Familial Adenomatous Polyposis Syndrome Research Articles

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.

Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.

Abdominal Desmoid: Course, Severe Outcomes, and Unique Genetic Background in a Large Local Series.

Simple SummaryAbdominal desmoids are rare fibroblastic tumors. Though these tumors do not display metastatic potential, their locally aggressive nature can cause severe outcomes. Most cases appear sporadically, but 5–15% are associated with familial adenomatous polyposis (FAP) syndrome. Current consensus recommendations do not offer a standard sequence of therapy due to the lack of data for some treatment options. Here, we present an ongoing clinical experience with abdominal desmoids. The majority of our patients suffered severe outcomes such as need for surgery or major tumor complications. A small, but unique group of 16 non-FAP mesenteric desmoid was found to harbor genetic alterations in cancer associated genes other than APC, including CHEK2, BLM, ERCC5, MSH6, and PALB2.Introduction: Abdominal desmoid tumors are locally aggressive tumors that develop in familial adenomatous polyposis (FAP) patients, within the mesentery or abdominal wall. The understanding and implications of the treatment regimens are evolving. Aim: To assess the course, treatment, and outcomes of FAP and non-FAP abdominal desmoids and their related genetic alterations. Methods: Retrospective cohort study. Demographics, tumor characteristics, oncological and surgical history, complications, genetic-testing, and mortality data were retrieved from two tertiary referral centers. Results: Sixty-two patients were identified (46 FAP and 16 non-FAP). Thirty-eight patients (61.3%) underwent surgical procedures (12 urgent and 26 elective). Out of 33 tumor resections, 39.4% recurred. Hormonal therapy, COX-inhibitors, chemotherapy, imatinib, and sorafenib were used in 35 (56.4%), 30 (48.4%), 18 (29.1%), 7 (11.3%), and 8 (12.9%) of patients, respectively, with a 2 year progression-free survival of 67.8%, 57.7%, 38.4%, and 28.5%, respectively. Forty-one patients (66.1%) suffered complications: bowel obstruction (30.6%), hyperalimentation (14.5%), ureteral obstruction (12.9%), perforation (11.3%), abscess formation (3.2%), and spinal cord compression (3.2%). Non-FAP patients carried pathogenic mutations in CHEK2, BLM, ERCC5, MSH6, and PALB2. Conclusions: Abdominal desmoids are mostly FAP-related and are associated with severe outcomes. We also report a group of non-FAP abdominal desmoids, which includes patients with additional cancer-related gene alterations. This interesting group should be further explored.

Hereditary and Inflammatory Bowel Disease-Related Early Onset Colorectal Cancer Have Unique Characteristics and Clinical Course Compared with Sporadic Disease.

Early onset colorectal cancer (EoCRC), diagnosed in those <50 years old, is increasing in incidence. We sought to differentiate characteristics and outcomes of EoCRC in patients with sporadic disease or preexisting conditions. We evaluated 2,135 patients with EoCRC in a population-based cohort from the Canadian province of British Columbia. Patients were identified on the basis of presence of hereditary syndromes (n = 146) or inflammatory bowel disease (IBD; n = 87) and compared with patients with sporadic EoCRC (n = 1,902). Proportions of patients with preexisting conditions were highest in the youngest decile of 18-29 (34.3%, P < 0.0001). Patients with sporadic EoCRC were older, more likely female, and had increased BMI (P < 0.05). IBD-related EoCRC had the highest rates of metastatic disease, poor differentiation, adverse histology, lymphovascular, and perineural invasion (P < 0.05). Survival was lower in patients with IBD (HR, 1.80; 95% CI, 1.54-3.13; P < 0.0001) and higher in hereditary EoCRC (HR, 0.47; 95% CI, 0.45-0.73; P < 0.0001) compared with sporadic. Prognosis did not differ between ulcerative colitis or Crohn's disease but was lower in those with undifferentiated-IBD (HR, 1.87; 95% CI, 1.01-4.05; P = 0.049). Lynch syndrome EoCRC had improved survival over familial adenomatous polyposis (HR, 0.31; 95% CI, 0.054-0.57; P = 0.0037) and other syndromes (HR, 0.43; 95% CI, 0.11-0.99; P = 0.049). In multivariate analysis controlling for prognostic factors, hereditary EoCRC was unchanged from sporadic; however, IBD-related EoCRC had worse overall survival (HR, 2.21; 95% CI, 1.55-3.16; P < 0.0001). EoCRC is heterogenous and patients with preexisting conditions have different characteristics and outcomes compared with sporadic disease. Prognostic differences identified here for young patients with colorectal cancer and predisposing conditions may help facilitate treatment planning and patient counseling.See related commentary by Hayes, p. 1775.

