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BACKGROUND Individuals with Lynch syndrome (LS) and hereditary non-polyposis colorectal cancer (HNPCC) are at increased risk of both colorectal cancer and other cancers. The interplay between immunosuppression, a comorbid inflammatory condition (CID), and HNPCC on cancer risk is unclear. AIM To evaluate the impact of CIDs, and exposure to monoclonal antibodies and immunomodulators, on cancer risk in individuals with HNPCC. METHODS Individuals prospectively followed in a hereditary cancer registry with LS/HNPCC with the diagnosis of inflammatory bowel disease or rheumatic disease were identified. We compared the proportion of patients with cancer in LS/HNPCC group with and without a CID. We also compared the proportion of patients who developed cancer following a CID diagnosis based upon exposure to immunosuppressive medications. RESULTS A total of 21 patients with LS/HNPCC and a CID were compared to 43 patients with LS/HNPCC but no CID. Cancer occurred in 84.2% with a CID compared to 76.7% without a CID (P = 0.74) with no difference in age at first cancer diagnosis 45.5 ± 14.6 vs 43.8 ± 7.1 years (P = 0.67). LS specific cancers were diagnosed in 52.4% with a CID vs 44.2% without a CID (P = 0.54). Nine of 21 (42.9%) patients were exposed to biologics or immunomodulators for the treatment of their CID. Cancer after diagnosis of CID was seen in 7 (77.8%) of exposed individuals vs 5 (41.7%) individuals unexposed to biologics/immunomodulators (P = 0.18). All 7 exposed compared to 3/5 unexposed developed a LS specific cancer. The exposed and unexposed groups were followed for a median 10 years and 8.5 years, respectively. The hazard ratio for cancer with medication exposure was 1.59 (P = 0.43, 95%CI: 0.5-5.1). CONCLUSION In patients with LS/HNPCC, the presence of a concurrent inflammatory condition, or use of immunosuppressive medication to treat the inflammatory condition, might not increase the rate of cancer occurrence in this limited study.

Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.

Background & Aims Ampullary and duodenal cancer are the leading causes of death in patients with familial adenomatous polyposis (FAP) after colectomy has been performed. Risk of duodenal cancer is determined based on Spigelman stage (SS) of duodenal polyposis. Guidelines recommend endoscopic surveillance of the duodenum and visualization of the papilla to stage duodenal polyposis. There is no consensus on whether biopsies should be routinely collected from duodenal papilla and findings included in SS. Additionally, there are no data on the risk of pancreatitis after biopsy collection from papilla of patients with FAP. We studied the incidence of pancreatitis after biopsy of the papilla in patients with FAP and effects of biopsy findings on SS. Methods We identified consecutive patients with FAP at a single center from January 2011 through December 2018 with ≥1 endoscopy with biopsy of the papilla. Patients with history of foregut surgery were excluded. We identified 273 patients with FAP who had biopsies collected from papilla over 792 EGDs, with 1–8 independent exams with biopsy per patient. We collected demographic, endoscopic, and histology data from patients and calculated SS with vs without biopsy findings. Post-procedural pancreatitis was defined by 2 of the following: abdominal pain, lipase level 3-fold the upper limit of normal, or radiography findings consistent with pancreatitis within 7 days of esophagogastroduodenoscopy (EGD). Results Pancreatitis developed in 2 patients (0.73%): 1 after biopsy of a normal-appearing papilla and 1 after biopsy of an abnormal appearing papilla. Inclusions of biopsy data increased SS in 36 patients (13.2%), with consideration of prophylactic duodenectomy for 3.3%. Conclusions Pancreatitis after biopsy of the duodenal papilla is rare. Histology data obtained from biopsy of the papilla in patients with FAP can change SS and affect patient management.

INTRODUCCION El Registro de Cancer Colorrectal Hereditario es uno de los registros mas antiguos y mas grandes de su tipo. Incluye a los pacientes con todos los sindromes hereditarios de cancer colorrectal, utilizando los tres enfoques basicos, la atencion al paciente, la educacion y la investigacion. Este articulo resume la estructura y funcion del registro, y da ejemplos de sus contribuciones al manejo de los pacientes afectados. ACTIVIDAD En el ano 2016 el registro atendio a mas de 1000 familias con poliposis adenomatosa familiar, 224 familias con sindrome de Lynch, 61 con poliposis asociada a MYH y 146 con poliposis hamartomatosa. En el ano 2016 hubo 1009 visitas de pacientes con 80 nuevos pacientes y 879 endoscopias. Se realizaron mas de 60 cirugias. RESUMEN Se describe el enfoque de “Cleveland Clinic” para el cancer colorrectal hereditario. Esto es multidisciplinario, involucrando varias especialidades y asi como servicios de asesoramiento genetico y de salud mental dentro del registro.

