A FANCC intronic variant of uncertain significance in a child with metastatic pancreatic adenocarcinoma

A FANCC intronic variant of uncertain significance in a child with metastatic pancreatic adenocarcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A FANCC intronic variant of uncertain significance in a child with metastatic pancreatic adenocarcinoma Katelin Magnan, Linford Williams, Qian Wang, Julia Meade This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3838058/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has been reported to have a germline genetic association in about 5.5% of isolated cases and 10–13% of familial or hereditary cohorts. Studies are linking new germline variants to PDAC annually, with numerous variants of uncertain significance (VUS) in candidate genes being reported. Case presentation: A 9-year-old boy presented with a 3-week history of abdominal pain, weight loss, and vomiting, with subsequent development of jaundice and pruritis. Imaging revealed an obstructive abnormality in the head of the pancreas with extra- and intrahepatic dilation of the bile ducts and a 1 c lesion in the liver. Biopsy of the liver lesion revealed metastatic PDAC. Extensive pathology review demonstrated atypical epithelial proliferation forming irregular and anastomosing glands. Germline evaluation was conducted with a 29-gene pancreatic cancer panel and revealed a c.345 + 6A > T VUS in the FANCC gene. This VUS affects a nucleotide in the consensus splice site in intron 4. The tumor was microsatellite stable with a tumor mutation burden of 3.4 Mutations/Mb. The child started chemotherapy with several cycles of FOLFIRINOX followed by Gemcitabine/Nab-paclitaxel but ultimately experienced tumor progression. He then pursued additional cancer directed therapy outside of our institution. As of the last evaluation, the child is alive with progressive disease. Conclusions Pancreatic adenocarcinoma is essentially unheard of in children under 10 years old. In adults, PDAC has been associated with a variety of cancer predisposition genes, and the National Comprehensive Cancer Network® (NCCN®) has issued surveillance guidelines for adults carrying germline variants in TP53, BRCA1/2, ATM, PALB2, CDKN2A, among others. Emerging data has identified germline FANCC variants in patients with PDAC. Further studies of FANCC variants of uncertain significance are necessary for variant reclassification and to allow review of current screening guidelines in adults. Pancreatic ductal adenocarcinoma FANCC variant of uncertain significance hereditary cancer Figures Figure 1 Figure 2 Figure 3 Background Pancreatic ductal adenocarcinoma (PDAC) is exceedingly rare in children. Malignant pancreatic tumors have an overall incidence of 0.46 cases per 1 million in individuals less than 30 years old, and of those, carcinomas represent < 5% [ 1 ]. In the rare cases reported in adolescents, PDAC is most often identified in the late teenage years, with males tending to be more affected [ 2 ]. More than half of patients with PDAC present with distant metastasis, and the diagnosis is overall associated with a poor prognosis [ 3 , 4 ]. In adults, overall five year survival is less than 10% [ 5 , 6 ]. In children, PDAC is associated with the worst prognosis of any pancreatic malignancy [ 3 , 7 ]. Amongst seven children and adolescents diagnosed with PDAC in the SEER 21 database, the fifteen-year survival rate was 21% [ 2 , 4 ]. PDAC has been reported to have a germline genetic association in about 5.5% of isolated cases and 10–13% of familial or hereditary cohorts [ 8 , 9 ]. Several different hereditary syndromes have been implicated in PDAC including Herediatry Breast and Ovarian Cancer ( BRCA1/BRCA2 ), Familial Atypical Multiple Mole Melanoma ( p16/CDKNA ), ataxia telangiectasia ( ATM ), Hereditary Pancreatitis ( PRSS1/SPINK1 ), Peutz-Jeghers syndrome ( STK11/LKB1 ), and Lynch syndrome ( MLH1/PMS1/PMS2/MSH2/MSH6 ) [ 1 , 8 , 9 ]. In addition, studies are linking new germline variants to PDAC annually, with numerous variants of uncertain significance (VUS) in candidate genes being reported including FANCC , CFTR, APCY , and MUTYH [ 8 ]. Case Presentation A 9-year-old boy presented to a tertiary care children’s hospital with a 3-week history of progressively worsening abdominal pain and vomiting. The child had lost 13 pounds over the same timeframe. One day prior to presentation, he developed jaundice and pruritus. He endorsed darkening of his urine and pale stools over the past 24 hours as well. On presentation, he was afebrile with normal vital signs. The initial physical exam