Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer.

Familial adenomatous polyposis (FAP) is an autosomal-dominant condition characterized by the presence of multiple colorectal adenomas, caused by germline variants in the adenomatous polyposis coli (APC) gene. More than 300 germline variants have been characterized. The detection of novel variants is important to understand the mechanisms of pathophysiology. We identified a novel pathogenic germline variant using next-generation sequencing (NGS) in a proband patient. The variant is a complex rearrangement (c.422+1123_532-577 del ins 423-1933_423-1687 inv) that generates a complete deletion of exon 5 of the APC gene. To study the variant in other family members, we designed an endpoint PCR method followed by Sanger sequencing. The variant was identified in the proband patient's mother, one daughter, her brother, two cousins, a niece, and a second nephew. In patients where the variant was identified, we found atypical clinical symptoms, including mandibular, ovarian, breast, pancreatic, and gastric cancer. Genetic counseling and cancer prevention strategies were provided for the family. According to the American College of Medical Genetics (ACMG) guidelines, this novel variant is considered a PVS1 variant (very strong evidence of pathogenicity), and it can be useful in association with clinical data for early surveillance and suitable treatment.

Upper gastrointestinal neoplasia in familial adenomatous polyposis: prevalence, endoscopic features and management.

BACKGROUND: To evaluate the prevalence of upper gastrointestinal (GI) polyps in familial adenomatous polyposis (FAP), and to discuss current therapeutic recommendations. METHODS: Clinical, endoscopic, histological and treatment data were retrieved from charts of 102 patients [1958-2016]. Duodenal adenomatosis was classified according to Spigelman stages. RESULTS: this series comprised 59 women (57.8%) and 43 men (42.1%) with a median age of 32.3 years. Patients underwent 184 endoscopic procedures, the first at a median age of 35.9 years (range, 13-75 years). Fundic gastric polyps (n=31; 30.4%) prevailed in the stomach. While only 5 adenomas were found in the stomach, 33 patients (32.4%) presented duodenal ones. Advanced lesions (n=13; 12.7%) were detected in the stomach (n=2) and duodenum (n=11). During follow-up, Spigelman stages improved in 6 (12.2%) patients, remained unchanged in 25 (51.0%) and worsened in 18 (36.7%). Carcinomas were diagnosed in the stomach and duodenum (4 lesions each, 3.9%), at median ages of 50.2 and 55.0 years, respectively. Advanced lesions and carcinomas were managed through local or surgical resections. Severe complications occurred in only 2 patients (one death). Enteroscopy in 21 patients revealed jejunal adenomas in 12, 11 of whom also presented duodenal adenomas. CONCLUSIONS: There is a high prevalence of upper GI adenomas and cancer in FAP. There were diagnosed fundic gastric polyps (30.4%), duodenal (32.4%) and jejunal adenomas (11.8%), respectively. One third of duodenal polyps progressed slowly throughout the study. The rates of advanced gastroduodenal lesions (12.7%) and cancer (7.8%) raise the need for continuous surveillance during follow-up.

Laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP).

OBJECTIVE: To discuss and evaluate the safety and value of laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP). METHODS: From March 2010 to June 2015, 38 cases were retrospectively analyzed and divided into 2 groups, of which 17 cases used laparoscopy adjuvant total colorectal resection, and 21 cases used conventional laparotomy. Clinical data were obtained, and the safety and prognosis were observed. RESULTS: Seventeen cases using laparoscopy adjuvant total colorectal resection achieved success with no conversion to laparotomy and intraoperative complications. There was no significant difference in operation time between the two groups. There were significant differences in blood loss, the length of incision, postoperative recovery time of intestinal function and postoperative hospital stay between the two groups (P < 0.05). The trauma in laparoscopy group was less, and could recover faster, and there was no significant difference in complications between the two groups. In addition, there were no recurrence, distant metastasis and death in the follow-up period from 6 to 56 months. CONCLUSION: Laparoscopy adjuvant total colorectal resection is more safe and feasible, which has minimal invasion and can recover fast.

Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance.

Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.

Advanced duodenal neoplasia and carcinoma in familial adenomatous polyposis: outcomes of surgical management.

BACKGROUND: In addition to the presence of neoplasia in the colon and rectum, patients with familial adenomatous polyposis (FAP) may develop numerous polyps and carcinoma within the upper gastrointestinal tract. METHODS: The aim of the present paper was to review the incidence advanced duodenal polyposis or cancer and their surgical outcomes. A retrospective review of patients' records from our department was performed. Information was retrieved from a prospective collected data, including clinical (gender, age, family history), endoscopic [association with colorectal cancer (CRC), polyposis severity, age at diagnosis] and surgical management (age, time from the index surgery, type of procedure, morbidity). Duodenal adenomatosis at the time of surgery was classified according to Spigelman stages. RESULTS: In a group of 145 FAP patients, 8 (5.5%) had been surgically treated for duodenal advanced neoplasia [3] or cancer [5]. There were included 2 women and 6 men whose first endoscopic examination and diagnosis of advanced neoplasia/cancer was made at median ages of 47.3 [28-63] and 51.8 years, respectively. Duodenal carcinomas occurred later (55.8 years) when compared to advanced adenomatosis (45.3 years). Three patients were diagnosed due to symptoms, while the others were detected under endoscopic surveillance. Age interval between FAP treatment and duodenal neoplasia diagnosis was 15.3 years [0-47]. All but one patient underwent duodenopancreatectomy (DP). Two from the 7 patients undergoing DP died, one from pulmonary embolism 30 days after surgery and the other from recurrent T4N0 duodenal tumor. Thus, major operative morbidity and mortality were 12.5%. CONCLUSIONS: In this single-center Brazilian series of FAP patients: (I) advanced duodenal neoplasia or cancer requiring surgery occurred in 5.5% of patients; (II) when reaching the fifth decade of life, patients should be carefully evaluated to diagnose and treat early lesions; (III) in spite of the technical complexity of DP, operative morbidity is acceptable in experienced hands; and (IV) continuous surveillance is necessary during follow-up.