The timing of prophylactic colorectal surgery in patients with familial adenomatous polyposis (FAP) is based on the immediacy of the colorectal cancer risk. The ability to predict the need for surgery may help patients and their families plan in the context of life events and CRC risk. We created a model to predict the likelihood of surgery within 2 and 5 years of first colonoscopy at our institution. A single institution hereditary colorectal syndrome (Cologene™) database was interrogated for all patients with FAP having a deleterious APC mutation. Patients with first colonoscopy after age 30 and before year 2000 were excluded. Cox regression analysis was done to assess multiple factors associated with surgery, followed by stepwise Cox regression analysis to select an optimal model. Receiver operator curve (ROC) analysis was performed to assess the model. A total of 211 (53% female) patients were included. Forty-five percent underwent surgery after an average of 3.8 years of surveillance. The final model was created based on initial clinical characteristics (age, gender, BMI, family history of desmoids, genotype–phenotype correlation), initial colonoscopic characteristics (number of polyps, polyp size, presence of high-grade dysplasia); and on clinical events (chemoprevention and polypectomy). AUC was 0.87 and 0.84 to predict surgery within 2 and 5 years, respectively. The final model can be accessed at this website: http://app.calculoid.com/#/calculator/29638 . This web-based tool allows clinicians to stratify patients’ likelihood of colorectal surgery within 2 and 5 years of their initial examination, based on clinical and endoscopic features, and using the philosophy of care guiding practice at this institution.

OBJECTIVES: Duodenal cancer in familial adenomatous polyposis (FAP) arises from adenomas. Differentially expressed genes (DEGs) in the duodenal adenoma-carcinoma pathway have been identified in murine FAP models, but similar data in patients with FAP are limited. Identifying such changes may have significance in understanding duodenal polyposis therapies and identifying cancer biomarkers. We performed a genome-wide transcriptional analysis to describe the duodenal adenoma-carcinoma sequence and determine changes distinguishing patients with FAP with and without duodenal cancer. METHODS: Transcriptional profiling was performed with the Affymetrix Human Transcriptome Array 2.0 on duodenal biopsies from 12 FAP patients with duodenal cancer (FAP cases) and 12 FAP patients without cancer (FAP controls). DEGs were compared between cancer-normal, adenoma-normal, and cancer-adenoma in FAP cases and between adenomas from FAP cases and FAP controls. Significant results at P < 0.05 were filtered using fold change > 2. RESULTS: Two hundred twenty-four DEGs were identified at an absolute fold change > 2. In adenoma-normal, downregulation of DEGs involved in metabolism of brush border proteins (LCT), lipids (APOB/A4), reactive oxygen species (GSTA2), and retinol (RBP2) was observed. In the cancer-adenoma comparison, upregulation of DEGs involved in cell invasion/migration (POSTN, SPP1) and downregulation of DEGs involved in Paneth differentiation (DEFA5/6) were observed. In the adenoma-adenoma comparison, downregulation of several DEGs (CLCA1, ADH1C, ANXA10) in FAP case adenomas was observed. DEGs with therapeutic potential include SPP1, which is involved in both cyclooxygenase and epidermal growth factor receptor pathways targeted by the sulindac/erlotinib combination for duodenal polyposis. DISCUSSION: We describe DEGs in the human duodenal adenoma-carcinoma sequence in FAP, which may have prognostic and therapeutic significance. Validation studies are needed to confirm these findings.

Background Preliminary data suggests the APC protein is critical for dependent pathways in the cochlea and may be important in cognition. Abnormal audiometries have been documented in Familial Adenomatous Polyposis (FAP). We studied cognitive function among patients with FAP. Methods FAP patients were recruited for an IRB (Institutional Review Board) approved study assessing intelligence using the Kaufman Brief Intelligence Test (KBIT-2), which provides Verbal, Nonverbal and Composite IQs. The KBIT-2 was administered and scored by individuals experienced in administration of psychometric measures. Mean scores were analyzed and compared to standard normal ranges. Results 44 subjects from 42 families (22 men), mean age of 42 years were included. KBIT-2 Composite IQ score was 98.4 ± 12.4, (95% CI (confidence interval) 94.5-102.3) which is within the average range of 90-109. 27 % of patients scored below average (less than 90) and 15% scored above average (greater than 109), not a significant imbalance (sign test p=0.33). Nonverbal IQ scores show no difference from average, mean=100.5; 24% scored below and 27% scored above average. Verbal scores were 95.5 ± 12.0 (95% CI 91.7 -99.2) significantly lower than average (one-sample T-test p=0.020). There is an imbalance among patients with 27% below and 7% above the average range and a tendency toward lower than average scores (sign test P=0.06). The mean number of points by which Nonverbal IQ exceeded Verbal IQ was 5.0 ± 12.5 (95% CI 1.1 -9.0), (one-sample T-test p=0.013). The non-verbal score exceeded the verbal score for 27 patients (65.9%), while the verbal score was larger for only 10 patients (24.4%) (Sign test p=0.008). Conclusion Composite IQ scores suggest that FAP patients do not have lower IQ from the general population. However the verbal scores of FAP patients which are dependent on hearing are significantly lower than average and may reflect abnormal audiometries or other effects of the APC mutation on cognitive function.

