risk of colorectal cancer (pilot study).

Genetic variations in immune signaling genes may have regulatory effect on phenotypic heterogeneity of immune cells and immune functions, hence promoting tumor growth. We compared the frequencies of potentially functional CD38 gene single nucleotide polymorphisms rs1130169 (T > C) in 86 healthy controls and 90 colorectal cancer (CRC) cases to assess their association with cancer risk and CD38 gene expression. The association between allele C rs1130169 and CRC risk was observed. Allele C was also significantly correlated with an increased CD38 mRNA level and CD38 positive cell percentages in peripheral blood of healthy controls that could be a possible explanation for CRC risk in C allele carriers. In peripheral blood of CRC patients CD38 mRNA and serum soluble CD38 protein levels significantly differed from those in healthy controls. Calculation of the CD38 full-length and with the third exon deletion mRNA ratio in corresponding samples showed that the mRNA isoform ratio was significantly higher in CRC cases than in controls. It suggests that alternative splicing regulates elevation of CD38 full-length mRNA level in peripheral blood of CRC patients. We also have observed higher expression levels of CD38 full-length mRNA in peripheral blood of CRC patients with lymph node metastases compared to patients without metastases. This study indicated biological significance of rs1130169 variations that can alter differences in CRC risk by regulating CD38 gene expression.

A U.S. Cancer Center's Interactive Cancer Education Program for Spanish-Speaking Latinos during COVID-19 Pandemic

Cancer is a leading cause of mortality in U.S. Latino adults, a group with limited access to screening, higher rates of advanced disease, and prone to online misinformation. Our project created a Facebook Live social media video campaign on general cancer prevention, screening, risk, information, and resources, targeting Spanish-monolingual Latinos during the COVID-19 pandemic. Our project consisted of a hybrid video campaign model released to Facebook social media platform between October and December 2021, where pre-recorded videos or livestream interviews were delivered in Spanish with auto-generated, language-concordant subtitles to increase accessibility for the hearing-impaired. The videos featured fluent and ethnically concordant cancer topic experts. The content of these videos included introductions to the local academic cancer center as a resource, general cancer risk factors, screening, early detection and lifestyle modifications. The livestream interview format consisted of structured questions followed by time allocation for community members to ask questions in real time through Facebook Live comments. At interview conclusion, the recording was promptly uploaded within minutes for future replay. Performance metrics as reported by Facebook media analytics were collected, including total views, people reached, impressions, engagements, and shares. A total of 7 videos (4 pre-recorded, 3 livestream interviews) were released onto Facebook social media platform generating 2 hours, 55 minutes, and 32 seconds of playtime, 161 shares, 1000 engagements, 12,000 views, 19,000 people reached, and 34,000 impressions from October 2021 to January 2022. The video with the most views (4,400), people reached (7,100), and impressions (10,000) was the pre-recorded "The importance of a healthy diet in the prevention of cancer." The video with the least views (355), people reached (747), and impressions (904) was the livestream interview, "Cancer and nutrition." The pre-recorded videos accumulated more views (9,607) than the livestream interviews (2,707). The highest performing livestream interview by views, people reached, impressions, shares, and engagements were, "Cancer in the Latino community." Our project bidirectionally engaged Spanish-monolingual Latino community members and culturally/linguistically concordant cancer experts during the COVID-19 pandemic. Strengths included developing community partnerships and collaborations, providing evidence-based cancer information in a culturally responsive manner to a marginalized group, and presenting an academic cancer center as an accessible resource to its community. Programmatic efforts to improve our project include formalizing evaluation strategies to capture medical engagement via cancer screening and detection rates, delivering focused cancer discussions by disease sites, and further expanding audience base through mixed media formats.

Retrospective Cohort Study on the Limitations of Direct-to-Consumer Genetic Screening in Hereditary Breast and Ovarian Cancer.