Endoscopic Management of Ampullary Adenomas in Familial Adenomatous Polyposis Syndrome: A Systematic Review with Pooled Analysis.

Endoscopic papillectomy is a viable therapy in ampullary lesions. Prior studies have reported on outcomes of sporadic ampullary lesions, and only small cohort studies have reported outcomes associated with familial adenomatous polyposis (FAP) syndrome. We performed a systematic review with pooled analysis to assess the safety and efficacy of EP for treating ampullary adenomas in FAP. We performed a comprehensive literature search of major databases from inception to May 2020. Studies that included patients with endoscopically resected ampullary lesions and FAP were eligible. The rate of technical success, en bloc resection, piecemeal resection, recurrence, and adverse events was pooled by means of a random-effects model to obtain a proportion with a 95% confidence interval (CI). Six studies, including a total of 99 patients, were included in our final analysis. Patient age ranged from 28 to 91years. Pooled technical success was 90.3% (CI 76.9-96.3%, I2 = 31%). Rate of en bloc resection was 60.6% (CI 47.9-72.0%, I2 = 0%). Recurrence rate was 25.4% (5.7-65.9%, I2 = 82%). The post-procedural pancreatitis rate was 14.7% of which 68% (51 of 75) utilized prophylactic pancreatic stenting. Other adverse events included bleeding (9.2%) and perforation (4%). Endoscopic papillectomy offers high technical success but remains challenging in patients with FAP, particularly due to high recurrence rates.

Paediatric polyposis syndromes: burden of disease and current concepts.

Polyposis syndromes are rare but significant entities that often present during childhood and adolescence. Polyposis syndromes should remain high on the differential diagnoses for any child presenting with rectal bleeding, protein-losing enteropathy or intussusception in the setting of multiple polyps in the gastrointestinal tract. There are three primary paediatric polyposis syndromes: Juvenile polyposis syndrome (JPS), Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS). This review will cover recent guidelines for these conditions and advances in genetic testing. The first set of paediatric guidelines were released in 2019 by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for FAP, JPS and PJS. Even with advances in genetic testing, a significant proportion of patients with polyposis syndromes have no identifiable genetic mutations. Recent research has shown that polyps behave differently in patients with and without disease-causing variants, emphasizing the role of genetic testing in the diagnosis and management of polyposis syndromes. Polyposis syndromes in the paediatric population are growing due to increased recognition and advances in genetic testing. A timely diagnosis and surveillance of a paediatric polyposis syndrome are pivotal for the management of disease burden and early identification of cancers within the gastrointestinal tract and beyond. Paediatricians, paediatric gastroenterologists, paediatric oncologists and paediatric surgeons should be familiar with the presentation and comorbidities of polyposis syndromes in children and adolescents. Further research into genotype-phenotype correlations is needed to tailor the care for paediatric patients with polyposis syndromes.

