Risk Of Other Cancers Research Articles

Postoperative ileus in obstetric and gynecological practice: a prospective solution to the problem

Proton pump inhibitors (PPIs) are the undisputed leaders in the treatment of acid-related diseases. In actual clinical practice, the use of PPIs has been growing exponentially in recent decades. For a long time, PPIs were considered completely safe drugs for both short-term and long-term use. However, modern clinical guidelines and reviews and meta-analyses of the current decade on the safety of PPI use note that when prescribing PPIs in large doses for a long period, the possibility of developing numerous side effects should be taken into account. We searched the PubMed and Scopus information databases for publications on the safety of PPI use, including sources up to 12/01/2023. The review addresses issues of drug interactions between PPIs and chemotherapeutic drugs, which should certainly be taken into account in real clinical practice. In addition, recent reviews and meta-analyses have examined side effects of long-term PPI use, such as increased risk of infection (Clostridium difficile infection, community-acquired pneumonia), electrolyte disturbances, kidney damage, increased risk of hip, wrist and spine fractures; increased cardiovascular risk and a number of others, which can also have an adverse effect on the prognosis of cancer patients. The risk of developing gastric cancer with long-term PPI therapy can be considered as a likely side effect, since their association with PPI use is not denied or questioned in recent reviews and meta-analyses. There is still uncertainty regarding the increased risk of other cancers, since there are publications that do not confirm their association with PPI use. However, the presented review, despite a number of contradictions, allows us to conclude that the increased cancer risk with long-term use of PPIs is real and must be taken into account when prescribing PPIs for a long term.

Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequence data

BackgroundDeleterious germline variants in ATM and CHEK2 have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear.MethodsCancer associations for coding variants in ATM...

Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families

PurposeFemale CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether CHEK2 c.1100delC is associated with an increased risk for other cancers within these families. MethodsIncluding 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10,000 person-years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onward. Attained-age analyses were performed for sites in which significant increased risks were found. Considering the study design, we primarily focused on cancer risk in women. ResultsWe found significant increased risks of colorectal cancer (CRC; SIR = 1.43, 95% CI = 1.14-1.76; AER = 1.43) and hematological cancers (SIR = 1.32; 95% CI = 1.02-1.67; AER = 0.87). CRC was significantly more frequent from age 45 onward. ConclusionA significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some CHEK2 c.1100delC families might benefit from this surveillance as well; however, further research is needed to determine who may profit from this additional colorectal surveillance.

Common skin cancers and their association with other non-cutaneous primary malignancies: a review of the literature.

It has long been recognized that a history of skin cancer puts one at risk for additional primary skin cancers. However, more variable data exists for the risk of developing a non-cutaneous primary cancer following a diagnosis of skin cancer. The data are most variable for Basal Cell Carcinoma (BCC), the most common and least aggressive type of skin cancer. While early studies imply that BCC does not impart a larger risk of other primary non-cutaneous cancers, more recent studies with larger populations suggest otherwise. The cancers most significantly associated with BCC are lip, oropharyngeal, and salivary gland cancer. There is also burgeoning evidence to suggest a link between BCC and prostate, breast, and colorectal cancer, but more data are needed to draw a concrete conclusion. Squamous Cell Carcinoma (SCC), the second most common type of skin cancer, has a slightly more defined risk to other non-cutaneous primary malignancies. There is a notable link between SCC and non-Hodgkin's lymphoma (NHL), possibly due to immunosuppression. There is also an increased risk of other cancers derived from squamous epithelium following SCC, including oropharyngeal, lip, and salivary gland cancer. Some studies also suggest an increased risk of respiratory tract cancer following SCC, possibly due to shared risk factors. Melanoma, a more severe type of skin cancer, shows a well-defined risk of additional primary non-cutaneous malignancies. The most significant of these risks include NHL, thyroid cancer, prostate cancer, and breast cancer along with a host of other cancers. Each of these three main skin cancer types has a profile of genetic mutations that have also been linked to non-cutaneous malignancies. In this review, we discuss a selection of these genes to highlight the complex interplay between different tumorigenesis processes.

Molecular Mechanism of Breast Cancer and Predisposition of Mouse Mammary Tumor Virus Propagation Cycle.