was notable for jaundice and scleral icterus as well as tenderness to palpation of the right upper quadrant, without appreciated masses or hepatosplenomegaly. Laboratory work-up was notable for direct hyperbilirubinemia (total bilirubin level 10.9 mg/dL [186.4 µmol/L], direct bilirubin level 6.6 mg/dL [176.2 µmol/L]). GGTP was elevated to 690 units/L and lipase was elevated to 1225 units/L. He also had transaminitis with ALT 552 units/L and AST 169 units/L. A complete blood count revealed normal hemoglobin and white blood cells. Coagulation studies were also normal. Cancer Antigen 19 − 9 (CA 19 − 9) was elevated at 162 units/mL. Imaging was obtained, with abdominal ultrasound showing extra- and intrahepatic biliary and pancreatic dilatation, concerning for obstruction. Magnetic Resonance Imaging (MRI) of the abdomen with contrast revealed an obstructive abnormality in the uncinate process of the pancreas with extra- and intrahepatic dilation of the bile ducts in the liver as well as a 1 cm enhancing lesion in the liver (Fig. 1 ). Biopsy of the liver lesion was consistent with metastatic PDAC. The liver biopsy demonstrated an infiltrating tumor with glandular and cribriform architecture (Fig. 2 A). The adjacent non-neoplastic liver parenchyma showed significant cholestasis and ductular proliferation (not shown in the figure). Immunohistochemistry revealed that the tumor was focally positive for CK7 (heterogenous) and beta-catenin (membranous, non-mutated). SMAD4 was retained. Neoplastic cells were negative for CK20, BCL10, synaptophysin, trypsin, CDX2, TTF-1, and SALL4. EUS-guided fine needle biopsy of the pancreatic head mass showed an adenocarcinoma with infiltrating glandular structures, similar to that in the liver (Fig. 2 B). Microarray of the tumor was negative for copy number abnormalities, DNA mutations, and gene fusions. The tumor was microsatellite stable with a tumor mutation burden of 3.4 Mutations/Mb. The child was initially started on chemotherapy with FOLFIRINOX (folic acid, fluorouracil, irinotecan, and oxaliplatin) as per the adult National Comprehensive Cancer Network® (NCCN®) PDAC guidelines and experienced 30% reduction in tumor volume after 2 cycles with biochemical response (CA 19 − 9 decreased to 65.2 units/mL from 162 units/mL at the time of chemotherapy initiation). However, after cycle 4 of FOLFIRINOX, he was noted to have tumor progression of 150% on imaging. His regiment was changed to Gemcitabine and Nab-paclitaxel. Unfortunately, he had further progression after cycle 4 of Gemcitabine/Nab-paclitaxel with an increased number of hepatic metastases and a slight increase in tumor size. After that point, he pursued further cancer directed therapy outside of our institution. As of the last encounter, the child is alive with progressive disease. Given pancreatic adenocarcinoma in a child, genetics was consulted for evaluation of an underlying cancer predisposition syndrome. The child’s family history is significant for cancer in both maternal and paternal relatives; however, no other relative has had PDAC (Fig. 3 ). Germline evaluation was conducted via commercial laboratory with a 29-gene pancreatic cancer panel and revealed a c.345 + 6A > T variant of uncertain significance (VUS) in the FANCC gene. This VUS affects a nucleotide in the consensus splice site in intron 4. Discussion and Conclusions Pancreatic adenocarcinoma is exceedingly rare in pediatric patients and essentially unheard of in children under 10 years old. In adults, PDAC has been associated with germline pathogenic variants in a variety of cancer predisposition genes. Emerging data has identified germline FANCC variants as enriched in patients with PDAC [ 10 – 13 ]. We report here a case of a rare diagnosis of pancreatic ductal adenocarcinoma in a 9-year-old male, found to have a VUS in the FANCC gene. FANCC is one of over 20 genes associated with Fanconi Anemia. It encodes a protein that forms part of a nuclear complex which monoubiquinates the FANCI/FANCD complex [ 12 , 14 ]. This pathway is important for DNA repair and adequate response to DNA damage by cross linking agents through participation in homologous recombination and non-homologous end joining [ 12 , 14 ]. Understanding the potential involvement of FANCC with regards to the development of pancreatic cancer has important treatment implications. Fanconi cells are known to be hypersensitive to cross-linking agents like mitomycin and cisplatin, highlighting an important chemotherapeutic opportunity [ 10 , 12 ]. In addition, the NCCN has issued surveillance guidelines for adults carrying germline variants