Classical Familial Adenomatous Polyposis Research Articles

Large Rearrangements in Genes Responsible for Familial Adenomatous Polyposis, <i>MUTYH</i>-Associated Polyposis and Peutz–Jeghers Syndrome in Russian Patients

Аim: to reveal the rate of large rearrangements in the genes responsible for familial adenomatous polyposis, MUTYH-associated polyposis and Peutz–Jeghers syndrome.Materials and methods. The MLPA method was used for identification of large rearrangements. A total number of 135 patients was included in the study: 83 patients with a clinical diagnosis of “familial adenomatous polyposis”, 18 — with suspected MUTYH-associated polyposis, and 34 — with a clinical diagnosis of “Peutz–Jeghers syndrome”.Results. Seven large deletions and one large duplication in the APC gene were identified in 83 patients with classic familial adenomatous polyposis, with rate of large rearrangements 9.6 % (8/83). In 18 patients with suspected MUTYH-associated polyposis, no large rearrangements were found in the MUTYH gene. Four large deletions in the STK11 gene (12 %, 4/34) were detected in 34 patients with Peutz–Jeghers syndrome.Conclusion. For the first time, the expediency of including the method of detecting large rearrangements in routine DNA test list for Russian patients with various hereditary polyposis syndromes is demonstrated. Routine use of MLPA method makes it possible to increase the total frequency of detection of pathogenic variants in the APC and STK11 genes above 90 %. At the same time, the need for searching of large rearrangements in the MUTYH gene were not justified.

Hereditary Colorectal Cancer and Polyposis Syndromes

The majority of cases of inherited colorectal cancer (CRC) are accounted for by two syndromes: Lynch syndrome and familial adenomatous polyposis (FAP). In the management of FAP, the role of prophylactic surgery is clearly defined, although the optimal procedure for an individual patient depends on a number of factors. In the management of Lynch syndrome, the indications for prophylactic procedures are emerging. The authors address the clinical evaluation, investigation findings, medical and surgical therapy, and extracolonic diseases of FAP, attenuated form of FAP (AFAP), MYH-associated polyposis, Lynch syndrome, familial colorectal cancer type X (FCCTX), hyperplastic polyposis syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. AFAP has been described that is associated with fewer adenomas and later development of CRC compared with classic FAP. The AFAP phenotype occurs in less than 10% of FAP patients. The clinical criteria for AFAP are no family members with more than 100 adenomas before the age of 30 years and (1) at least two patients with 10 to 99 adenomas at age over 30 years or (2) one patient with 10 to 99 adenomas at age over 30 years and a first-degree relative with CRC with few adenomas. Given that polyposis has a later onset and the risk of CRC is less well established in AFAP, some authors question whether prophylactic colectomy is necessary in all AFAP patients. This review contains 26 tables and 173 references Keywords: Colorectal cancer, Lynch syndrome, hyperplastic polyp, Peutz-Jeghers syndrome, juvenile polyposis syndrome, familial adenomatous polyposis

Hereditary Colorectal Cancer and Polyposis Syndromes

The majority of cases of inherited colorectal cancer (CRC) are accounted for by two syndromes: Lynch syndrome and familial adenomatous polyposis (FAP). In the management of FAP, the role of prophylactic surgery is clearly defined, although the optimal procedure for an individual patient depends on a number of factors. In the management of Lynch syndrome, the indications for prophylactic procedures are emerging. The authors address the clinical evaluation, investigation findings, medical and surgical therapy, and extracolonic diseases of FAP, attenuated form of FAP (AFAP), MYH-associated polyposis, Lynch syndrome, familial colorectal cancer type X (FCCTX), hyperplastic polyposis syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. AFAP has been described that is associated with fewer adenomas and later development of CRC compared with classic FAP. The AFAP phenotype occurs in less than 10% of FAP patients. The clinical criteria for AFAP are no family members with more than 100 adenomas before the age of 30 years and (1) at least two patients with 10 to 99 adenomas at age over 30 years or (2) one patient with 10 to 99 adenomas at age over 30 years and a first-degree relative with CRC with few adenomas. Given that polyposis has a later onset and the risk of CRC is less well established in AFAP, some authors question whether prophylactic colectomy is necessary in all AFAP patients. This review contains 26 tables and 173 references Keywords: Colorectal cancer, Lynch syndrome, hyperplastic polyp, Peutz-Jeghers syndrome, juvenile polyposis syndrome, familial adenomatous polyposis