Over the past few decades, women have been troubled by grave diseases such as breast cancer, which are biologically and molecularly classified as hereditary diseases. Even though the risk of other cancers is relatively different and the downstream pathway of genetic mutation differs from breast cancer, the continued transformation of genes such as BRCA1 and BRCA2 leads to breast cancer malignancy. Notably at the molecular level, a parallel connection between the normal growth of breast and the progression of mammary cancer where the breast cancer stem cells play a crucial role in the advancement of mammary carcinoma. Arguably, several significant signaling pathways, for instance, ER signaling, HER2 signaling, and Wnt signaling control the typical breast development as well as breast stem cells, thereby cell proliferation, cell differentiation, and cell motility are involved. Incidentally, the Mouse Mammary Tumor Virus (MMTV) is notable among the unexplained viral components influenced by virus-corrupting mammary carcinomas. According to the genesis, MMTV proviral DNA is integrated into mammary epithelial cells, and genomic lymphoid cells during viral replication and triggers the progression of cellular oncogenesis. This overview reveals the deadliest theories on breast cancer, molecular mechanisms, and the MMTV transmission cycle. To establish prevention therapies that are both acceptable and efficacious, addressing apprehensions related to the toxicity of these interventions must be a preliminary hurdle to overcome.

Abstract PO3-24-06: Integrative genomic and CRISPR screen analysis identifies synthetic viability interactions in BRCA1/2 cancers

Abstract Background Pathogenic BRCA1 and BRCA2 (BRCA1/2) germline mutations contribute to hereditary breast cancer and are linked with increased risk of other cancers. Paradoxically, bi-allelic inactivation of BRCA1/2 (bBRCA1/2) is embryonically lethal. Although TP53 loss can at least in part mitigated the deleterious impact of Brca1 deficiency in mice, this is insufficient in human cells to compensate for decreased proliferative capacity. What other compensatory mechanisms facilitate oncogenesis remains unclear. Methods We performed an integrative analysis of cancer genomes from bBRCA1/2 tumors and CRISPR/Cas9 screens from cellular models to identify novel gene candidates that facilitate synthetic viability. First, we analyzed cancer genomes from ovarian and breast cancer derived from TCGA and identified genomic loci, which were enriched for recurrent copy number alterations (CNAs) in bBRCA1/2 tumors. We subsequently identified genes from these CNA loci that had corresponding changes in gene expression. Then, we used high-throughput genome-wide CRISPR/Cas9 knockout screens in BRCA1/2−/− cell lines (BRCA1−/- in RPE1 cells, BRCA2−/− in DLD1 cells) to identify which of these genes increased cell proliferation in vitro. Lastly, we experimentally validated these synthetic viable interactions using an orthogonal MCF12a system to evaluate changes in colony formation with a clonogenic cell survival assay. Results In human cancer genomes, we identified that bBRCA1/2 tumors harbored recurrent large-scale genetic deletions significantly more frequent than histologically matched control tumors. We identified 148 cytobands (23 distinct genomic loci) frequently deleted in bBRCA1/2 ovarian cancers (N=92), and 90 cytobands (15 distinct genomic loci) in bBRCA1/2 ER+ breast cancers (N=30). Subsequent computational analysis of gene expression data identified transcriptionally decreased genes in the frequently deleted loci. Cross-referencing with CRISPR/Cas9 screens in BRCA1/2−/− cells, we ultimately identified 277 and 218 genes that were altered in human tumors and putatively enhanced viability in BRCA1/2-null models but not in isogenic wild-type cell lines in BRCA1 and BRCA2 models, respectively. We subsequently selected 17 genes that either increased viability in BRCA1, BRCA2, or both contexts for experimental validation. Of these, about 40% (7 of 17) were experimentally validated (RIC8A, GNA12, ATMIN, IPO7, ATXN2, KDM1A, and NUP98) and had evidence of synthetic viability in this cellular context. Interestingly, RIC8A and GNA12 interact with each other, are both involved in G protein-coupled signaling pathway, and are synthetically viable with both BRCA1−/− and BRCA2−/− cells. In a re-analysis of a recently published genomic dataset on metastatic breast cancer, we found that homologous recombination deficient tumors developed additional loss of function mutations in RIC8A in the metastatic setting. Conclusions This study provides insights into the oncogenesis of BRCA1/2 malignancies and describes a high-throughput framework to identify synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers. Citation Format: Yingjie Zhu, Xin Pei, Ardijana Novaj, Jeremy Setton, Fatemeh Derakhshan, Pier Selenica, Niamh McDermott, Sonali Sinha, Atif Khan, Simon Powell, Jorge Reis-Filho, Nadeem Riaz. Integrative genomic and CRISPR screen analysis identifies synthetic viability interactions in BRCA1/2 cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-06.