in TP53, BRCA1/2, ATM, PALB2, STK11, CDKN2A, EPCAM and Lynch Syndrome genes. Further studies related to FANCC variants of uncertain significance are necessary for variant reclassification, which would have implications related to chemotherapeutic targets and screening recommendations in adults. Abbreviations PDAC Pancreatic ductal adenocarcinoma VUS Variants of uncertain significance FOLFIRINOX (folic acid, fluorouracil, irinotecan, and oxaliplatin) NCCN National Comprehensive Cancer Network Declarations Ethical approval and consent to participate Not applicable Consent for publication The authors hereby confirm that the consent of the parents of the child to publish this case report has been obtained. Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests. Funding The authors have no sources of funding to declare. Authors’ contributions All authors have contributed to the manuscript in significant ways. K.M. wrote the main manuscript text, with mentorship and input from J.M.. K.M. prepared Figure 1. Q.W. prepared Figure 2. L.W. prepared Figure 3. All authors reviewed the manuscript. Acknowledgements Not applicable References PDQ® Pediatric Treatment Editorial Board. Childhood Pancreatic Cancer Treatment. Bethesda, Maryland. Updated 02/17/2023. National Cancer Institute. Available at: https://www.cancer.gov/types/pancreatic/hp/child-pancreatic-treatment-pdq . Accessed 10/08/2023. PMID: 31661209. Qiu L, Trout AT, Ayyala RS, Szabo S, Nathan JD, Geller JI, et al. Pancreatic Masses in Children and Young Adults: Multimodality Review with Pathologic Correlation. Radiographics. 2021;41(6):1766–84. Perez EA, Gutierrez JC, Koniaris LG, Neville HL, Thompson WR, Sola JE. Malignant pancreatic tumors: incidence and outcome in 58 pediatric patients. J Pediatr Surg. 2009;44(1):197–203. Patterson KN, Trout AT, Shenoy A, Abu-El-Haija M, Nathan JD. Solid pancreatic masses in children: A review of current evidence and clinical challenges. Front Pediatr. 2022;10:966943. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. Sarantis P, Koustas E, Papadimitropoulou A, Papavassiliou AG, Karamouzis MV. Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy. World J Gastrointest Oncol. 2020;12(2):173–81. Park M, Koh KN, Kim BE, Im HJ, Kim DY, Seo JJ. Pancreatic neoplasms in childhood and adolescence. J Pediatr Hematol Oncol. 2011;33(4):295–300. Earl J, Galindo-Pumariño C, Encinas J, Barreto E, Castillo ME, Pachón V, et al. A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants. EBioMedicine. 2020;53:102675. Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018;319(23):2401–9. van der Heijden MS, Yeo CJ, Hruban RH, Kern SE. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003;63(10):2585–8. Couch FJ, Johnson MR, Rabe K, Boardman L, McWilliams R, de Andrade M, et al. Germ Line Fanconi Anemia Complementation Group C Mutations and Pancreatic Cancer. Cancer Res. 2005;65(2):383–6. van der Heijden MS, Brody JR, Gallmeier E, Cunningham SC, Dezentje DA, Shen D, et al. Functional defects in the fanconi anemia pathway in pancreatic cancer cells. Am J Pathol. 2004;165(2):6517. Yin L, Wei J, Lu Z, Huang S, Gao H, Chen J, et al. Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China. JAMA Netw Open. 2022;5(2):e2148721. Del Valle J, Rofes P, Moreno-Cabrera JM, López-Dóriga A, Belhadj S, Vargas-Parra G et al. Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients. Cancers (Basel). 2020;12(4). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3838058","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":266199245,"identity":"e4d0cb29-b4f9-405f-9025-523a44780ee5","order_by":0,"name":"Katelin Magnan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYBACCRDxwADK42GwYTCAMPBpYWZgSEBoSSNWC4zHw3CYsBbJ9vMHHyQU3GGQb+99+OBt23l5c+kGRiADtxZpnmRmgwSDZwwGZ44bG85tu224c84BZiADtxY5hmQ2iQQDoHsk0tikedtuJxjcSAAx8Gjhf8z+A6RFfv4zkMpzIC3sv/FpkZZIZmMAaWG4wQbScgBsCzM+LZIzHhuDHMZjcCaN2XDOuWTDDXcONkvOOYdbi8T5xIcfPvw5LCfffozxwZsyO3mD280HP7wpw60FBiARwcgGMoWxgbB6BPjDAE1Do2AUjIJRMAoQAABroU5l4Ie0DQAAAABJRU5ErkJggg==","orcid":"","institution":"UPMC Children’s Hospital of Pittsburgh","correspondingAuthor":true,"prefix":"","firstName":"Katelin","middleName":"","lastName":"Magnan","suffix":""},{"id":266199246,"identity":"43455be6-c9f7-4588-b045-702e27eac069","order_by":1,"name":"Linford Williams","email":"","orcid":"","institution":"UPMC Children’s Hospital of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Linford","middleName":"","lastName":"Williams","suffix":""},{"id":266199247,"identity":"2fc98b94-f3fc-421a-8fc1-db8215c7699d","order_by":2,"name":"Qian Wang","email":"","orcid":"","institution":"UPMC