Genotype and phenotype of patients with both familial adenomatous polyposis and thyroid carcinoma

The incidence of thyroid carcinoma in familial adenomatous polyposis (FAP) is thought to be 1%–2%, with the majority of cases being female. We have investigated the phenotype and genotype of 16 patients with FAP associated thyroid carcinoma. Among 1194 FAP patients studied in two high risk registries in North America (Familial Gastrointestinal Cancer Registry, Toronto and University California, San Francisco), 16 (1.3%) unrelated patients with FAP associated thyroid cancers were identified. Adenomatous polyposis coli (APC) gene testing was performed in 14 of the 16 cases. The average age of diagnosis for FAP and thyroid carcinoma was 29 years (range 17–52 years) and 33 years (range 17–55 years), respectively. All FAP patients except 1 had more than 100 colonic adenomas. Extracolonic manifestations, beside thyroid cancer, were presented in 81% (n = 13) of the patients, including gastric and duodenal polyps, desmoid tumor, osteoma, epidermoid cyst, sebaceous cyst and lipoma. Colorectal cancer was diagnosed in 38% (n = 6) of the patients. The pathology of the FAP associated thyroid cancer was predominantly papillary carcinoma. Germline mutations were identified in 12 of 14 patients tested. Mutations proximal to the mutation cluster region (1286–1513) were detected in 9 cases. Thyroid cancer in our FAP population was rare, predominantly in females and showed papillary carcinoma histology. Additionally, thyroid cancer in our patients occurred in the setting of classic FAP phenotype. Germline mutations were located predominantly outside the APC mutation cluster region. This revised version was published online in August 2006 with corrections to the Cover Date.     

Rectal cancers in patients with familial adenomatous polyposis

Patients with familial adenomatous polyposis may develop rectal cancer at their initial presentation (primary) or after colectomy and ileorectal anastomosis (secondary). Little is known about whether differences in presentation impact survival. We hypothesize that patients with secondary rectal cancer have better oncologic outcomes. Patients with rectal cancer in the context of familial adenomatous polyposis were classified into 3 groups: known rectal cancer at presentation, incidental rectal cancer unrecognized before proctocolectomy, and rectal cancer diagnosed after ileorectal anastomosis. Primary endpoint was 5-year survival. There were 58 patients, 39 with primary rectal cancer, 5 of which were incidental, and 19 with secondary rectal cancer. Median ages at diagnosis were 32 years (range 14–56) for primary cancer, 35 years (range 22–56) for incidental cancer and 49 years (range 24–66) for secondary cancer (p = 0.001). 76 % of those with primary rectal cancer had symptoms, similar to those with incidental cancer (60 %) but more than secondary cancer (21 %) (p < 0.001). 47 % of primary cancers were advanced (stages III and IV) compared to 20 % of incidental cancers and 32 % of secondary cancers. There was no local recurrence in any patient, but 9 patients had distant recurrences (16 % overall). Overall 5-year survival of patients with primary cancer was 72.4 %, incidental cancer was 100 %, and secondary cancer was 69.7 % (p = 0.031). More patients with primary rectal cancer have advanced disease but survival is similar to those with cancer diagnosed on surveillance. More patients with primary rectal cancer have a restorative resection when compared to other groups.     

Extracolonic features of familial adenomatous polyposis in patients with sporadic colorectal cancer.

We have investigated the occurrence of attenuated extracolonic manifestations (AEMs) of familial adenomatous polyposis (FAP) in patients with non-polyposis colorectal cancer. In a prospective case-control study, we observed that significantly more colorectal cancer patients exhibited AEM than did age and sex-matched controls (19.5% vs 7.5%, P < 0.004). However patients with AEMs do not have occult FAP, as we found no heterozygous adenomatous polyposis coli (APC) gene mutations despite extensive analysis of constitutional DNA. Genome-wide DNA replication errors (RERs) occur in a proportion of colorectal cancers, particularly right-sided lesions and in almost all tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients. As AEMs have been reported in familial colon cancer cases, we investigated the relationship of AEMs to tumour RER phenotype. There was indeed an excess of AEMs in patients with right-sided tumours (30.2% of 53 patients vs 14.7% of 116 patients, P < 0.03) and in those with RER tumours (3 out of 12 patients with RER tumours vs none out of 21 patients with non-RER tumours, P < 0.05). Two patients with AEM were from HNPCC families compared with none of those without AEM (P < 0.05). The association of AEMs with colorectal cancer is intriguing, and we speculate that it may be a manifestation of mutational mosaicism of the APC gene, perhaps associated with a constitutional defect in DNA mismatch pair.     