Paired Somatic-Germline Testing of 15 Polyposis and Colorectal Cancer–Predisposing Genes Highlights the Role of APC Mosaicism in de Novo Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome responsible for 1% of colorectal cancers (CRCs). Up to 90% of classic FAPs are caused by inactivating mutations in APC, and mosaicism has been previously reported in 20% of de novo cases, usually linked to milder phenotypic manifestations. This study aimed to explore the prevalence of mosaicism in 11 unsolved cases of classic FAP and to evaluate the diagnostic yield of somatic testing. Paired samples of colorectal polyps, tumors, and/or mucosa were analyzed using a custom next-generation sequencing panel targeting 15 polyposis and CRC-predisposing genes. Whenever possible, the extension of mosaicism to blood or sperm was also examined. Of 11 patients with classic adenomatous polyposis, a mosaic pathogenic variant in APC was identified in 7 (64%). No other altered genes were identified. In two of seven patients (29%), mosaicism was found restricted to colonic tissues, whereas in five of seven patients (71%), it was extended to the blood. Germline affectation was confirmed in one patient. We report the first analysis at a somatic level of 15 genes associated with CRC susceptibility, which highlights the role of APC mosaicism in classic FAP etiology. The results further reinforce the importance of testing target tissues when blood test results are negative.

Rapid Rectal Polyposis Development in a Patient With Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is a well-described genetic condition that results in the development of multiple benign and malignant lesions throughout the gastrointestinal tract. The development of colorectal cancer is nearly universal in classic FAP, and total proctocolectomy after polyp development is recommended. We present a patient with FAP who was unable to undergo proctectomy. Despite careful removal of all rectal polyps before subtotal colectomy with ileorectal anastomosis, he developed 12 rectal polyps, including 4 advanced neoplastic lesions, within 73 days after initial endoscopic removal. This case highlights the rapid regrowth rate of colorectal adenomas in FAP.

Hepatocellular Carcinoma in the Adolescent With Classical Familial Adenomatous Polyposis: Clinical Case

Background. Hepatocellular carcinoma is rare disease in pediatrics, it affects mostly male adolescents aged 10–15 years. There are only 10 described cases of hepatocellular carcinoma and familial adenomatous polyposis combination.Clinical Case Description. Patient G., 16 years, visited the pediatrician with complaints on low fever episodes and abdominal pain. The abdominal ultrasound was performed. Non-homogeneous mass was revealed in the left lobe of the liver. Contrast X-ray computer tomography has revealed large pathological mass in the left lobe of the liver (atypical haemangioma? adenoma?). Adenoma phenotype was established in obtained needle biopsy material. The child has undergone the resection of the left lobe of the liver with plastic reconstruction of the left hepatic vein entry. Histological examination of the surgical specimen has confirmed the presence of hepatocellular carcinoma. Peripheral blood α-fetoprotein levels remained within normal range throughout the follow-up. In past medical history: classical familial adenomatous polyposis in the mother (diagnosis has been established 3 years before the clinical events in the child). The genetic testing of APC gene (Adenomatous Poliposis Coli) was performed after detection of the tumor in the child’s liver. The pathological allele similar to that previously found in the mother has been identified. Conclusion. Timely diagnosis of familial adenomatous polyposis, risk awareness on combined course of polyposis with various malignant tumors, as well as monitoring of health condition of the child are necessary to diagnose hepatocellular carcinoma on its early stages.

In patients with a positive family history of familial adenomatous polyposis can the condition be diagnosed from the presence of congenital hypertrophy of the retinal pigment epithelium detected via an eye examination: A systematic review.

In classic familial adenomatous polyposis (FAP) adenomas become malignant. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a retinal pigmented lesion and is the earliest and most common potential extraintestinal manifestation of FAP. This review aims to summarize and analyse all of the published data on CHRPE in patients with classic FAP and then ascertain whether these patients should undergo a relatively cheap and non-invasive dilated fundus examination to screen for CHRPE. Adhering to Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines our database search identified 102 relevant articles of which 13 were selected for further analysis. The percentage of FAP patients with CHRPE was found to be 80.00%, whereas the percentage of at-risk patients with CHRPE was 31.12%. Despite various statistically significant findings, CHRPE alone cannot be used as a surrogate for diagnosing FAP in those with a positive family history. The authors advocate a combined approach of eye examinations, colonoscopy and genetic testing.