Children’s Hospital of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Wang","suffix":""},{"id":266199248,"identity":"f4f4153b-4723-4dfc-8375-914d2bd30958","order_by":3,"name":"Julia Meade","email":"","orcid":"","institution":"UPMC Children’s Hospital of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Meade","suffix":""}],"badges":[],"createdAt":"2024-01-05 19:29:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3838058/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3838058/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49435777,"identity":"9f74d8c2-d9d5-4361-b598-7136dc0a4576","added_by":"auto","created_at":"2024-01-10 20:04:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":344684,"visible":true,"origin":"","legend":"\u003cp\u003eMRI of the Abdomen with Contrast\u003c/p\u003e\n\u003cp\u003e(A) MRI of the abdomen with contrast demonstrates a mass of the pancreatic head measuring 3.3 x 2.7 x 3.4 cm, with biliary and pancreatic ductal dilation secondary to this mass. (B) There is a solitary 1 cm enhancing liver lesion on the coronal view, representing a metastatic lesion.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3838058/v1/4a4b661ce5185c74a025cb23.png"},{"id":49435776,"identity":"ad11c09e-dc31-4f90-9309-c75cc68893f1","added_by":"auto","created_at":"2024-01-10 20:04:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":514379,"visible":true,"origin":"","legend":"\u003cp\u003eTumor Pathology\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(A) Core biopsy from the liver shows an adenocarcinoma with glandular and cribriform pattern. (B) SharkCore EUS-guided fine-needle biopsy from the pancreas head shows infiltrating tumor with similar morphological features as (A). Scale bar=50um\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3838058/v1/791b9ed15ab84adc4a4aec7f.jpg"},{"id":49435779,"identity":"7dbfcdb4-6701-4c4d-b7b6-763df11f5655","added_by":"auto","created_at":"2024-01-10 20:04:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":88661,"visible":true,"origin":"","legend":"\u003cp\u003eFamily Pedigree\u003c/p\u003e\n\u003cp\u003e* indicates patient.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3838058/v1/9d106ef2a283398f0b8e9879.png"},{"id":53511217,"identity":"de98e4e7-a30e-47a9-918a-87a9906b4d2d","added_by":"auto","created_at":"2024-03-26 22:52:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":795769,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3838058/v1/f17c63bb-dcbc-4262-a9e9-d2ac21485e9b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A FANCC intronic variant of uncertain significance in a child with metastatic pancreatic adenocarcinoma","fulltext":[{"header":"Background","content":"\u003cp\u003ePancreatic ductal adenocarcinoma (PDAC) is exceedingly rare in children. Malignant pancreatic tumors have an overall incidence of 0.46 cases per 1\u0026nbsp;million in individuals less than 30 years old, and of those, carcinomas represent\u0026thinsp;\u0026lt;\u0026thinsp;5% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In the rare cases reported in adolescents, PDAC is most often identified in the late teenage years, with males tending to be more affected [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. More than half of patients with PDAC present with distant metastasis, and the diagnosis is overall associated with a poor prognosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In adults, overall five year survival is less than 10% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In children, PDAC is associated with the worst prognosis of any pancreatic malignancy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Amongst seven children and adolescents diagnosed with PDAC in the SEER 21 database, the fifteen-year survival rate was 21% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePDAC has been reported to have a germline genetic association in about 5.5% of isolated cases and 10\u0026ndash;13% of familial or hereditary cohorts [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Several different hereditary syndromes have been implicated in PDAC including Herediatry Breast and Ovarian Cancer (\u003cem\u003eBRCA1/BRCA2\u003c/em\u003e), Familial Atypical Multiple Mole Melanoma (\u003cem\u003ep16/CDKNA\u003c/em\u003e), ataxia telangiectasia (\u003cem\u003eATM\u003c/em\u003e), Hereditary Pancreatitis (\u003cem\u003ePRSS1/SPINK1\u003c/em\u003e), Peutz-Jeghers syndrome (\u003cem\u003eSTK11/LKB1\u003c/em\u003e), and Lynch syndrome (\u003cem\u003eMLH1/PMS1/PMS2/MSH2/MSH6\u003c/em\u003e) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In addition, studies