Abstract 6144: A polymorphic TERT tandem repeat creating an expandable intronic G4 quadruplex is associated with TERT expression, relative leukocyte telomere length and cancer risk

Abstract A multi-cancer GWAS region at human chromosome 5p15 encodes telomerase reverse transcriptase (TERT). One of the GWAS signals is rs10069690-T, which creates an alternative intron 4 splicing site, co-producing full-length (FL) and truncated INS1b transcript for dominant-negative telomerase-nonfunctional TERT. A variable number tandem repeat (VNTR6-1, 38 bp repeat unit) within intron 6 remains uncharacterized in relation to GWAS signals and cancer risk. We hypothesized that VNTR6-1 might contribute to GWAS signals represented by rs10069690. We scored VNTR6-1 and rs10069690 in short-read WGS data (n=3,202) from the 1000 Genomes Project with a machine learning model using the GLMnet engine, and in phased long-read assemblies (n=544). We defined two VNTR6-1 groups: Short (24-27 copies) and Long (40.5-66.5 copies); the VNTR6-1-Long group was preferentially linked with rs10069690-T compared to C allele (p=2.53E-13). We show that haplotypes of rs56345976 and rs33961405 alleles can predict VNTR6-1 groups. We imputed VNTR6-1 in UK Biobank controls (n=351,634), PLCO cancer cases and controls (n=100,445), and African Burkitt lymphoma cases (aBL, n=79). Functional studies in aBL tumors revealed a suggestive association between reduced total TERT expression, rs10096690-T (p=0.035) and VNTR6-1-Long (p=0.053). VNTR6-1 forms a G4 quadruplex structure sensitive to G4 stabilizing ligands, altering the ratio between FL-TERT and a dominant-negative TERT-β isoform in isogenic cell lines with/without VNTR6-1. In GTEx and TCGA, several metrics related to cell proliferation and telomerase activity correlated positively with FL-TERT expression and negatively with TERT-β expression. We created a composite marker with 0, 1 or 2 copies of the FL-TERT-associated haplotype (VNTR6-1-Short/rs10069690-C) to capture the effects of these variants that negatively affect TERT expression and telomerase activity. The number of copies of the VNTR6-1/rs10069690 haplotype was associated with relative leukocyte telomere length in UK Biobank controlling for sex and age (β=0.049, p=8.75E-78). This marker was also associated with a reduced risk of bladder and prostate cancer but an increased risk of breast, endometrial, ovarian, thyroid cancer, and glioma in PLCO. Our findings reveal that germline variants VNTR6-1-Long/rs10069690-T underlie the multi-cancer GWAS signal and jointly decrease TERT expression and telomerase activity, potentially reducing the risk of some cancers by limiting cell growth. However, decreased telomerase activity could deregulate stem cell-driven tissue regeneration and genome integrity, increasing the risk of other cancers. Our findings unveil novel mechanisms of cancer susceptibility and propose therapeutic avenues for targeting TERT isoform ratios to modulate telomerase activity and its cellular effects. Citation Format: Oscar Florez-Vargas, Michelle Ho, Max Hogshead, Chia-Han Lee, Kaitlin Forsythe, Brenen Papenberg, Kristine Jones, Wen Luo, Kedest Teshome, Cornelis Blauwendraat, Mikhail Kolmogorov, Stephen J. Chanock, Mitchell J. Machiela, John Schneekloth, Shahinaz Gadalla, Sharon A. Savage, Sam M. Mbulaiteye, Ludmila Prokunina-Olsson. A polymorphic TERT tandem repeat creating an expandable intronic G4 quadruplex is associated with TERT expression, relative leukocyte telomere length and cancer risk [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 6144.