Abstract 655: Clinicopathological and genetic features of colorectal cancer in Algerian patients

Abstract Background Colorectal carcinoma is the third most common form of cancer worldwide. It is the second most common cancer in men and women in Algeria.The aim of this study was to determine clinicopathological and genetic features of colorectal cancer in Algerian patients. For the genetic study, we focused on the two major forms of hereditary colorectal cancer, Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (LS), respectively. Materials and Methods The study population included 366 patients diagnosed with colorectal cancer (CRC). Colorectal carcinoma was diagnosed between January 2017 to March 2018. Clinical and tumor data: age at diagnosis, site of tumor and TNM stage were collected from the medical records of the patients. We screened by PCR-direct sequencing exon 15 of APC gene in 30 patients with a strong family history of classic FAP. 30 patients with Lynch syndrome who fulfilled Amsterdam criteria were screened by PCR- direct sequencing for germline mutations in the MMR genes: MLH1 (exons 9,10,13,16), MSH2 (exons 5,6,7,12) and MSH6 (exon 4). Two FAP patients and two LS patients were screened by NGS using a cancer panel of 30 hereditary cancer genes (Color Genomics, California, USA). Results In this retrospective study, there were 183 women (50%) and 183 men (50%).The median age at diagnosis cancer was 58 years old. The highest proportions of CRC were observed for the age groups 60-69, 50-59 and 40-49 years, 25.4%, 23.49%, 20.49% respectively. We noticed that colorectal tumors were not uniformly distributed through the large bowel. Rectum was the most common site (26.8%) followed by right colon (20.5%), sigmoid colon (18.9%) left colon (13.7%) and caecum (7.4%). Our results showed that 75.95% of the CRC patients were diagnosed at TNM stage II (9.02%), stage III (48.63%) and stage IV (18.31%), respectively. The analysis of DNA samples of FAP patients revealed that 6 patients carried pathogenic variants in APC gene. 3 distinct pathogenic variants: c.1605dupT ( one patient), c.3784delT (2 related patients), and c.3927_3931delAAAGA (3 unrelated patients) were identified in APC gene. Moreover, three distinct germline mutations: c.55_63delATCGCGGCGinsT in exon 1 of MLH1 (one patient), c.1165C>T in exon 7 of MSH2 ( one patient) and the Newfoundland mutation c.942 +3A>T in exon 5 of MSH2 (3 unrelated patients) were detected in 5 Lynch syndrome families.The APC c.1605dupT and c.3784delT and the MLH1 c.55_63delATCGCGGCGinsT new variants have never been reported in LOVD, UMD and ClinVar databases and could be specific of Algerian FAP patients and Lynch syndrome patients, respectively. Haplotype analysis of the APC c.3927_3931delAAAGA and the c.942+3A>T MSH2 variants will establish their genetic origin in Algeria. Conclusions The accumulative knowledge about clinicopathological and genetic characteristics of colorectal cancer in Algerian patients will impact on clinical management in the areas of both prevention and treatment. Citation Format: Farid Cherbal, Asma Lamia Boumehdi, Feriel Khider, Fatma Narimane Nouredine, Karim Layaida, Hassen Mahfouf, Mustapha Maaoui. Clinicopathological and genetic features of colorectal cancer in Algerian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 655.

Optimizing the timing of colorectal surgery in patients with familial adenomatous polyposis in clinical practice

Background: Familial adenomatous polyposis (FAP) is characterized by the development of hundreds of colorectal adenomas in the second decade of life, and prophylactic colectomy is usually performed around age of 20. A common question is the appropriate timing of surgery and which endoscopic findings indicate surgery.Methods: All FAP patients known at Leiden University Medical Centre from 1985 onwards were included. The patients were then subdivided into those diagnosed before or after 2000. Patient information included age at diagnosis, colonic phenotype, age at surgery, pathological findings and the outcome of follow-up colonoscopies in whom surgery was postponed.Results: The 72 FAP patients identified consisted of 33 patients diagnosed before (group A) and 39 after (group B) 2000. The median age at diagnosis for patients with classical FAP was 18 in groups A and B. All patients diagnosed before 2000 underwent colorectal surgery versus 68% of those diagnosed >2000. The median age at surgery for classical FAP patients was 19 and 24 years in groups A and B, respectively. In patients with intact colon, the number of adenomas gradually increased over many years. Although most adenomas remained <5 mm, the proportion of 5–15 mm adenomas slowly increased. Only one patient developed a high-grade adenoma. None of the patients developed CRC.Conclusions: Surgery today in FAP is performed less often and at a more advanced age. Our experience also suggests that surgery can be safely postponed in selected patients. The most important endoscopic indication for surgery is substantial number of large adenomas of >5–10 mm.