are linking new germline variants to PDAC annually, with numerous variants of uncertain significance (VUS) in candidate genes being reported including \u003cem\u003eFANCC\u003c/em\u003e, \u003cem\u003eCFTR, APCY\u003c/em\u003e, and \u003cem\u003eMUTYH\u003c/em\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 9-year-old boy presented to a tertiary care children\u0026rsquo;s hospital with a 3-week history of progressively worsening abdominal pain and vomiting. The child had lost 13 pounds over the same timeframe. One day prior to presentation, he developed jaundice and pruritus. He endorsed darkening of his urine and pale stools over the past 24 hours as well. On presentation, he was afebrile with normal vital signs. The initial physical exam was notable for jaundice and scleral icterus as well as tenderness to palpation of the right upper quadrant, without appreciated masses or hepatosplenomegaly.\u003c/p\u003e \u003cp\u003eLaboratory work-up was notable for direct hyperbilirubinemia (total bilirubin level 10.9 mg/dL [186.4 \u0026micro;mol/L], direct bilirubin level 6.6 mg/dL [176.2 \u0026micro;mol/L]). GGTP was elevated to 690 units/L and lipase was elevated to 1225 units/L. He also had transaminitis with ALT 552 units/L and AST 169 units/L. A complete blood count revealed normal hemoglobin and white blood cells. Coagulation studies were also normal. Cancer Antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9) was elevated at 162 units/mL.\u003c/p\u003e \u003cp\u003eImaging was obtained, with abdominal ultrasound showing extra- and intrahepatic biliary and pancreatic dilatation, concerning for obstruction. Magnetic Resonance Imaging (MRI) of the abdomen with contrast revealed an obstructive abnormality in the uncinate process of the pancreas with extra- and intrahepatic dilation of the bile ducts in the liver as well as a 1 cm enhancing lesion in the liver (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Biopsy of the liver lesion was consistent with metastatic PDAC.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe liver biopsy demonstrated an infiltrating tumor with glandular and cribriform architecture (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The adjacent non-neoplastic liver parenchyma showed significant cholestasis and ductular proliferation (not shown in the figure). Immunohistochemistry revealed that the tumor was focally positive for CK7 (heterogenous) and beta-catenin (membranous, non-mutated). SMAD4 was retained. Neoplastic cells were negative for CK20, BCL10, synaptophysin, trypsin, CDX2, TTF-1, and SALL4. EUS-guided fine needle biopsy of the pancreatic head mass showed an adenocarcinoma with infiltrating glandular structures, similar to that in the liver (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Microarray of the tumor was negative for copy number abnormalities, DNA mutations, and gene fusions. The tumor was microsatellite stable with a tumor mutation burden of 3.4 Mutations/Mb.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe child was initially started on chemotherapy with FOLFIRINOX (folic acid, fluorouracil, irinotecan, and oxaliplatin) as per the adult National Comprehensive Cancer Network\u0026reg; (NCCN\u0026reg;) PDAC guidelines and experienced 30% reduction in tumor volume after 2 cycles with biochemical response (CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 decreased to 65.2 units/mL from 162 units/mL at the time of chemotherapy initiation). However, after cycle 4 of FOLFIRINOX, he was noted to have tumor progression of 150% on imaging. His regiment was changed to Gemcitabine and Nab-paclitaxel. Unfortunately, he had further progression after cycle 4 of Gemcitabine/Nab-paclitaxel with an increased number of hepatic metastases and a slight increase in tumor size. After that point, he pursued further cancer directed therapy outside of our institution. As of the last encounter, the child is alive with progressive disease.\u003c/p\u003e \u003cp\u003eGiven pancreatic adenocarcinoma in a child, genetics was consulted for evaluation of an underlying cancer predisposition syndrome. The child\u0026rsquo;s family history is significant for cancer in both maternal and paternal relatives; however, no other relative has had PDAC (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Germline evaluation was conducted via commercial laboratory with a 29-gene pancreatic cancer panel and revealed a c.345\u0026thinsp;+\u0026thinsp;6A\u0026thinsp;\u0026gt;\u0026thinsp;T variant of uncertain significance (VUS) in the \u003cem\u003eFANCC\u003c/em\u003e gene. This VUS affects a nucleotide in the consensus splice site in intron 4.