Dental anomalies in pediatric patients with familial adenomatous polyposis

Familial adenomatous polyposis patients often present with non-malignant extra-intestinal manifestations which include dental anomalies that may be evident prior to the appearance of the colonic adenomas. The aims of this study were to describe the prevalence and type of dental anomalies and the relationships between gene mutations and dental anomalies in these patients. Twenty-two pediatric familial adenomatous polyposis patients and 46 controls, who were age and gender matched participated. Familial adenomatous polyposis patient’s had a dental examination with panoramic radiograph and medical record review for age at diagnosis, the presence of the adenomatous polyposis coli gene mutation, and determination of other extra-intestinal manifestations on the body. The control group was identified from a retrospective chart review and selected if there was a current panoramic radiograph. The only significant difference between familial adenomatous polyposis patients and controls were the presence of jaw osteomas and sclerosis (p?=?.0001). Patients with a mutation in, or upstream of codon 1309 had a higher frequency of osteomas (77.8%) and jaw-bone sclerosis (44.4%), and 77% of these had at least one dental anomaly. This preliminary study showed an association between a genetic variant at, or upstream of codon 1309, and radiographic dental anomalies.     

Chemoprevention of familial adenomatous polyposis

Familial adenomatous polyposis (FAP) has always been first and foremost a surgical disease, whose treatment with colectomy has long been known to reduce risk of premature cancer death. The notion of reducing polyp burden and potentially delaying surgical intervention has spawned a host of “chemoprevention” trials. In this paper I selectively review the findings from these studies, highlighting trial design issues and in particular some of the limitations of historical and existing trial endpoint measures. Nonsteroidal anti-inflammatory agents have been the most commonly employed chemopreventive agents. Sulindac, largely by historical accident, has been the most extensively studied, and is widely considered the standard of care when a clinical decision to intervene medically is made. Newer trials are evaluating combinations of agents in order to take advantage of differing mechanisms of action, in the hope of achieving synergy, as no single agent predictably or completely suppresses adenoma growth. Some of these studies and other single-agent interventions are discussed, though an exploration of the various mechanisms of action is beyond the scope of this paper. It is essential that future trials focus on the issue of “clinical benefit”, not simply because the US Food and Drug Administration has insisted on it, but because only real evidence-based advances can improve the standard of medical care for FAP patients. Hence my focus on issues of trial design and clinically relevant endpoints.     

Hepatoblastoma and familial adenomatous polyposis

Eleven children have been identified as having hepatoblastoma and a family history of adenomatous polyposis, and 14 additional instances of this association have been collected from the literature. Among the 11 survivors of hepatoblastoma in the combined series, adenomatous lesions have been sought in seven and detected in six patients at ages 7 to 25 years. Five of these patients also have congenital hypertrophy of the retinal pigment epithelium, a marker for carriers of the polyposis gene. These findings strengthen the association between hepatoblastoma and familial adenomatous polyposis and have led to the establishment of the Hepatoblastoma-Adenomatous Polyposis Registry.     

Prospective enteroscopic evaluation of jejunal polyposis in patients with familial adenomatous polyposis and advanced duodenal polyposis

Duodenal cancer originating from duodenal adenomas is an important cause of death in patients with familial adenomatous polyposis (FAP). Small intestinal adenomas also occur distal to the duodenum, and literature suggests that they mainly occur in the proximal jejunum in patients with severe duodenal polyp burden. We recently reported on 3 FAP-patients with a jejunal adenocarcinoma, all also harbouring advanced duodenal polyposis. Therefore we questioned whether FAP patients should also be submitted to endoscopic surveillance of the jejunum. The aim of this study was to determine the incidence and burden of jejunal adenomas in patients with FAP and advanced duodenal disease. All patients with FAP and advanced duodenal polyposis (Spigelman stage IV) at our academic centre were invited to undergo antegrade single balloon enteroscopy (Olympus SIF-Q180) with propofol-sedation. Patient characteristics, procedural characteristics (success, depth of insertion) and enteroscopic findings (number, size and pathology) are described. We identified 18 patients with FAP and duodenal polyposis Spigelman stage IV. Thirteen participated in the study with a mean age of 54 (30–64) years. SBE was successfully performed in 10 patients, with a mean depth of insertion of 72 cm beyond the ligament of Treitz. Adenomatous polyps were detected in 9 patients. Only one of them had extensive polyposis beyond Treitz, with large polyps covering up to one-third of the jejunal circumference. No cancers or adenomas with high-grade dysplasia were detected. Clinically significant jejunal polyposis in FAP is rare, even in high-risk patients with advanced duodenal disease. Routine jejunoscopy does not seem warranted in patients with FAP.     