Genotype-phenotype correlation in 99 familial adenomatous polyposis patients: A prospective prevention protocol.

BackgroundFamilial adenomatous polyposis (FAP) is a syndrome caused by germline pathogenic variants in the tumor suppressor gene adenomatous polyposis coli (APC). Identification of APC pathogenic variants sites and the genotype‐phenotype correlation are important for characterizing, monitoring, and treating members of affected families. The aim of this study was to correlate genotype‐phenotype of Brazilian individuals carrying APC pathogenic germline variants and that have FAP.MethodsThe polyposis phenotype of 99 individuals from 35 families between July 2013 and December 2014 were prospectively evaluated based on the InSIGHT polyposis staging classification. Seven extra‐colonic manifestations were assessed and the clinical manifestations correlated with the APC genotype.ResultsThe age of the study participants ranged from 12 to 67 years (median of 29 years). Twenty‐six APC pathogenic variants were identified. Fifty‐five cases harbored nonsense pathogenic variants (55.6%). Frameshift alterations were noted in 39 cases (39.4%). Aberrant splicing was noted in 1 case (1%). Rearrangements were observed in 3 cases (3%). An association between nonsense variants and rearrangement was noted in 1 case (1%). The genotype‐phenotype correlation analysis led the identification of classic FAP in 94 cases (94.9%). Profuse polyposis was identified in 5 cases (5.1%). Thirty‐six cases were diagnosed with cancer of which 29 cases (80.6%) were colorectal cancer, 1 case (2.7%) was brain cancer, 4 cases (11.2%) were papillary thyroid cancer, and 2 cases (5.5%) were stomach cancer. The extra‐colonic manifestations included 9 individuals with desmoids tumors, 10 with osteomas, and 9 with congenital hypertrophy of the retinal pigment epithelium.ConclusionsThe genotype‐phenotype correlation in Brazilian individuals with FAP revealed specific findings not previously reported for other cohorts, demonstrating the relevance of knowledge regarding the variable pathogenic variants and clinical presentation in different populations for adequate individual clinical management of patients harboring this medical condition.

Variables affecting penetrance of gastric and duodenal phenotype in familial adenomatous polyposis patients

BackgroundPatients with familial adenomatous polyposis (FAP) frequently undergo colectomy to reduce the 70 to 90% lifetime risk of colorectal cancer. After risk-reducing colectomy, duodenal cancer and complications from duodenal surgeries are the main cause of morbidity. Our objective was to prospectively describe the duodenal and gastric polyp phenotype in a cohort of 150 FAP patients undergoing pre-screening for a chemoprevention trial and analyze variables that may affect recommendations for surveillance.MethodsIndividuals with a diagnosis of FAP underwent prospective esophagogastroduodenoscopy using a uniform system of mapping of size and number of duodenal polyps for a 10 cm segment. Gastric polyps were recorded as the total number.ResultsThe distribution of the count and sum diameter of duodenal polyps were statistically different in two genotype groups, those with APC mutations associated with classic FAP had a greater count (median 17) and sum diameter of polyps (median 32 mm) than those with APC mutations associated with attenuated FAP (median count 4 and median sum diameter of 7 mm) (p < 0.0001). The number of gastric polyps did not differ based on genotype (p = 0.67) but advancing age correlated with severity of gastric polyposis (p = 0.019). Spigelman (modified) staging of II or greater was found in 88% of classic FAP patients and 48% attenuated FAP patients. Examples of severe and mild upper GI phenotype are observed in patients with identical APC mutations, showing that the APC mutation location is not absolutely predictive of an upper GI phenotype.ConclusionsMost FAP patients have duodenal and gastric polyps which become more prevalent and advanced with age. Standard upper endoscopic surveillance is recommended based on personal history independent of APC mutation location.Trial registrationNCT 01187901 registered August 24, 2010, prospective to enrollment.