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003ePancreatic adenocarcinoma is exceedingly rare in pediatric patients and essentially unheard of in children under 10 years old. In adults, PDAC has been associated with germline pathogenic variants in a variety of cancer predisposition genes. Emerging data has identified germline \u003cem\u003eFANCC\u003c/em\u003e variants as enriched in patients with PDAC [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. We report here a case of a rare diagnosis of pancreatic ductal adenocarcinoma in a 9-year-old male, found to have a VUS in the \u003cem\u003eFANCC\u003c/em\u003e gene. \u003cem\u003eFANCC\u003c/em\u003e is one of over 20 genes associated with Fanconi Anemia. It encodes a protein that forms part of a nuclear complex which monoubiquinates the FANCI/FANCD complex [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This pathway is important for DNA repair and adequate response to DNA damage by cross linking agents through participation in homologous recombination and non-homologous end joining [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUnderstanding the potential involvement of \u003cem\u003eFANCC\u003c/em\u003e with regards to the development of pancreatic cancer has important treatment implications. Fanconi cells are known to be hypersensitive to cross-linking agents like mitomycin and cisplatin, highlighting an important chemotherapeutic opportunity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In addition, the NCCN has issued surveillance guidelines for adults carrying germline variants in \u003cem\u003eTP53, BRCA1/2, ATM, PALB2, STK11, CDKN2A, EPCAM\u003c/em\u003e and Lynch Syndrome genes. Further studies related to \u003cem\u003eFANCC\u003c/em\u003e variants of uncertain significance are necessary for variant reclassification, which would have implications related to chemotherapeutic targets and screening recommendations in adults.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePDAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePancreatic ductal adenocarcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVariants of uncertain significance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFOLFIRINOX\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e(folic acid, fluorouracil, irinotecan, and oxaliplatin)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNCCN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNational Comprehensive Cancer Network\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors hereby confirm that the consent of the parents of the child to publish this case report has been obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The authors have no sources of funding to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;All authors have contributed to the manuscript in significant ways. K.M. wrote the main manuscript text, with mentorship and input from J.M.. K.M. prepared Figure 1. Q.W. prepared Figure 2. L.W. prepared Figure 3. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePDQ\u0026reg; Pediatric Treatment Editorial Board. Childhood Pancreatic Cancer Treatment. Bethesda, Maryland. Updated 02/17/2023. National Cancer Institute. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cancer.gov/types/pancreatic/hp/child-pancreatic-treatment-pdq\u003c/span\u003e\u003cspan address=\"https://www.cancer.gov/types/pancreatic/hp/child-pancreatic-treatment-pdq\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 10/08/2023. PMID: 31661209.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQiu L, Trout AT, Ayyala RS, Szabo S, Nathan JD, Geller JI, et al. Pancreatic Masses in Children and Young Adults: Multimodality Review with Pathologic Correlation. Radiographics. 2021;41(6):1766\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez EA, Gutierrez JC, Koniaris LG, Neville HL, Thompson WR, Sola JE. Malignant pancreatic tumors: incidence and outcome in 58 pediatric patients. J Pediatr Surg. 2009;44(1):197\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatterson KN, Trout AT, Shenoy A, Abu-El-Haija M, Nathan JD. Solid pancreatic masses in children: A review of current evidence and clinical challenges. Front Pediatr. 2022;10:966943.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarantis P, Koustas E, Papadimitropoulou A, Papavassiliou AG, Karamouzis MV. Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy. World J Gastrointest Oncol. 2020;12(2):173\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark M, Koh KN, Kim BE, Im HJ, Kim DY, Seo JJ. Pancreatic neoplasms in childhood and adolescence. J Pediatr Hematol Oncol. 