CHEK2 Founder Variants and Thyroid Cancer Risk.

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

Telomere length and cancer risk: finding Goldilocks.

Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.

Prédispositions génétiques au cancer bronchopulmonaire: Genetic predisposition to lung cancer

While thoracic oncologists are familiar with somatic pathogenic variants in lung cancer, they only have limited knowledge of genetic predisposition to the disease. Genetic predisposition refers to the presence of a germline pathogenic variant (present in the patient’s DNA) that is the main cause of the lung cancer diagnosis. This review article presents the major lung cancer predisposition syndromes, such as EFGR-associated syndrome and Li-Fraumeni. Identifying a genetic predisposition has consequences for the patient, for whom long-term lung cancer screening is warranted. Additionally, if the risk of other cancers is increased, as in Li-Fraumeni syndrome, the patient is offered multiorgan screening, including annual whole-body MRI. There are also implications for the family, as it then becomes necessary to identify other carriers among relatives, and offer them personalized surveillance.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Cancer risk and temporal trends in people with HIV during a quarter of a century – a nationwide population-based matched cohort study

Background It is important to understand current trends in cancer risk among people living with HIV (PLWH) to improve outcomes and to commission and delivery appropriate services. Methods Nationwide, population-based, matched cohort study on all adult PLWH treated at Danish HIV health care centres since 1 January 1995 and a comparison cohort, randomly selected from the background population and matched on sex and date of birth. Results We included 6327 PLWH and 63,270 individuals in the comparison cohort − 74% were men and median age was 37 (interquartile range: 30–46). For both smoking related cancers, virological cancers and other cancers, incidence was substantially higher in the first year of observation for PLWH than for the remaining observation period. The risk of smoking related cancer remained stably increased throughout the observation period, whereas the relative risk of virological cancers decreased, especially in the first year of follow up. Finally, the risk of other cancers for PLWH decreased to a level below that of the background population during the study period. Conclusion The fact that the risk of other cancers was probably not higher among PLWH than in the comparison cohort is encouraging, as the excess risk of virological and smoking related cancers is potentially preventable by timely treatment of HIV and smoking cessation.

Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations.

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.

Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls

Familial adenomatous polyposis (FAP) is a hereditary disorder that predisposes patients to colorectal cancer (CRC). Prophylactic colectomy has greatly reduced the risk of CRC. However, new associations between FAP and the risk of other cancers have subsequently emerged. In this study, we assessed the risk of specific primary and secondary cancers among patients with FAP compared with matched controls. All known patients with FAP up until April 2021 were identified in the nationwide Danish Polyposis Register and paired with 4 unique controls matched by birth year, sex, and postal code. The risk of overall cancers, specific cancer types, and risk of a second primary cancer was assessed and compared with controls. The analysis included 565 patients with FAP and 1890 controls. The overall risk of cancer was significantly higher for patients with FAP than for controls (hazard ratio [HR], 4.12; 95% confidence interval [CI], 3.28-5.17; P < .001). The increased risk was mainly due to CRC (HR, 4.61; 95% CI, 2.58-8.22; P < .001), pancreatic cancer (HR, 6.45; 95% CI, 2.02-20.64; P= .002), and duodenal/small-bowel cancer (HR, 14.49; 95% CI, 1.76-119.47; P= .013), whereas no significant difference was observed for gastric cancer (HR, 3.29; 95% CI, 0.53-20.23; P= .20). Furthermore, the risk of a second primary cancer was significantly higher for patients with FAP (HR, 1.89; 95% CI, 1.02-3.50; P= .042). Between 1980 and 2020, the risk of cancer among patients with FAP decreased by ∼50%. Despite an absolute reduction in the risk of developing cancer among patients with FAP, the risk remained significantly higher than for the background population due to colorectal, pancreatic, and duodenal/small-bowel cancers.