Collaborating genomic, transcriptomic and microbiomic alterations lead to canine extreme intestinal polyposis

Extreme intestinal polyposis in pet dogs has not yet been reported in literature. We identified a dog patient who developed numerous intestinal polyps, with the severity resembling human classic familial adenomatous polyposis (FAP), except the jejunum-ileum junction being the most polyp-dense. We investigated this dog, in comparison with 22 other dogs with spontaneous intestinal tumors but no severe polyposis, and with numerous published human cancers. We found, not APC mutation, but three other alteration pathways as likely reasons of this canine extreme polyposis. First, somatic truncation mutation W411X of FBXW7, a component of an E3 ubiquitin ligase, over-activates MYC and cell cycle-promoting network, accelerating crypt cell proliferation. Second, genes of protein trafficking and localization are downregulated, likely associated with germline mutation G406D of STAMBPL1, a K63-deubiquitinase, and MYC network activation. This inhibits epithelial apical-basolateral polarity establishment, preventing crypt cell differentiation. Third, Bacteroides uniformis, a commensal gut anaerobe, thrives and expresses abundantly thioredoxin and nitroreductase. These bacterial products could reduce oxidative stress linked to host germline mutation R51X of CYB5RL, a cytochrome b5 reductase homologue, decreasing cell death. Our work emphasizes the close collaboration of alterations across the genome, transcriptome and microbiome in promoting tumorigenesis.

Characteristics of Adrenal Masses in Familial Adenomatous Polyposis.

Adrenal masses are a known extraintestinal manifestation of familial adenomatous polyposis. However, the literature on this association is largely confined to case reports. This study aimed to determine the characteristics of adrenal masses in familial adenomatous polyposis and their clinical significance, as well as to estimate their prevalence. Mutational analysis was conducted to determine if any potential genotype-phenotype correlations exist. This is a retrospective cohort study. Analysis included all patients meeting the criteria of classic familial adenomatous polyposis who were registered with the Familial Gastrointestinal Cancer Registry, a national Canadian database. Appropriate imaging or autopsy reports were available in 311 registry patients. Patients with adrenal metastases were excluded. Data collection included demographic data, mutation genotype, adrenal mass characteristics, surgical interventions and mortality. The prevalence of adrenal masses was 16% (n = 48/311). The median age at diagnosis of adrenal mass was 45 years. The median diameter of adrenal mass at diagnosis was 1.7 cm (interquartile range, 1.4-3.0) with a median maximal diameter of 2.5 cm (interquartile range, 1.7-4.1) with median imaging follow-up of 48 months. The majority of adrenal masses were benign (97%, n = 61/63). Surgery was performed on 7 patients because of concerns for size, malignancy, or hormonal secretion. One adrenal-related death was due to an adrenocortical carcinoma. Mutation analysis did not identify any specific genotype-phenotype correlations. There were incomplete or insufficient endocrinology data available in the registry to allow for the analysis of hormone secretion patterns. Adrenal masses are approximately twice as prevalent in the familial adenomatous polyposis population as in previous studies of the general population. Nearly all mutations led to truncation of the APC gene; however, there was no genetic signature to help predict those at increased risk. The majority of adrenal lesions identified were of benign etiology; thus, an intensive management or surveillance strategy with imaging screening is likely unwarranted. See Video Abstract at http://links.lww.com/DCR/A507.

Bilateral breast fibromatosis after silicone prosthetics in a patient with classic familial adenomatous polyposis: A case report.

Breast fibromatosis is a benign fibroblastic proliferation accounting for less than 0.2% of breast tumors. It presents sporadically or as a manifestation of familial adenomatous polyposis (FAP). Fibromatosis in FAP may develop in patients with adenomatous polyposis coli (APC) gene mutations at any location through the gene. Notably, there is an increased risk if mutation is downstream codon 1400. The present case report described a 33-year-old woman with recurrent bilateral breast fibromatosis after breast implants in a context of classic FAP. APC mutation (codon-935) was detected at the age of 16. In the same year, a thyroidectomy for a cribriform-morular papillary thyroid carcinoma (pT1) was performed. Seven years later, a prophylactic total colectomy with >100 adenomas without invasive carcinoma was performed and the patient was kept under surveillance. At the age of 30 years old, she underwent breast silicone implantation for cosmetic reasons. One year later, bilateral breast tumors were diagnosed in core biopsy as fibromatosis (nuclear β-catenin+, estrogen receptors-). After no success with medical treatment with tamoxifen, bilateral mastectomy was performed. The patient relapsed one year later and a fibromatosis lesion in the right thoracic wall was excised again. The patient demonstrated no signs of relapse 24 months after the surgery. This rare case illustrates that the increased risk of developing fibromatosis in patients with FAP, even in the classic form, should be considered before deciding to place breast implants.