Among cancer predisposition genes, most direct-to-consumer (DTC) genetic tests evaluate three Ashkenazi Jewish (AJ) founder mutations in BRCA1/2, which represent a small proportion of pathogenic or likely pathogenic variants (PLPV) in cancer predisposing genes. In this study, we investigate PLPV in BRCA1/2 and other cancer predisposition genes that are missed by testing only AJ founder BRCA1/2 mutations. Individuals were referred to genetic testing for personal diagnoses of breast and/or ovarian cancer (clinical cohort) or were self-referred (nonindication-based cohort). There were 348,692 participants in the clinical cohort and 7,636 participants in the nonindication-based cohort. Both cohorts were analyzed for BRCA1/2 AJ founder mutations. Full sequence analysis was done for PLPV in BRCA1/2, CDH1, PALB2, PTEN, STK11, TP53, ATM, BARD1, BRIP1, CHEK2 (truncating variants), EPCAM, MLH1, MSH2/6, NF1, PMS2, RAD51C/D, and 22 other genes. BRCA1/2 AJ founder mutations accounted for 10.8% and 29.7% of BRCA1/2 PLPV in the clinical and nonindication-based cohorts, respectively. AJ founder mutations accounted for 89.9% of BRCA1/2 PLPV in those of full AJ descent, but only 69.6% of those of partial AJ descent. In total, 0.5% of all individuals had a BRCA1/2 AJ founder variant, while 7.7% had PLPV in a high-risk breast/ovarian cancer gene. For non-AJ individuals, limiting evaluation to the AJ founder BRCA1/2 mutations missed >90% of mutations in actionable cancer risk genes. Secondary analysis revealed a false-positive rate of 69% for PLPV outside of non-AJ BRCA 1/2 founder mutations. DTC genetic testing misses >90% of BRCA1/2 PLPV in individuals of non-AJ ancestry and about 10% of BRCA1/2 PLPV among AJ individuals. There is a high false-positivity rate for non-AJ BRCA 1/2 PLPV with DTC genetic testing.

Engaging the community served: a U.S. Cancer Center's Facebook live cancer awareness campaign for Spanish-speaking Latinos during COVID-19.

Cancer is the leading cause of mortality in U.S. Latino adults, a group with limited access to screening, higher rates of advanced disease, and prone to online misinformation. Our project created a Facebook Live social media video campaign on general cancer prevention, screening, risk, information, and resources, targeting Spanish-monolingual Latinos during the COVID-19 pandemic. Content was delivered in Spanish by fluent, ethnically concordant topic experts and cancer center staff. Four prerecorded and three livestream interview videos were produced, amassing over 161 shares, 1,000 engagements, 12,000 views, 19,000 people reached, and 34,000 impressions in a span of four months. Strengths of this project included developing community partnerships and collaborations, providing evidence-based cancer information in a culturally responsive manner to often-excluded community members during COVID-19 pandemic, and presenting our cancer center as an accessible resource to the wider community. Future directions include formalizing evaluation strategies to capture medical engagement via cancer screening and detection rates, delivering focused cancer discussions by disease sites, and further expanding audience base through mixed media formats.

Most people share genetic test results with relatives even if the findings are normal: Family communication in a diverse population

PurposeWith increasing utilization of genetic testing, sharing genetic information can become part of general family health communication while providing biological relatives with important information about their own genetic risk. Importantly, little is known about motivations for and barriers to family communication of genetic information in historically underserved populations. MethodsUsing mixed methods, we explored patient experiences with family communication in a study population of English- and Spanish-speaking adults aged 18 to 49 years, enriched for participants from historically underserved backgrounds. Risk screening for hereditary cancer guided genetic testing for cancer risk genes and other medically actionable findings. ResultsMost participants overall (91%), including most with normal findings (89%), shared or planned to share their results with relatives. Common motivations for sharing results were to give relatives information about their genetic risk and because the participant thought the results were interesting. Reasons for not sharing were limited contact with relatives, perceptions of limited clinical utility for relatives, and concern that discussion of genetic information was stigmatized or taboo. ConclusionResults demonstrate high rates of sharing genetic information, indicate motivations for sharing go beyond facilitating genetic testing for relatives, and suggest general willingness to share genetic information as part of family health communication.

The Impact of Germline Alterations in Appendiceal Adenocarcinoma.

More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch syndrome. We defined the clinical and molecular impact of heritable alterations in appendiceal adenocarcinoma to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants. We performed an integrated germline and somatic molecular analysis for patients with confirmed appendiceal adenocarcinoma. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer risk genes and 505 genes for somatic mutation profiling. We defined the cooccurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated. Twenty-five of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and appendiceal adenocarcinoma-specific survival were similar in patients with or without germline variants. Most (92%, N = 23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However, only one patient tumor exhibited APC-mediated WNT signaling dysregulation: a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch syndrome, yet their cancers were microsatellite-stable. Germline variants are likely incidental without a contributory driver role in appendiceal adenocarcinoma. Appendiceal adenocarcinoma screening in patients with germline variants is not clearly merited.