Familial aggregation of early‐onset cancers in early‐onset breast cancer families

The risk of early-onset (EO) breast cancer is known to be increased in relatives of EO breast cancer patients, but less is known about the familial risk of other EO cancers. We assessed familial risks of EO cancers (aged ≤40 years) other than breast cancer in 54 753 relatives of 5562 women with EO breast cancer (probands) by using a population-based cohort from Finland. Standardized incidence ratios (SIRs) and 95% confidence intervals (CI) were estimated by using gender-, age- and period-specific cancer incidences of the general population as reference. The risk of any cancer excluding breast cancer in first-degree relatives was comparable to population cancer risk (SIR 0.99, 95% CI: 0.84-1.16). Siblings' children of women with EO breast cancer were at an elevated risk of EO testicular and ovarian cancer (SIR = 1.74, 95% CI: 1.07-2.69 and 2.69, 95% CI: 1.08-5.53, respectively). The risk of EO pancreatic cancer was elevated in siblings of the probands (7.61, 95% CI: 1.57-22.23) and an increased risk of any other cancer than breast cancer was observed in children of the probands (1.27, 95% CI: 1.03-1.55). In conclusion, relatives of women with EO breast cancer are at higher familial risk of certain discordant EO cancers, with the risk extending beyond first-degree relatives.

Abstract P6-02-06: Implementation and outcomes of population-based hereditary cancer testing across a diverse multi-location breast imaging center

Abstract Introduction: Up to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes, and genetic testing at the time of breast imaging may identify more patients who could benefit from enhanced surveillance and/or risk reduction interventions. Data are limited on the yield of PVs in the setting of a breast imaging center. Hypothesis: Hereditary cancer gene screening at the time of breast imaging may identify patients and families who could benefit from cancer risk management. Methods: This retrospective cohort study included de-identified clinical data and commercial multi-cancer panel (40 genes) test results from sequential patients undergoing breast imaging at 3 centers in Texas over a 17 month period. Patients of providers who elected not to participate were excluded from this cohort. PV prevalence was quantified and stratified based on level of risk for BC and other cancers: high-risk (relative risk &amp;gt;4) for BC, moderate-risk (relative risk 2-4) for BC, high-risk for other cancers, moderate-risk or undefined risk for other cancers. Results: A total of 1,943 patients undergoing breast imaging chose to have genetic testing during the study period. Median age was 66 yrs (range 18-89 yrs). Self-reported race/ethnicity: White (34.5%), Hispanic (27.7%), African American (17.9%), Asian (4.5%), Ashkenazi Jewish (0.6%), Other (3.5%) and unreported (13.0%). A personal history of breast or ovarian-related cancers was reported in 4% (n=78) and a family history of these cancers was reported in 38.9% (n=835) of patients. Among those tested, 44/1,943 (2.3%) had one or more PV in an autosomal dominant clinically actionable gene, further categorized as: high-risk BC gene (36.3%) moderate-risk BC gene (34.1%), high-risk gene for other cancers (13.6%), moderate-risk gene for other cancers (6.8%), or uncertain level of increased risk for other cancers (9.1%). A heterozygous PV in an autosomal recessive gene was present in 31/1943 (1.6%) patients. Overall, 354/1943 (18.2%) patients met current NCCN guidelines for hereditary breast and ovarian cancer (HBOC) gene testing. Only 15/44 (34.1%) patients with an autosomal dominant clinically actionable PV met current NCCN guidelines for HBOC testing. Genetic education was provided to 20/44 (45.5%) patients by lab-based genetic counselors and/or the patient’s healthcare provider. Conclusions: Offering genetic testing in a diverse breast imaging center population was associated with a significant yield (4%) of both dominant and recessive clinically actionable PVs. Of note, almost 2/3 of PVs in hereditary cancer genes were among women who did not meet NCCN testing guidelines. Identification of a PV enables risk stratification, cascade testing of family members and an opportunity to access enhanced surveillance and risk reduction interventions. Citation Format: Darlene Miltenburg, Laura Westbrook, Vivienne Souter, Melissa K. Maisenbacher, Katherine L. Howard, Youbao Sha, Maygol Yavari, Nicholas Kypraios, Sofia Hurtado, Mayra Rodas, Jeffrey N. Weitzel. Implementation and outcomes of population-based hereditary cancer testing across a diverse multi-location breast imaging center [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 P6-02-06.

Molecular Genetic Characteristics of FANCI, a Proposed New Ovarian Cancer Predisposing Gene.