Ileoanal pouch

Proctocolectomy with an ileoanal pouch is the procedure of choice for a variety of underlying diseases, such as ulcerative colitis, classical familial adenomatous polyposis (FAP) and other polyposis syndromes or conditions with multiple synchronous cancers involving the rectum. Recently the indications for Crohn’s colitis and slow transit constipation are being revisited. Since the first description of the procedure in 1978 by Parks and Nicholls with an S‑pouch and the J‑pouch by Utsunomiya in 1983, the latter has become the overall recommended standard. Multiple procedural details are not described in the literature; however, these may contribute to important differences in functional outcome. The methodology varies with the recommended one, two and three-stage procedures and also in being performed conventionally or laparoscopically. Additionally, since the introduction of taTME for rectal cancer, a retake of the discussion regarding the most recommendable ileal pouch-anal anastomosis has evolved. In this article we describe our technical approach for a one-stage procedure of laparoscopic proctocolectomy. It has become our strategy of choice to defer from routine ileostomy and to perform the rectal resection as transanal laparoscopic total mesorectal excision (taTME). Additionally, perioperative management, outcome and the current literature are discussed. The report is illustrated with pictures of a 26-year-old female patient with FAP and profuse distal polyposis reaching the supra-anal level.

A novel APC promoter 1B deletion shows a founder effect in Italian patients with classical familial adenomatous polyposis phenotype.

Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a "classical" polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions versus point mutations in the APC-5' regulatory region.

NSAIDs and EGFR Inhibitors for Duodenal Polyp Prevention.

Familialadenomatouspolyposis (FAP)andattenuatedFAP(AFAP) are relatedgeneticconditions thatarecharacterizedbymultiple synchronous and metachronous colorectal adenomas with a 70% to 100%riskofdevelopingcolorectal cancer (CRC)and, lessoften,duodenal neoplasia. Although both of these conditions are caused by mutations in the coding region of the adenomatous polyposis coli (APC) tumor suppressor gene, thephenotypespresentquitedistinctly in correlationwith the position of the mutation within the coding region. In classic FAP, which presents with amuch greater polyp burden at an earlier age and a greater risk of CRC than AFAP, the mutation occurs in the central region of the protein, whereas mutations in the Nor CterminusareassociatedwithAFAP.TheAmericanGastroenterological Association recommends an annual sigmoidoscopy, beginning at ages 10 to 12 years, for patients with a genetic diagnosis of FAP, or at-risk familymemberswhohavenotundergonegenetic testing.1 Genetic and endoscopic screening of patients and family members, followed by timely treatment, has led to a 55% reduction in the occurrence of CRC at diagnosis of FAP, and improved cumulative survival amongall FAPpatients. In fact, duodenal cancer is now amore common cause of death than CRC in this population. TreatJAMA

Surgical considerations in FAP-related pouch surgery: Could we do better?

The ileoanal pouch has become the standard restorative procedure of choice for patients with the classical phenotype in FAP (familial adenomatous polyposis) and also for ulcerative colitis (UC). Whilst we tend to encounter descriptive analyses comparing functional outcome, fertility and quality of life (QOL) between series in literature, there may be an urgent need to discuss the subtle technical modifications that may be pivotal for improving long-term QOL in FAP patients. Our aim is to review the current literature and discuss the aspects of ileal pouch-anal anastomosis that may require specific reevaluation for FAP. Surgical strategies aimed at minimizing post-interventional desmoid growth is one of the most important aspects. For this study, the following topics of interest were selected: Timing of surgery, IRA or ileoanal pouch for classical FAP, laparoscopic or conventional surgery, TME or mesenteric dissection, preservation of the ileocolic vessels, handsewn or double-staple anastomosis, shape and size of pouch, protective ileostomy, Last and definitely not least: how to manage desmoid plaques or desmoids at the time of prophylactic surgery. For the depicted technicalities of the procedure, a review of recent literature was performed and evaluated. For the topics selected, only sparse reference in literature was identified that was focused on the specific condition situation of FAP. Almost all pouch literature focusses on the procedural aspects, and FAP patients are always a very minor number. Therefore it becomes obvious that the specific entity is not adequately taken into account. This is a serious bias for identification of important steps in the procedure that may be beneficial for patients with either of the diseases. The results of this study demonstrate that several technical differences for construction of ileoanal pouches in FAP patients deserve more attention and prospective evaluation-perhaps even randomized trials. The role, importance and potential benefit or deterioration of outcome in most of the discussed technicalities remains unclear to date. Significant differences between the underlying diseases (UC and FAP) have not been taken into consideration, such as specifically the management of precursor desmoid lesions at the time of prophylactic surgery as well as prevention of desmoid tumors. Several of the aspects discussed in this paper should be prospectively evaluated in larger and exclusive series of FAP patients.