Cutaneous desmoid‐type fibromatosis: A rare case with molecular profiling

Fibromatoses encompass a broad group of histopathologically similar fibroblastic/myofibroblastic proliferations with divergent clinical manifestations and behavior. Deep (desmoid-type) fibromatoses are typically large, rapidly growing, and locally aggressive tumors that occur in the abdominal wall, mesentery, and extra-abdominal soft tissue, principally the musculature of the trunk and extremities. Most sporadic cases of desmoid fibromatosis harbor inactivating mutations in CTNNB1, the gene encoding beta-catenin. Tumors occurring in the context of familial adenomatous polyposis and Gardner syndrome bear inactivating mutations in APC. By contrast, mutations in CTNNB1 or APC have not been identified in cases of superficial fibromatosis. Cutaneous involvement by desmoid fibromatosis is exceedingly rare. Here we present a 78-year-old male with desmoid-type fibromatosis arising in the dermis of the right medial calf with a pathogenic mutation in CTNNB1 and a variant of unknown significance in APC.

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer

Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.

EP218 - Symmetrical calvarium thickening: an atypical presentation in a child with familial adenomatous polyposis syndrome

eP218 - Symmetrical calvarium thickening: an atypical presentation in a child with familial adenomatous polyposis syndrome

APC c.4621C>T variant causing Gardner's syndrome in a Han Chinese family may be inherited through maternal mosaicism.

Gardner's syndrome is a rare autosomal dominant hereditary disease that is characterized by multiple colorectal polyps combined with extra-colonic presentation (such as osteoma or desmoid tumors) of familial adenomatous polyposis syndrome. Gardner's syndrome is caused by the mutation of the adenomatous polyposis coli (APC) gene, which is located at 5q21. The aim of the current study was to investigate the APC gene mutations present in a Han Chinese family diagnosed with Gardner's syndrome. The 38-year-old proband presented with clinical symptoms, and was later diagnosed with Gardner's syndrome. Genomic DNA was extracted from the peripheral venous blood of 150 normal controls as well as the family members of the proband. Analysis of the respective APC gene sequences was performed using PCR amplification and Sanger sequencing. Pathogenesis associated with the APC mutation was investigated using reverse-transcription quantitative PCR and determined through bioinformatics approaches. Haplotype analysis was performed to identify the genetic source of the mutation(s). In the initial screening for APC variants, the APC c.4621C>T variant was detected in the proband and his son, but was not detected in the proband's affected mother. The mRNA expression changed significantly according to age and the presence of the mutation in the blood of the patients. Haplotype analysis suggested the presence of maternal mosaicism for this mutation. Haplotype analysis revealed that the APC c.4621C>T variant in a patient with Gardner's syndrome was most likely derived from his mother through mosaicism. These results indicate the necessity to verify the possibility of gonadal mosaicism when a proband diagnosed with Gardner's syndrome appears to exhibit a de novo mutation.

The clinical and molecular characteristics of patients with personal history of colorectal cancer evaluated by cancer genetics counseling services.