FANCI was recently identified as a new candidate ovarian cancer (OC)-predisposing gene from the genetic analysis of carriers of FANCI c.1813C>T; p.L605F in OC families. Here, we aimed to investigate the molecular genetic characteristics of FANCI, as they have not been described in the context of cancer. We first investigated the germline genetic landscape of two sisters with OC from the discovery FANCI c.1813C>T; p.L605F family (F1528) to re-affirm the plausibility of this candidate. As we did not find other conclusive candidates, we then performed a candidate gene approach to identify other candidate variants in genes involved in the FANCI protein interactome in OC families negative for pathogenic variants in BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, and FANCI, which identified four candidate variants. We then investigated FANCI in high-grade serous ovarian carcinoma (HGSC) from FANCI c.1813C>T carriers and found evidence of loss of the wild-type allele in tumour DNA from some of these cases. The somatic genetic landscape of OC tumours from FANCI c.1813C>T carriers was investigated for mutations in selected genes, copy number alterations, and mutational signatures, which determined that the profiles of tumours from carriers were characteristic of features exhibited by HGSC cases. As other OC-predisposing genes such as BRCA1 and BRCA2 are known to increase the risk of other cancers including breast cancer, we investigated the carrier frequency of germline FANCI c.1813C>T in various cancer types and found overall more carriers among cancer cases compared to cancer-free controls (p = 0.007). In these different tumour types, we also identified a spectrum of somatic variants in FANCI that were not restricted to any specific region within the gene. Collectively, these findings expand on the characteristics described for OC cases carrying FANCI c.1813C>T; p.L605F and suggest the possible involvement of FANCI in other cancer types at the germline and/or somatic level.

Risk of Non-cutaneous Cancers in Individuals with Basal Cell Carcinoma: A Population-based Cohort Study.

Evidence of the association between a personal history of basal cell carcinoma and the risk of non-cutaneous malignancies is conflicting. The aim of this study was to retrospectively clarify the risk of non-cutaneous cancers in individuals with basal cell carcinoma using nationwide Finnish registry data for 96,304 patients and 394,503 randomly selected population controls. In this study, individuals with basal cell carcinoma have an increased risk of other cancers (odds ratio (OR) 1.38; 95% confidence interval (95% CI) 1.36-1.40). The risk was most prominent for lip cancer (OR 5.29; 95% CI 4.50-6.21), mycosis fungoides (OR 3.13; 95% CI 2.31-4.23) and soft tissue cancers (OR 2.77; 95% CI 2.43-3.16). In age-adjusted model, men had higher risk of cancers overall compared with women (p < 0.05). In conclusion, the study found increased overall cancer risk among patients with basal cell carcinoma compared with randomly selected population controls.

S2483 Combined Endoscopic Ultrasound and Endobronchial Ultrasound to Stage and Diagnose Non-Small Cell Lung Cancer in the Setting of CLL/SLL

Introduction: Chronic lymphocytic leukemia and small lymphocytic lymphoma is an indolent leukemia with a variable course affecting 4-5 per 100,000 population in the US/year. Patients with CLL are at an increased risk of other cancers, including lung cancer. Endosonography can be used to diagnose and stage suspected lung cancer. EUS-FNA can be used not only for cancers of the gastrointestinal tract, but can also be utilized as an alternative to surgical staging for lung cancer, such as mediastinoscopy. We present a case of lung cancer that was staged and diagnosed via combined endoscopic and endobronchial ultrasound with biopsies. Case Description/Methods: A 78-year-old man with a history of CAD, prostate cancer in remission and chronic lymphocytic leukemia (CLL) presented to the ED from his scheduled bronchoscopy for a right hilar mass with pleural effusion and 2 weeks of progressive dyspnea. During hospitalization, gastroenterology was consulted for a EUS-FNA for the patient’s subcarinal node seen on imaging and pulmonology consulted for an EBUS due to this left hilar mass with mediastinal lymph nodes. EBUS revealed an extrinsic compression of the RLL and RUL and EBNA performed on 3 mediastinal lymph nodes. EUS-FNA showed 3-4 cm conglomeration of well-defined, round and hypoechoic lymph nodes in the subcarinal space with fine needle biopsy. Final pathology of these specimens diagnosed stage III non-small cell lung cancer. Discussion: EUS can be utilized to reach the left and lower paraesophageal structures as well as structures below the diaphragm. EUS-FNA added tissue samples from his subcarinal lymph nodes that supported the correct diagnosis of non-small cell lung cancer. Due to the diagnosis of non-small cell lung cancer from his combined EBUS/EUS-FNA, the patient did not require surgical staging. Our case demonstrates the need use of a combined EUS/EBUS approach to diagnose a patient with CLL with non-small cell lung cancer. Second malignancies in CLL cases are rare and approximately 2% of patients with CLL develop lung carcinoma. Recent studies showed that patients with CLL less than 55 years old have a greater risk of developing secondary solid tumors, not like our patient who was 78 years old. Tissue samples from the EUS-FNA/EBUS are very important to help guide therapy due to the high resistance to conventional chemotherapy in patients with CLL and a second malignancy. A multidisciplinary approach can be used to diagnose and stage lung cancers with EBUS/EUS-FNA in the setting of CLL.