Hepatoblastoma is a rare hepatic malignancy that is seen in Familial Adenomatous Polyposis (FAP). The occurrence is four hundred fold higher than the general population [1]. Hepatoblastoma is generally treatable with surgery; in addition it is highly responsive to chemotherapy. While the literature reports on this extracolonic manifestation of FAP, no screening recommendations exist, this may be due to the rarity of the condition and paucity of published literature. Our aim was to examine and assess the number of hepatoblastoma patients, their associated demographics and the outcome of disease.

Purpose The identification of individuals with Hereditary Non Polyposis Colorectal Cancer (HNPCC) in the population is suboptimal. Causes include lack of physician recognition or failure to take an accurate family history. While colorectal cancer (CRC) in HNPCC is preventable by annual colonoscopy it is underutilized in part by lack of physician recommendation or poor understanding of personal risk of disease. We developed an online CRC risk assessment (http://www.clevelandclinic.org/score) incorporating family and personal history of adenomas and CRC which generated a pedigree, risk category and screening recommendations based on ACG guidelines. Modifiable lifestyle factors were also assessed and personalized recommendations were provided to minimize neoplasia due to those factors. We assessed the feasibility and online uptake of this tool and determined the proportion of high risk individuals who meet criteria suspicious for HNPCC. Methods The assessment included questions on demographics, use of previous CRC screening, and family and personal history of adenomas and CRC in 3 generations. Height, weight, age > or < 50, race, smoking exposure, physical activity, and dietary habits assessed. Risk categories included average, low, medium, and high.

Background Hyperplastic Polyposis Syndrome (HPS) is a rare disease characterized by multiple or large hyperplastic polyps and carries an approximately 40% lifetime colorectal cancer risk. Although a genetic basis has not been established, HPS is believed to be a heritable syndrome and is diagnosed by clinical criteria as set forth by the World Health Organization (WHO). Based on clinical experience, we hypothesized that WHO criteria may be narrowly restrictive and misses some patients with an increased malignancy risk.

Background The APC protein has an important role in maintaining function of microtubules in the ear which playa significant part in the mechanism of hearing. Preliminary data suggests that the APC protein is associated with an increased incidence of abnormal hearing which may affect intellectual function. We sought to assess the hearing among patients with FAP (Familial Adenomatous Polyposis). Methods Patients with FAP were recruited for an IRB (Institutional Review Board) approved study assessing hearing and intelligence. Hearing was tested by pure tone air conduction audiometry, less than or equal to 30 db at 3/4 of the following frequencies (500 Hz, 1000 Hz, 2000 Hz and 4000 Hz). Subjects were then administered the Kaufman Brief Intelligence Test (KBIT-2). We then analyzed the proportion of individuals with an abnormal audiometry as compared to age and gender adjusted normalized hearing standards. Results 44 patients were recruited from 42 families. Subjects included 22 men with a mean age of 42 years. When compared to normalized hearing standards, 19 (43.2%) of the 44 patients failed to meet the standard normal range. Audiologic abnormalities showed unilateral hearing impairment was documented in 6 patients, bilateral impairment in 13. Of these patients 63% were impaired at a single frequency; the other 37% were at multiple frequencies. 59% of patients showed right hearing impairment with the highest deficit (35%) at 2000 Hz. 71% of patients had left sided impairment with the greatest number (32%) at 4000 Hz. Conclusion A large subset of our sample of FAP patients (43.2%) had abnormal audiologic results when compared to the normalized standard. Differences in IQ scores for patients with and without audiologic abnormalities are not statistically significant, suggesting that these results do not reflect an association between hearing and intellectual functioning in our sample.

Background Patients with FAP are at risk of dying from multiple benign and malignant tumors, from surgical complications, and comorbid diseases. We previously evaluated and published causes of death in FAP patients in 1990. This study analyzes patterns of mortality in the ensuing 2 decades and compares the two time periods to determine if advances in medicine and technology have changed clinical outcomes.

Background MYH-Associated Polyposis (MAP) is an autosomal recessive condition caused by bi-allelic mutations in MYH. Individuals with MAP tend to develop numerous polyps in their colon and rectum and have an increased risk of developing colorectal cancer. Recommendations for MAP treatment vary in the literature ranging from frequent surveillance colonoscopy to prophylactic surgery depending on polyp burden. The aim of this study was to report the management and outcome of a single institution series of patients with MAP. Methods Patients with biallelic mutations in MYH were accrued over 23 years from a query of a comprehensive polyposis database using Cologene© software. Demographics, family history, upper and lower endoscopy frequency, polyp burden, and cancer data, and treatment were recorded.