46 Background: Genetic susceptibility to colorectal cancer (CRC) include well-defined hereditary syndromes such as Lynch Syndrome, Familial Adenomatous Polyposis syndrome (FAP), MUTYH-Associated Polyposis syndrome (MAP) and other less common syndromes. National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals meeting certain criteria have detailed risk assessment and potential genetic testing. Here, we describe the clinical and molecular characteristics of patients with personal history of CRC evaluated by cancer genetics counseling services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of CRC were identified (N = 52) and their clinical and molecular characteristics were summarized. Results: The median age is 50 years-old (29-82). Thirty-five (67%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 75%, 19% and 6% respectively. The primary tumor location was in the right colon, left colon and rectum in 29%, 37% and 27% of our cohort respectively. In 7%, the primary location of the tumor was not available. In our cohort, 11 out of 52 (21%) patients had a pathogenic germline mutation and 9 patients (17%) had a germline variant of unknown significance (VUS). Among patients with pathogenic germline mutations (N = 11), 4 patients had MSH2 mutations (MSH2 c.1759+1G &gt; A, MSH2 c. 1687dupT, MSH2 c.1861C &gt; T and MSH2 c.811_814delTCTG), 1 patient had a MSH6 mutation (MSH6 c.1012A &gt; T), 1 patient had a PMS2 mutation (PMS2 c.2182_2184delACTinsG), 3 patients had CHEK2 mutations (CHEK2 c.1100delC and CHEK2 c.470T &gt; C (p.I157T)), 2 patients had MUTYH mutations (MUTYH c.1187G &gt; A and MUTYH c.536A &gt; G) and 1 patient had a BRCA2 mutation (BRCA2 c.2808_2811delACAA). One patient had a CHEK2 and a MUTYH mutation. The VUS mutations in our cohort were POLE c.1645T &gt; C, POLE c.5480C &gt; T, c.2999G &gt; A, MLH1 c.1628A &gt; G, CTNNA1 c.503G &gt; A, MSH2 c.128A &gt; G, NBN c.16C &gt; T, ATM c.6537T &gt; G and AXIN2, BRCA1, NTHL1 mutations. Conclusions: In our cohort of patients with personal history of CRC, the majority of patients (62%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 21% and 17% of the patients respectively. Lynch Syndrome was the most commonly diagnosed hereditary CRC syndrome with 6 out of 11 patients found to have MMR germline mutations. Other pathogenic mutations were identified in the CHEK2, MUTYH and BRCA2 genes.

Germline testing of patients with personal history of colorectal polyposis by cancer genetics counseling services.

47 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals with &gt;10 adenomatous polyps, ≥2 hamartomatous polyps, or ≥5 serrated polyps proximal to the sigmoid colon have detailed risk assessment and potential genetic testing to rule out polyposis syndrome. Here, we describe germline testing of patients with a personal history of colorectal polyposis by Cancer Genetics Counseling Services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of colorectal polyposis were identified (N=20) and their germline testing results were summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services were personal history of &gt;10 adenomatous polyps (N=13), personal and family history of colorectal polyposis (N=3), personal history of juvenile colorectal polyps (N=3) or personal history of ≥2 hamartomatous polyps (N=1). The median age is 58 years-old (1-84). Ten (50%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 80%, 10% and 10% respectively. In our cohort, 6 out of 20 (30%) patients had a pathogenic germline mutation, 5 (25%) patients had variant of unknown significance (VUS) and 9 (45%) patients had negative testing. Among patients with pathogenic germline mutations, 3 patients had a pathogenic APC mutation (APC c.1659G&gt;A, APC c.2802C&gt;A and APC c.1643dupT) and were diagnosed with Familial Adenomatous Polyposis (FAP). One patient had 2 pathogenic MUTYH mutations (MUTYH c.536A&gt;G and MUTYH c.1187G&gt;A) and was diagnosed with One patient had a pathogenic PTEN c.634+5G&gt;A mutation and was diagnosed with PTEN Hamartoma Tumor Syndrome. Among the 3 patients with a personal history of juvenile colorectal polyps, one patient had a CHEK2 c.190G&gt;A mutation while the other two had negative genetic test results. The VUS mutations in our cohort were MRE11A c.826C&gt;T, BLM c.3478T&gt;C, BRCA2 c.2519T&gt;C, CHEK2 p.V395L and CTNNA1 c.392dupT. Conclusions: In our cohort of patients with personal history of colorectal polyposis, the majority of patients (45%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 30% and 25% of the patients, respectively. FAP Syndrome was the most commonly diagnosed hereditary polyposis syndrome with 3 patients found to have APC germline mutations. Other pathogenic mutations were identified in the MUTYH, PTEN and CHEK2 genes. Patients with MUTYH and PTEN mutations were diagnosed with MAP and PTEN Hamartoma Tumor Syndromes respectively.