The relationship between processed meat, red meat, and risk of types of cancer: A Mendelian randomization study.

BackgroundObservational studies have suggested processed and red meat may increase the risk of cancer. However, the causal effects and direction between them were still unclear. We conducted two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of processed meat and red meat on the risk of nine common types of cancer, namely, lung, ovarian, endometrial, breast, kidney, gastric, prostate, skin, and oropharyngeal cancer.MethodsGenome-wide association studies (GWAS) for processed meat and red meat (pork, beef, and mutton) were obtained from the UK Biobank. GWAS of types of cancer in this study were extracted from the genetic consortia and the FinnGen consortium. The inverse variance weighted (IVW) was carried out as the main method for two-sample MR analysis. Sensitivity analyses were used to assess the robustness of the results.ResultsGenetically predicted processed meat intake was causally associated with increased risk of lung cancer (OR [odds ratio] = 1.923, 95% CI = 1.084–3.409, P = 0.025). There is no convincing evidence for the associations between genetically determined processed meat, red meat, and the risk of other cancers we studied.ConclusionOur results suggested that intake of processed meat may increase the risk of lung cancer. These findings provided no evidence to support that consumption of processed and red meat has a large effect on the risk of other cancers we studied. Further research is needed to clarify the results.

Normal gastrointestinal mucosa at biopsy and subsequent cancer risk: nationwide population-based, sibling-controlled cohort study

BackgroundWhile individuals with normal gastrointestinal (GI) mucosa on endoscopy have a lower risk of colorectal cancer, risks of other cancers remain unexplored.MethodsThrough Sweden’s 28 pathology departments, we identified 415,092 individuals with a first GI biopsy with histologically normal mucosa during 1965–2016 and no prior cancer. These individuals were compared to 1,939,215 matched reference individuals from the general population. Follow-up began 6 months after biopsy, and incident cancer data were retrieved from the Swedish Cancer Register. Flexible parametric model was applied to estimate cumulative incidences and hazard ratios (HRs) for cancers. We also used full siblings (n = 441,534) as a secondary comparison group.ResultsDuring a median follow-up of 10.9 years, 40,935 individuals with normal mucosa (incidence rate: 82.74 per 10,000 person-years) and 177,350 reference individuals (incidence rate: 75.26) developed cancer. Restricting the data to individuals where follow-up revealed no cancer in the first 6 months, we still observed an increased risk of any cancer in those with a histologically normal mucosa (average HR = 1.07; 95%CI = 1.06–1.09). Although the HR for any and specific cancers decreased shortly after biopsy, we observed a long-term excess risk of any cancer, with an HR of 1.08 (95%CI = 1.05–1.12) and a cumulative incidence difference of 0.93% (95%CI = 0.61%-1.25%) at 30 years after biopsy. An elevated risk of gastric cancer, lung cancer, and hematological malignancy (including lymphoproliferative malignancy) was also observed at 20 or 30 years since biopsy. Sibling analyses confirmed the above findings.ConclusionIndividuals with a histologically normal mucosa at biopsy and where follow-up revealed no cancer in the first 6 months, may still be at increased risk of cancer, although excess risks are small.