Hereditary Cancer Screening and Outcomes at an Urban Safety-Net Hospital.

PURPOSE: Patients with hereditary cancer syndromes (HCS) have a high lifetime risk of developing cancer. Historically underserved populations have lower rates of genetic evaluation. We sought to characterize demographic factors that are associated with undergoing HCS evaluation in an urban safety-net patient population. METHODS: All patients who met inclusion criteria for this study from 2016 to 2021 at an urban safety-net hospital were included in this analysis. Inclusion criteria were pathologically confirmed breast, ovarian/fallopian tube, colon, pancreatic, and prostate cancers. Patients also qualified for hereditary breast and ovarian cancers or Lynch syndrome on the basis of National Comprehensive Cancer Network guidelines. Institutional review board approval was obtained. Demographic and oncologic data were collected through retrospective chart review. Univariable and multivariable logistic regression models were constructed. RESULTS: Of the 637 patients included, 40% underwent genetic testing. Variables associated with receiving genetic testing on univariable analysis included patients living at the time of data collection, female sex, Latinx ethnicity, Spanish language, family history of cancer, and referral for genetic testing. Patients identifying as Black, having Medicare, having pancreatic or prostate cancer, having stage IV disease, having Eastern Cooperative Oncology Group (ECOG) prognostic score ≥1, having medium or high Charlson comorbidity index, with current or previous cigarette use, and with previous alcohol use were negatively associated with testing. On multivariable modeling, family history of cancer was positively associated with testing. Patients identifying as Black, having colon or prostate cancer, and having ECOG score of 2 had significantly lower association with genetic testing. CONCLUSION: Uptake of HCS was lower in patients identifying as Black, those with colon or prostate cancer, and those with an ECOG score of 2. Efforts to increase HCS testing in these patients will be important to advance equitable cancer care.

Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.

[Multiple primary tumors in children: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features of children with metachronous or synchronous primary tumors and to identify related genetic tumor syndromes. Methods: The clinicopathological data of 4 children with multiple primary tumors diagnosed in the Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from 2011 to 2023 were collected. The histological, immunophenotypic and molecular characteristics were examined using H&E staining, immunohistochemical staining, PCR, Sanger sequencing and next-generation sequencing (NGS). The patients were followed up. Results: Case 1 was an 8-year-old boy with the adrenal cortical carcinoma, and 5 years later a poorly differentiated gastric adenocarcinoma was detected. Case 2 was a 2-year-old boy, presented with a left ventricular choroid plexus carcinoma, and a hepatoblastoma was detected 8 months later. Case 3 was a 9-month-old girl, diagnosed with renal rhabdoid tumor first and intracranial atypical teratoid/rhabdoid tumor (AT/RT) 3 months later. Case 4 was a 7-year-old boy and had a sigmoid colon adenocarcinoma 3 years after the diagnosis of a glioblastoma. The morphology and immunohistochemical features of the metachronous or synchronous primary tumors in the 4 cases were similar to the corresponding symptom-presenting/first-diagnosed tumors. No characteristic germ line mutations were detected in cases 1 and 2 by relevant molecular detection, and the rhabdoid tumor predisposition syndrome was confirmed in case 3 using NGS. Case 4 was clearly related to constitutional mismatch repair deficiency as shown by the molecular testing and clinical features. Conclusions: Childhood multiple primary tumors are a rare disease with histological morphology and immunophenotype similar to the symptom-presenting tumors. They are either sporadic or associated with a genetic (tumor) syndrome. The development of both tumors can occur simultaneously (synchronously) or at different times (metachronously). Early identification of the children associated with genetic tumor syndromes can facilitate routine tumor screening and early treatment.

Novel Cancer Prevention Strategies in Individuals With Hereditary Cancer Syndromes: Focus on BRCA1, BRCA2, and Lynch Syndrome.

Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks of multiple cancer types including colorectal and uterine cancers. Current cancer risk mitigation strategies have focused on pharmacologic risk reduction, enhanced surveillance, and preventive surgeries. While these approaches can be effective, they stand to be improved on because of either limited efficacy or undesirable impact on quality of life. The current review summarizes ongoing investigational efforts in cancer risk prevention strategies for patients with germline PVs in BRCA1, BRCA2, or LS-associated genes. These efforts span radiation, surgery, and pharmacology including vaccine strategies. Understanding the molecular events involved in the premalignant to malignant transformation in high-risk individuals may ultimately contribute significantly to novel prevention strategies.