Clinical management of familial adenomatous polyposis

Familial adenomatous polyposis is a generalized growth disorder. It manifests itself in a catastrophic way with the inevitable development of colorectal cancer if left untreated. The aim of clinical management should be to detect this disease at its earliest possible stage by treatment of the family as a unit and identification of those at risk with appropriate screening. Early surgical intervention with, most commonly, colectomy with ileorectal anastomosis or, in more advanced cases, with colectomy, rectal mucosectomy and ileoanal pouch procedure is appropriate. Following colorectal cancer the major risks of death from this disease include upper gastrointestinal cancer, desmoid tumour and a number of other malignancies throughout the body. The exact magnitude of the risk of malignant degeneration of these extracolonic manifestations is as yet uncertain. Surveillance is required particularly for upper gastrointestinal adenomas, as there is a significant risk for the development of duodenal carcinoma and it is obvious that prophylactic colectomy alone does not cure this disease predictably. The role of a familial polyposis registry in managing these patients is important not only in maintaining compliance with surveillance and therefore early detection of the disease but also in educating the family members and gaining long-term follow-up data on these cases to more accurately define the risk of death from extracolonic malignancy.     

家族性腺瘤性息肉病的外科治疗

家族性腺瘤性息肉病（family adenomatous polyposis,FAP）属常染色体显性遗传疾病,目前被认为是癌前病变,而且癌变往往为多发性、多中心性。我们收集了28例FAP患者的临床资料,就FAP的临床特点和外科治疗进行探讨。     

Gonadal mosaicism and familial adenomatous polyposis

De novo mutations in the adenomatous polyposis coli (APC) gene are estimated to constitute approximately 25% of familial adenomatous polyposis (FAP) cases. A small percentage of these arise in the mosaic form, affecting only a subset of cells in the affected individual. A family is described here whereby an unaffected mother with no detectible mutation in APC, transmitted the identical APC c.4729G>T (p.Glu1577X) mutation to two children. A third child, with the same APC allelic haplotype received a normal APC allele, suggesting that the mutation originated in the gonadal tissues of the mother. These results underscore the utility of mutation-specific genetic testing for the parents and siblings of a proband of an adult-onset disease, even if the proband appears to have a de novo mutation. Parents who test negative for the mutation should be counseled about the possibility of having another affected child due to gonadal mosaicism.     

Urological sequelae of desmoids associated with familial adenomatous polyposis

The aim of this retrospective cohort study was to review urological complication rates arising from familial adenomatous polyposis associated desmoid tumours and their management. All patients over a 35-year period were identified from a prospectively maintained polyposis registry database and had an intra-abdominal desmoid tumour. Those without ureteric complications (n?=?118, group A) were compared to those that developed ureteric obstruction (n?=?40, group B) for demographics, treatment interventions and survival outcomes. 158 (56% female) patients were identified. Median age at diagnosis was 31 years and desmoids typically occurred 3.6 years after colectomy for familial adenomatous polyposis. Ureteric obstruction secondary to tumour growth occurred in 25% of cases. There was no significant difference in gender distribution or overall age at desmoid diagnosis between the two groups. In group B, the median age at desmoid diagnosis was significantly younger in women compared to men (25 and 43 years, respectively) (p?=?0.01). Thirty-eight percent of patients already had ureteric obstruction at desmoid diagnosis, the remainder occurred after 48.6 months, but 20 years in two cases. Seventy-three percent (29/40) had ureteric stenting, a long-term requirement for most. Permanent renal injury occurred in six cases but survival between the two groups was not significantly different. Ureteric obstruction occurs frequently in patients with familial adenomatous polyposis and an intra-abdominal desmoid tumour. Those most at risk are the young following colectomy. Clinicians should actively survey the renal tract at regular intervals after a diagnosis of an intra-abdominal desmoid tumour as complications can arise insidiously, at any stage.     

Somatic mutation of the APC gene in thyroid carcinoma associated with familial adenomatous polyposis.

We report the existence of both germline and somatic mutations of the APC gene in thyroid carcinomas from familial adenomatous polyposis (FAP) patients. One papillary thyroid carcinoma from a 210-year-old woman, with germline mutation of the APC gene (TCA to TGA at codon 1110), showed a somatic mutation of AAAAC deletion between codons 1060 and 1063. Another somatic mutation of CAG to TAG at codon 886 was also found in one of multiple thyroid carcinomas from a 26-year-old woman with attenuated FAP and germline mutation at codon 175 (C deletion). This is the first evidence that total absence of the normal function of the APC gene is involved in development of thyroid carcinomas in FAP.     