2011;33(4):295\u0026ndash;300.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEarl J, Galindo-Pumari\u0026ntilde;o C, Encinas J, Barreto E, Castillo ME, Pach\u0026oacute;n V, et al. A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants. EBioMedicine. 2020;53:102675.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018;319(23):2401\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Heijden MS, Yeo CJ, Hruban RH, Kern SE. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003;63(10):2585\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCouch FJ, Johnson MR, Rabe K, Boardman L, McWilliams R, de Andrade M, et al. Germ Line Fanconi Anemia Complementation Group C Mutations and Pancreatic Cancer. Cancer Res. 2005;65(2):383\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Heijden MS, Brody JR, Gallmeier E, Cunningham SC, Dezentje DA, Shen D, et al. Functional defects in the fanconi anemia pathway in pancreatic cancer cells. Am J Pathol. 2004;165(2):6517.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin L, Wei J, Lu Z, Huang S, Gao H, Chen J, et al. Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China. JAMA Netw Open. 2022;5(2):e2148721.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDel Valle J, Rofes P, Moreno-Cabrera JM, L\u0026oacute;pez-D\u0026oacute;riga A, Belhadj S, Vargas-Parra G et al. Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients. Cancers (Basel). 2020;12(4).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pancreatic ductal adenocarcinoma, FANCC, variant of uncertain significance, hereditary cancer","lastPublishedDoi":"10.21203/rs.3.rs-3838058/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3838058/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePancreatic ductal adenocarcinoma (PDAC) has been reported to have a germline genetic association in about 5.5% of isolated cases and 10\u0026ndash;13% of familial or hereditary cohorts. Studies are linking new germline variants to PDAC annually, with numerous variants of uncertain significance (VUS) in candidate genes being reported.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eA 9-year-old boy presented with a 3-week history of abdominal pain, weight loss, and vomiting, with subsequent development of jaundice and pruritis. Imaging revealed an obstructive abnormality in the head of the pancreas with extra- and intrahepatic dilation of the bile ducts and a 1 c lesion in the liver. Biopsy of the liver lesion revealed metastatic PDAC. Extensive pathology review demonstrated atypical epithelial proliferation forming irregular and anastomosing glands. Germline evaluation was conducted with a 29-gene pancreatic cancer panel and revealed a c.345\u0026thinsp;+\u0026thinsp;6A\u0026thinsp;\u0026gt;\u0026thinsp;T VUS in the FANCC gene. This VUS affects a nucleotide in the consensus splice site in intron 4. The tumor was microsatellite stable with a tumor mutation burden of 3.4 Mutations/Mb. The child started chemotherapy with several cycles of FOLFIRINOX followed by Gemcitabine/Nab-paclitaxel but ultimately experienced tumor progression. He then pursued additional cancer directed therapy outside of our institution. As of the last evaluation, the child is alive with progressive disease.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePancreatic adenocarcinoma is essentially unheard of in children under 10 years old. In adults, PDAC has been associated with a variety of cancer predisposition genes, and the National Comprehensive Cancer Network\u0026reg; (NCCN\u0026reg;) has issued surveillance guidelines for adults carrying germline variants in TP53, BRCA1/2, ATM, PALB2, CDKN2A, among others. Emerging data has identified germline FANCC variants in patients with PDAC. Further studies of FANCC variants of uncertain significance are necessary for variant reclassification and to allow review of current screening guidelines in adults.\u003c/p\u003e","manuscriptTitle":"A FANCC intronic variant of uncertain significance in a child with metastatic pancreatic adenocarcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-10 20:04:32","doi":"10.21203/rs.3.rs-3838058/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1752590e-0029-4c23-b514-d8df9b0cb5f3","owner":[],"postedDate":"January 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-26T22:44:32+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-10 20:04:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3838058","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3838058","identity":"rs-3838058","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}