NLRC5 promotes endometrial carcinoma progression by regulating NF-κB pathway-mediated mismatch repair gene deficiency.

The innate immune molecule NLR family CARD domain-containing 5 (NLRC5) plays a significant role in endometrial carcinoma (EC) immunosurveillance. However, NLRC5 also plays a protumor role in EC cells. Mismatch repair gene deficiency (dMMR) can enable tumors to grow faster and also can exhibit high sensitivity to immune checkpoint inhibitors. In this study, we attempted to determine whether NLRC5-mediated protumor role in EC is via the regulation of dMMR. Our findings revealed that NLRC5 promoted the proliferation, migration, and invasion abilities of EC cells and induced the dMMR status of EC in vivo and in vitro. Furthermore, the mechanism underlying NLRC5 regulated dMMR was also verified. We first found NLRC5 could suppress nuclear factor-kappaB (NF-κB) pathway in EC cells. Then we validated that the positive effect of NLRC5 in dMMR was restricted when NF-κB was activated by lipopolysaccharides in NLRC5-overexpression EC cell lines. In conclusion, our present study confirmed the novel NLRC5/NF-κB/MMR regulatory mechanism of the protumor effect of NLRC5 on EC cells, thereby suggesting that the NLRC5-mediated protumor in EC was depend on the function of MMR.

Gastrointestinal Cancer Precursor Conditions and Their Detection.

Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.

Variant classification changes over time in the clinical molecular diagnostic laboratory setting.

BACKGROUND: Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario. METHODS: DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category). RESULTS: Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%). CONCLUSIONS: The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.

Fumarate hydratase-deficient renal cell carcinoma: an oncology care institutional experience.

Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)-deficient RCC. FH-deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH-deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo-cytoplasmic expression of S-(2-succino)-cysteine (2-SC), with loss of FH in seven cases. FH-deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2-SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members.

Immunohistochemical Approach to Mismatch Repair Deficiency in Pediatric High-Grade Glioma.

Knowledge of the molecular pathways of pediatric high-grade gliomas is increasing. Gliomas with mismatch repair deficiency do not currently comprise a distinct group, but data on this topic have been accumulating in recent publications. Immunohistochemistry can effectively determine mismatch repair status, indirectly suggesting the microsatellite instability of the tumor. This study aimed to determine the number of mismatch repair-deficient pediatric high-grade gliomas in a tertiary institution and assess the relationship between the survival and mismatch repair status of the patients. It also aimed to assess the potential for further clinical studies including immunotherapy. Of 24 patients with high-grade gliomas, 3 deceased patients were mismatch repair-deficient. Mismatch repair deficiency was significantly associated with shorter survival ( P =0.004). Immunotherapy trials need to progress, and patients with mismatch repair-deficient pediatric high-grade gliomas are the most suitable candidates for such studies.

Juvenile polyposis syndrome in children: The impact of SMAD4 and BMPR1A mutations on clinical phenotype and polyp burden.

OBJECTIVE: A constitutional disease-causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%-60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV-positive JPS compared to DCV-negative JPS. METHODS: Demographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group. RESULTS: A total of 124 children with JPS were included: 69 (56%) DCV-negative and 55 (44%) DCV-positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow-up of 4 (2.8-6.4) years. DCV-positive children were diagnosed at an older age compared to DCV-negative children [12 (8-15.7) years vs. 5 (4-7) years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). The incidence rate ratio for the development of new colonic polyps was 6.15 (95% confidence interval 3.93-9.63, p < 0.001) in the DCV-positive group compared to the DCV-negative group, with an average of 12.2 versus 2 new polyps for every year of follow-up. There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations. CONCLUSIONS: This largest international cohort of pediatric JPS revealed that DCV-positive and DCV-negative children exhibit distinct clinical phenotype. These findings suggest a potential need of differentiated surveillance strategies based upon mutation status.

Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.

BACKGROUND: Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. METHODS: A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). RESULTS: One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. CONCLUSION: These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.

Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort.

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.

Hereditary Cancer Syndrome Carriers: Feeling Left in the Corner.