Review on Colonrectal Cancer

The aim of the study of colon cancer is to introduce the basic information of cancer cell and the basic information of colon cancer. The research on colon cancer gave the information about hallmarks of cancer cell. exaggerated continuous proliferation, resistance to cell death as well as tumor suppressors, angiogenesis, spreading and metastasis and replicative immortality, the symptoms of colon cancer: Frequent bowel dysfunction (Diarrhea-constipation), Abdominal pain, nausea &amp; vomiting, Pain during defecation, and Bloating, the types of colon cancer: Familial Adenomatous Polyposis (FAP) and Lynch syndrome, nonpolyposis Colorectal Cancer, and the treatment of colon cancer: Treatment strategies differ according to the stage and development of the tumor. Surgery and adjuvant chemo are the two common methods in stages 2 and 3 of the disease. Palliative care is most common in patients at stage 4 to improve quality of life. The information which extracted from papers from other researchers formed the research of colon cancer.

Congenital hypertrophy of retinal pigment epithelium presenting as incidental finding in a middle aged woman

Introduction: Retinal Pigment epithelial hypertrophy are uncommon benign, epithelial malformation characterised by typical fundus findings, which is almost always congenital in nature. RPE hypertrophy occurs in three varieties: unifocal, unilateral lesion; multifocal unilateral lesion; and atypical multifocal, bilateral lesion. While the atypical multifocal, bilateral lesions are associated with familial adenomatous polyposis syndrome & requires systemic evaluation the other two varieties have benign coarse & doesnot require any intervention. Case Report: A 42yr Female noticed diminished vision in R/E following trivial trauma with fingernail 14 days back, it was not associated with pain, redness or any other symptoms. On evaluation, BCVA was 6/18p, N6 R/E & 6/6, N6 L/E; rest anterior segment evaluation was normal. R/E fundus showed focal, 1 DD sized, well-demarcated, hyperpigmented lesion just temporal to fovea with blocked fluorescence in all phase of FFA. OCT & B-scan showed slightly elevated retinal lesion with optical shadowing. Diagnosis of Retinal pigment epithelial hamartoma (RPEH) was made. Lesion was documented & followed. Discussion and Conclusion: RPE hypertrophy are presumed congenital stationary retinal malformation with characteristic ophthalmic, fluorescerin angiographic & OCT features. These lesions present as asympotomatic incidental findings in childhood or adults with good visual prognosis if located at extrafoveal sites. Gass et al & shields et al had described various types of RPE malformations & their characteristic features in FFA & OCT. In present case, we have reported a rare case of RPEH & also demonstrated the role of ancillary tests for diagnosis & followup. Keywords: Congenital retinal pigment epithelial hypertrophy, RPE hypertrophy, Congenital retinal malformation.

Spectrum of mutations in genes associated with familial colorectal cancer syndrome (MLH1, MSH2, PMS2, MSH6, and APC): A not so common hereditary cancer syndrome in Indian population.

Incidence of colorectal cancer (CRC) is lower in India than in other parts of the world. Approximately 5% to 10% of CRC is inherited. Hereditary non-polyposis colorectal cancer (HNPCC) syndrome and familial adenomatous polyposis (FAP) syndrome are the two known familial cancer syndromes of gastrointestinal tract, which occur due to inherited genetic predisposition. Not much is known about the molecular profile of families with inherited CRC syndromes seen in Indian population. At our institute, we have been providing genetic testing and counseling service to all the families referred to us with suspicion of inherited cancer predisposition syndrome. We analyzed 36 suspected families at our clinic. Personal and family history of cancer was obtained from the proband and appropriate genetic testing was performed in 19 patients (13 with HNPCC, 5 with FAP, and 1 with Cowden syndrome). We present here our experience and spectrum of pathogenic variants observed in this patient cohort and review on published studies describing molecular profile of Indian patients with CRC syndromes.