Modifiers of risk in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant condition caused by mutations in the adenomatous polyposis coli (APC) gene. The phenotypic expression of FAP is extremely variable, and only part of this variability reflects the influence of different germline APC mutations. The remaining differences are likely attributable to the action of modifier genes and environmental (including pharmacologic) factors. In this review, we discuss recent investigations of candidate modifiers of FAP risk, including studies examining the roles of the MutY homolog, insulin-like growth factor-2, EphB receptors, detoxification enzymes, cyclooxygenase-2, and lipoprotein lipase. Identification of FAP modifier genes will provide new insight into the mechanisms of colorectal cancer development and may suggest novel therapeutic targets as well as candidate genes for colorectal cancer susceptibility in the general population.     

Controversies in the surgery of patients with familial adenomatous polyposis and Lynch syndrome

Dominantly inherited syndromes of colorectal cancer predisposition are characterized by multifocal neoplasia with an early age of onset. The risk of colorectal cancer is high in affected patients and care of the patients is based on the aims of cancer prevention and cancer cure. At the same time, quality of life should be disturbed as little as possible. Because patients are generally young, the stakes are high. Injudicious decision-making can have unfortunate effects on patients and families. In this article the controversial aspects of surgery in familial adenomatous polyposis and Lynch syndrome are discussed. Specifically the controversies in familial adenomatous polyposis include the timing and the type of surgery while for Lynch syndrome discussion revolves about prophylactic surgery, primary, secondary and tertiary.     

Oxidative stress in familial adenomatous polyposis.

The prooxidant/antioxidant imbalance in familial adenomatous polyposis (FAP) is suggested by (i) the intimate connection between APC and prostaglandin H synthase-2 genes, (ii) the increase of the free radical-generating enzyme xanthine oxidase, and (iii) the decrease of antioxidant defences. In this research work we evaluated lipid peroxidation measuring the thiobarbituric acid (TBA) reactive products and we studied the activities of superoxide dismutase (SOD) and catalase as well as the levels of ascorbate and tocopherols in the peripheral blood cells from a total of 27 FAP patients and 83 normal controls. TBA-reactive products were determined according to a previously published method. SOD and catalase activities were determined by the spectrophotometric monitoring of the inhibition of pyrogallol autoxidation and the hydrogen peroxide decomposition rate, respectively. Ascorbate levels were determined by a modified 2,4-dinitrophenylhydrazine method and tocopherol levels by a modified Emmerie-Engle method. The levels of TBA-reactive products were higher in FAP patients than in normal controls. Although no statistically significant differences in SOD and catalase activities were observed between FAP patients and normal controls, we found that ascorbate and tocopherol levels were significantly lower in FAP patients than in normal controls, as assessed by the Mann-Whitney test. Hence, this finding of an imbalance in the prooxidant/antioxidant status may contribute towards new strategies for prevention and therapy in FAP patients.     

Gastroduodenal polyps in familial adenomatous polyposis.

A retrospective review of the medical records of 30 patients with familial adenomatous polyposis who underwent oesophagogastroduodenoscopy was performed to evaluate the spectrum of gastroduodenal polyps. Twenty-five patients (83%) had gastroduodenal polyps. Eighteen patients (60%) had gastric polyps and 21 patients (70%) had duodenal polyps. Five patients (17%) had gastric and 20 patients (67%) had duodenal adenomatous polyps. Three patients (10%) died from an upper gastrointestinal tract adenocarcinoma. Three of nine patients with periampullary adenomas had a normal-appearing papilla of Vater. Since gastroduodenal polyps are common in familial adenomatous polyposis, oesophagogastroduodenoscopy should be performed at the time of diagnosis. Biopsy of polyps as well as biopsy of a normal-appearing papilla of Vater should be performed. Due to their malignant potential, if identified, gastroduodenal adenomatous polyps should be destroyed.     

Chromosome changes in desmoid tumors developed in patients with familial adenomatous polyposis.

Chromosome analyses were performed on benign desmoid tumors obtained from two female patients with familial adenomatous polyposis (FAP), one of whom was diagnosed as having Gardner syndrome (GS). The modal chromosome number was 46 in both specimens, and detailed Q-banding analysis in Case 1 (GS) revealed a clonal abnormality of an interstitial deletion of the long arm of chromosome 5, del(5)(q21q31). The deleted region included an assigned locus for an FAP major gene (5q21-q22). All of the metaphases analyzed in this case showed an extra segment of bright fluorescence on the short arm of chromosome 15, but this unusual chromosome (15p+) was observed in both peripheral lymphocyte and skin fibroblast cultures from the patient, indicating that the 15p+ was constitutional in nature. In Case 2, no clonal rearrangements were identified and most cells had a normal karyotype. However, two cells showed rearrangements involving a 17q with non-identical breakpoints, one of which was observed as a solitary chromosome change. Based on the present findings in Case 1 and those reported so far, the chromosomal defect on 5q might be one of the causal genetic events primarily associated with the development of both benign desmoid tumors and colorectal adenomas and carcinomas in FAP patients.