Genotype-phenotype correlation of gastric cancer in familial adenomatous polyposis.

535 Background: Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colorectal tumor syndrome characterized by the formation of a number of adenomatous polyps throughout the entire colon. Clinically, a precise family history together with surveillance of the colon as well as extra-colonic organs for people at risk is important to prevent cancer progression because of an almost 100% lifetime risk of colorectal cancer if the colon is not removed. Although there are fascinating correlations between the location of the APC mutation and the clinical phenotype, none has reported about genotype-phenotype correlation of gastric cancer in FAP, which occupies 2.1-4.2% in East Asia. Methods: Peripheral blood samples were obtained from 29 probands that was clinically diagnosed with FAP and DNA was extracted from the peripheral blood. All the coding exons of APC and their boundary regions were amplified using PCR and were directly sequenced. For large deletion/insertion analysis, an MLPA was performed using MLPA kit (P043 APC, MRC-Holland). Using results from the APC mutation analysis, we examined correlation between location of APCgermline mutation and clinical phenotype including gastric cancer. Results: Among 16 probands (3 cases were severe FAP, 12 cases classical FAP, and one case attenuated FAP) that were identified APC germline mutation, correlation between density of colonic adenomatous polypsosis and distribution of the APC mutation donated the same tendency of previous report. Among the 16 probands, 11 had fundic gland polyposis (FGPs) of the stomach and three had gastric adenocarcinoma (one case with FGPs and others without FGPs). Interestingly, all the three cases did not have severe adenomatous polyposis of the colon and their APC mutations were distributed at the location that is reported to be correlated with attenuated FAP. Conclusions: Patients with gastric cancer in FAP clinically have a tendency of having non-severe adenomatous polyposis of the colon and their location of APC mutation may be correlated to the hot spot location of attenuated FAP, suggesting that patient with non-severe colonic adenomatous polyp should have upper GI screening for gastric cancer prevention.

Upper gastrointestinal tumours in Japanese familial adenomatous polyposis patients.

The upper gastrointestinal characteristics in Japanese familial adenomatous polyposis patients have not yet been clarified. The aim of the present study was to elucidate these characteristics in Japanese familial adenomatous polyposis patients. This study was conducted by the study group for familial adenomatous polyposis in the Japanese Society for Cancer of the Colon and Rectum. Familial adenomatous polyposis patients who underwent surgical resection from 2000 to 2012 were included in the study. In total, 303 familial adenomatous polyposis patients were enrolled, with 265 cases of classical familial adenomatous polyposis (≥100 adenomas) and 38 cases of attenuated familial adenomatous polyposis (<100 adenomas). Fundic gland polyps were significantly more common in classical familial adenomatous polyposis than in attenuated familial adenomatous polyposis; however, gastric cancer was significantly less common in classical familial adenomatous polyposis than in attenuated familial adenomatous polyposis. Gastric cancer and duodenal adenoma were significantly more common in familial adenomatous polyposis patients with gastric adenoma than in those without gastric adenoma. Duodenal cancer was detected in 7 of 72 familial adenomatous polyposis patients with duodenal adenoma. The median tumour risk in 50-year-old familial adenomatous polyposis patients was 55.3, 21.8, 3.8, 39.2 and 7.7% for fundic gland polyp, gastric adenoma, gastric cancer, duodenal adenoma and duodenal cancer, respectively. Upper gastrointestinal tumours/polyps were frequently found in familial adenomatous polyposis patients, and their incidences were correlated; however, the frequency of gastric cancer in Japanese familial adenomatous polyposis patients was similar to that in the general population.