S0726 A History of Smoking Is Not Associated With a Higher Risk of Pouchitis: A Systematic Review and Meta-Analysis

INTRODUCTION: Ileal pouch-anal anastomosis (IPAA) is a common surgical procedure in patients with an initial diagnosis of ulcerative colitis (UC), indeterminate colitis (IC), or familial adenomatous polyposis syndrome (FAP). Tobacco smoking has been associated with protection from onset of UC. Smoking has been reported to be both a protective factor and a risk factor for the development of pouchitis. In this systematic review and meta-analysis, we examine the influence of smoking on the risk of pouchitis. METHODS: We identified 16 studies evaluating smoking as a risk factor for developing pouchitis in patients with a history of IPAA in a systematic search performed from inception through May 2020. A meta-analysis was then performed using a random-effects model to generate risk ratios. RESULTS: A total of 2,389 IPAA patients were included in the systematic review and meta-analysis. In the included studies, the percentage of patients with a diagnosis of pouchitis ranged from 22% to 72%. The percentage of patients with a history of smoking ranged from 7% to 63%. In total, 919 patients had pouchitis (330 current or former smokers; 589 non-smokers), and 1,470 patients did not have pouchitis (485 current or former smokers; 985 non-smokers). A history of smoking compared with never smoking was not associated with an increased risk of developing pouchitis (RR = 0.96, 95% CI 0.78–1.17, I2 = 68.6%). There was also no significant risk of pouchitis when comparing current smokers versus non-smokers (RR = 1.09, 95% CI 0.93–1.28, I2 = 0%) and former smokers versus non-smokers (RR = 0.95, 95% CI 0.70–1.28, I2 = 79.8%). CONCLUSION: Smoking, past or present, is not associated with an increased risk for the development of pouchitis. This is important to consider when counseling patients on the risks of smoking and pouchitis.Figure 1.: History of smoking (current or former versus non-smokers) and risk of pouchitis.

Management of the patient with fibromatosis of the left anterior chest wall

Desmoid fibromatosis is a rare but locally aggressive tumour comprised of myofibroblasts. It is histologically benign but can behave aggressively. They do not have the ability to metastasize but can cause significant morbidity and mortality by local invasion. These tumours may occur anywhere on the body, but are commonly found on the abdominal wall and within the intestinal mesentery. Mutations in either the β-catenin or the adenomatous polyposis coli (APC) genes are usually the cause for the development of desmoid tumours with the former comprising the sporadic development of tumours and the latter being associated with familial adenomatous polyposis syndrome. Surgical resection with histologically negative margins has been the cornerstone of therapy for this disease, but this paradigm has begun to shift. It is now common to accept a microscopically positive margin after resection as recurrence rates may not be significantly affected. This case report intends to describe the clinical, diagnostic and pathologic features of a post-traumatic fibromatosis involving left side chest wall in a 45 years old female and causing worsening pain. The surgical management was successfully undertaken.

Stem cell models for genetically predisposed colon cancer.

Negative growth regulatory tumor suppressor genes and positive growth regulatory oncogenes serve important roles in initiation/progression of colon cancer. Germline mutation in the adenomatous polyposis coli (APC) tumor suppressor gene represents a primary genetic defect for familial adenomatous polyposis (FAP) syndrome, a predisposing factor for clinical colon cancer. Somatic mutations in the APC gene are common in sporadic colon cancer. Preclinical and clinical efficacy is documented for targeted therapy with non-steroidal anti-inflammatory drugs, selective cyclo-oxygenase-2 inhibitors for prostaglandin biosynthesis and selective inhibitor of ornithine decarboxylase for polyamine biosynthesis. However, these therapeutic options lead to systemic toxicity, acquired tumor resistance and emergence of therapy resistant cancer stem cells. By contrast, non-toxic natural products are unlikely to exhibit drug resistance and may represent testable alternatives for therapy resistant colon cancer. Tumorigenic Apc [-/-] colonic epithelial cell lines derived from preclinical FAP models provide novel cellular models for drug resistant cancer stem cells. Apc [-/-] Sulindac resistant (SUL-R) cells exhibit upregulated expression levels of cancer stem cell markers. Natural products, such as naturally occurring vitamin A derivative all-trans retinoic acid (ATRA) and the anti-cancer agent from Turmeric root curcumin (CUR), represent testable alternatives. Relative to the non-tumorigenic Apc [+/+] C57 COL colonic epithelial cells, the tumorigenic Apc [-/-] 1638N COL and Apc [-/-] 850 MIN COL cells exhibit aneuploid cell hyper-proliferation and upregulated expression of Apc target genes β-catenin, cyclin D1, c-myc and COX-2. The SUL-R phenotypes exhibit enhanced tumor spheroid formation and upregulated expression levels of stem cell markers CD44, CD133 and c-Myc. Treatment of the SUL-R stem cells with ATRA and CUR inhibits tumor spheroid formation and reduces the expression of stem cell markers. Stem cell models developed for FAP syndrome provide a novel experimental approach to identify mechanistic leads for efficacious natural products as testable alternatives for therapy-resistant, genetically predisposed colon cancer.