OBJECTIVES: There is limited evidence on health promotion interventions in people with hereditary cancer syndromes or on their main sources of support and information. This study aimed to understand these patients' experiences and needs, including their information needs, their views on prevention and mental health, and the support they want from nurses. METHODS: This qualitative study included 22 people (8 previvors and 14 survivors) with hereditary breast and ovarian syndrome or Lynch syndrome from 10 European countries. Participants underwent individual semi-structured interviews, which were recorded and transcribed for reflexive thematic analysis. The patient and public involvement panel provided input on study design and thematic analysis. RESULTS: Patient experiences were similar regardless of the country and access to testing and screening. Participants reported receiving little information on the importance of health behaviors for cancer risk and expressed their wish to be followed by cancer professionals. They felt compelled to seek support and information from the internet and patient groups. The main themes identified were: (unmet) informational and support needs, seeing life in a different way, and limitations of health care providers. CONCLUSIONS: People with hereditary cancer syndromes need professionals to be involved in their long-term management and to provide reliable information. As genomics are increasingly integrated in oncology, the need for professionals to support these populations will increase. IMPLICATIONS FOR NURSING PRACTICE: Nurses are crucial for promoting self-management and advocating for patient decision-making; however, they need skills and knowledge to do so. There is a need for nurses to get more involved in understanding hereditary cancer syndromes and an opportunity to take the lead in the care of these people.

Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

Phenotypic characterisation of SMAD4 variant carriers.

BACKGROUND: Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of SMAD4 variants followed in an HHT reference centre to further delineate the phenotype. METHODS: Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database. RESULTS: Thirty-three participants from 15 families, out of 1114 patients with HHT, had an SMAD4 variant (3%).Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed.Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass et al for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation. CONCLUSION: We describe a large cohort of SMAD4 variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with SMAD4 gene variants and justify systematic cardiac ultrasound and skeletal complications screening.

Surgical aspects related to hereditary pancreatic cancer.

The goal of surveillance programs for individuals at risk (IAR) from familial pancreatic cancer (FPC) families or families with other inherited tumor syndromes predisposing to the development of pancreatic adenocarcinoma (PDAC), such as hereditary pancreatitis or Peutz-Jeghers syndrome, is the dectection and consecutive curative resection of early PDAC or even better its high-grade precursor lesions. Although the indication for surgery is quite established, the extent of surgery is not well defined due to the lack of evidence-based data. In addition, multiple factors have to be taken into account to determine an optimal personalized surgical strategy. This holds especially true since pancreatic surgery is associated with a relatively high morbidity and might impair the quality of life significantly. In this article the surgical aspects in the setting of hereditary PDAC are discussed.

Cascade testing for hereditary cancer in Singapore: how population genomics help guide clinical policy.

Hereditary Cancer makes up around 5-10% of all cancers. It is important to diagnose hereditary cancer in a timely fashion, as not only do patients require long-term care from a young age, but their relatives also require management. The main approach to capture at-risk relatives is cascade testing. It involves genetic testing of relatives of the first detected carrier of a pathogenic variant in a family i.e. the proband. The current standard of care for cascade testing is a patient-mediated approach. Probands are then advised to inform and encourage family members to undergo genetic testing. In Singapore, cascade testing is inefficient, around 10-15%, lower than the 30% global average. Here, we describe the cascade testing process and its effort to increase testing in Singapore. Precision Health Research, Singapore (PRECISE), was set up to coordinate Singapore's National Precision Medicine strategy and has awarded five clinical implementation pilots, with one of them seeking to identify strategies for how cascade testing for hereditary cancer can be increased in a safe and cost-efficient manner. Achieving this will be done through addressing barriers such as cost, manpower shortages, exploring a digital channel for contacting at-risk relatives, and getting a deeper insight into why genetic testing gets declined. If successful, it will likely result in care pathways that are a cost-effective public health intervention for identifying individuals at risk. Surveillance and management of those unaffected at-risk individuals, if caught early, will result in improved patient outcomes, and further reduce the healthcare burden for the economy.

Genetic and other risk factors for pancreatic ductal adenocarcinoma (PDAC).

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage, resulting in poor prognosis and low 5-year survival rates. While early evidence suggests increased long-term survival in those with screen-detected resectable cancers, surveillance imaging is currently only recommended for individuals with a lifetime risk of PDAC ≥ 5%. Identification of risk factors for PDAC provides opportunities for early detection, risk reducing interventions, and targeted therapies, thus potentially improving patient outcomes. Here, we summarize modifiable and non-modifiable risk factors for PDAC. We review hereditary cancer syndromes associated with risk for PDAC and their implications for patients and their relatives. In addition, other biologically relevant pathways and environmental and lifestyle risk factors are discussed. Future work may focus on elucidating additional genetic, environmental, and lifestyle risk factors that may modify PDAC risk to continue to identify individuals at increased risk for PDAC who may benefit from surveillance and risk reducing interventions.