Abstract 2356: Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes

Abstract Hereditary colorectal cancer (CRC) syndromes accounts for approximately 5-10% of total CRC cases. Among those, Lynch syndrome (LS) is the most frequent, but the penetrance depends on the mismatch repair gene (MMR) affected. On the other hand, the Familial Adenomatous Polyposis (FAP) syndrome is less frequent, but with penetrance near to 100%. In Colombia we don't know the prevalence of these syndromes. In the National Cancer Institute from Colombia, the largest reference cancer center in the country, we aim to performed germline genetic analyses in Colombian CRC patients with a suspected hereditary cancer syndrome, as part of the Hereditary Cancer Program that seeks to identified high risk families to offer preventive measures and screening recommendations. A total of 66 patients with CRC fulfilling criteria have been so far analyzed with Next Generation Sequencing using a multigene panel. From those, the 32% have negative results, 41% have VUSs and 27% have positive results (meaning a pathogenic or potentially pathogenic genetic variant). The most prevalent CRC syndrome is Lynch (11/18, 61% with MMR mutated genes), followed by polyposis syndromes such as FAP (11% APC) and MAP (1.5% biallelic MUTYH). Most of our Lynch syndrome families fulfilled Bethesda or Amsterdam criteria. Two recurrent mutations in MLH1 were found in Lynch syndrome families (6/11, 54.5%), which are MLH1: c.1918C&amp;gt;T (p.Pro640Ser) and MLH1: c.790+1G&amp;gt;A. Further haplotype analysis will help us to determine if mutation carriers shared a common ancestry. Citation Format: Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Martha Lucía Serrano-López, Luis G. Carvajal-Carmona, María Carolina Sanabria-Salas. Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2356.

Roles of Capsule Endoscopy and Device-Assisted Enteroscopy in the Diagnosis and Treatment of Small-Bowel Tumors.

With the development of capsule endoscopy (CE) and device-assisted enteroscopy (DAE), the incidence of small-bowel tumors has increased and the characteristics of these tumors have changed. In addition, the diagnostic and therapeutic approaches for small-bowel tumors have diversified. CE is a simple, noninvasive method that aid in the visualization the entire small bowel. CE is considered the initial approach for small-bowel tumors. DAE can be used to perform endoscopic procedures such as bleeding control, polypectomy, stent insertion, and tattooing, as well as for diagnosis through visualization or tissue sampling. Therapeutic intervention with DAE is particularly useful in polyposis syndromes such as familial adenomatous polyposis and Peutz-Jeghers syndrome. This review will discuss the roles of CE and DAE in the diagnosis and treatment of small-bowel tumors.

First person profile: Monica Bertagnolli, MD: An international oncology leader and noted surgical oncologist, Dr. Monica Bertagnolli has forged her own path.

First person profile: Monica Bertagnolli, MD: An international oncology leader and noted surgical oncologist, Dr. Monica Bertagnolli has forged her own path.