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.     

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.     

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.     

Chemoprevention of familial adenomatous polyposis in Apc(Min/+) mice by phenethyl isothiocyanate (PEITC)

Phenethyl isothiocyanate (PEITC) is an isothiocyanate which is a major constituent of watercress and other cruciferous vegetables. Its chemopreventive potential has been previously shown in various rodent models of cancer. In this study, we investigated the chemopreventive efficacy of PEITC in the Apc(Min/+) mouse model. Apc(Min/+) mice were fed with diet supplemented with 0.05% of PEITC for 3-wk. Our results clearly demonstrated that Apc(Min/+) mice fed with PEITC supplemented diet developed significantly less (31.7% reduction) and smaller polyps in comparison to mice fed with the standard AIN-76A diet. Subsequent mechanistic study using Western blotting shows that inhibition of growth of adenomas by PEITC is associated with increase of apoptosis (cleaved-caspase-3, -caspase-7, and PARP). Treatments also led to the inhibition of cell cycle-related biomarkers such as the cyclins (D1, A, and E) and activation of p21. However, PEITC has no effect on the expression of p-Erk, p-JNK or p-p38. In conclusion, our results demonstrate that PEITC is a potent natural dietary compound for chemoprevention of gastrointestinal cancers. Its mechanism of actions may include induction of apoptosis and cell cycle arrest.     

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.     

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.     

A new phenotypic manifestation of familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disease with hundreds of colorectal adenomas in teenagers and progression to colorectal cancer if colectomy is not performed. We investigated the association of two phenotypic manifestations-oral mucosal vascular density (OMVD) and oral mucosal reflectance (OMR)––with FAP and patients with multiple colorectal adenomas. Thirty-three patients with FAP from 29 unrelated pedigrees with APC gene mutation, 5 with multiple adenomas and no known gene mutations, and 50 population controls were evaluated for the two different manifestations utilizing a photographic/spectrophotometric system capturing images and reflectance at various wavelengths. Statistical analysis was performed with student t test and test performance characteristics were calculated. There were no significant differences in demographic variables between the FAP and control group. A significant difference in OMVD between FAP patients and controls was noted, P < 0.001. The sensitivity and specificity of oral mucosal vascular density for FAP was 91 and 90%, respectively. No association between this phenotypic manifestation and age or gender was found. All 5 patient with multiple polyps were positive for OMVD and the value was significantly higher than controls, P = 0.002. No significant difference was noted in OMR between the two patient groups and controls. OMVD is a new phenotypic manifestation in patients with FAP and also may identify those with multiple adenomas without known gene mutation.     

Desmoids in familial adenomatous polyposis are monoclonal proliferations

Desmoids are poorly-understood, locally aggressive, non-metastasizing fibromatoses that occur with disproportionate frequency in patients with familial adenomatous polyposis (FAP). Their nature is controversial with arguments for and against a neoplastic origin. Neoplastic proliferations are by definition monoclonal, whereas reactive processes originate from a polyclonal background. We examined clonality of 25 samples of desmoid tissue from 11 female FAP patients by assessing patterns of X-chromosome inactivation to calculate a clonality ratio. Polymerase chain reaction (PCR) amplification of a polymorphic CAG short tandem repeat (STR) sequence adjacent to a methylation-sensitive restriction enzyme site within the human androgen receptor (HUMARA) gene using fluorescent-labelled primers enabled analysis of PCR products by Applied Biosystems Genescan II software. Twenty-one samples from nine patients were informative for the assay. Samples from all informative cases comprised a median of 66% (range 0-75%) clonal cells but from the six patients with a clonality ratio < or =0.5 comprised a median of 71% (65-75%) clonal cells. FAP-associated desmoid tumours are true neoplasms. This may have implications in the development of improved treatment protocols for patients with these aggressive tumours.     

Mouse models for human familial adenomatous polyposis.

Colorectal cancer (CRC) is the second most frequent type of cancer in the Western hemisphere. In the United States alone, it is estimated that 150 000 new cases are detected every year and more than 65 000 patients die from complications associated with this cancer. Identification of genes implicated in the initiation and progression of colorectal cancer in humans has prompted the generation of mouse models for this cancer. We will provide a brief overview of these mouse models for CRC and what they have contributed to our understanding of the events involved in the initiation and progression of this cancer.     

Disseminating risk information to familial adenomatous polyposis families

The Hereditary Cancer Registers (HCR) offer registration to individuals at risk of hereditary bowel cancer. Most families are registered to the HCR via Familial Cancer Clinics (FCC)s. The FCCs work together with the HCR to inform family members that they may be at increased risk of hereditary bowel cancer. In 2002, The Hunter Family Cancer Service (HFCS) and the HCR developed a system to ensure at risk family members become informed of their risk. Evaluation of this system is presented. The system involves tracking which family members are informed of their risk using a rating system. Being informed is graded numerically, from 5 (not informed) through to 1(definitely informed). Changes in score are brought about through staff and the FCC and HCR working with registrants to contact at risk family members. This study analyses data collected for a subgroup of 21 families registered with the HCR by the HFCS. Baseline and resulting scores indicated whether the 738 at risk family members had become better informed of their risk. One hundred and sixty eight individuals changed to a score of “definitely informed” and 230 individuals score changed from “not informed” to being better informed. The results demonstrate significant change in these family members towards becoming better informed (z = −13.88, P < 0.0001, Wilcoxon signed ranks test). These data suggest that the system for informing family members of their risk has resulted in significant positive change towards these individuals becoming more informed. The system has the potential to reach over 2,800 at risk family members, of registered families, resulting in improved surveillance and better health outcomes.     

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.     

Chemoprevention of familial adenomatous polyposis by bromo-noscapine (EM011) in the Apc(Min/+) mouse model

Germline mutation of the tumor suppressor gene, adenomatous polyposis coli (APC), is responsible for familial adenomatous polyposis (FAP) with nearly 100% risk for colon cancer at an early age. Although FAP is involved in only 1% of all colon cancer cases, over 80% of sporadic cancers harbor somatic mutations of APC. We show here that bromo-noscapine (EM011), a rationally designed synthetic derivative of a natural nontoxic tubulin-binding alkaloid-noscapine, that reduces the dynamics of microtubules, causes a reversible G(2) /M arrest in wild type murine embryonic fibroblasts (MEFs), but an aberrant exit from a brief mitotic block, followed by apoptosis in MEFs after APC deletion with small interfering RNA. Furthermore, both β-catenin levels and activity fell to half the original levels with a concomitant reduction of cell proliferation-inducing cyclin D1, c-Myc, and induction of cytostatic protein p21 before caspase-3 activation. Additionally, we show a statistically significant reduction in the number of newly emerging intestinal polyps (to 35% compared with untreated mice) as well as the mean size of polyps (to 42% compared with untreated mice) in EM011-treated Apc(Min/+) mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of Apc(Min/+) mice showed evidence of elevated apoptosis as revealed by immunohistochemistry. We failed to detect any evidence of histopathological and hematological toxicities following EM011 treatment. Taken together, our data are persuasive that a clinical trial of EM011 is possible for the prevention/amelioration of polyposis in FAP patients.     

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.     

Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse

Cancer chemopreventive agent sulforaphane (SFN) and dibenzoylmethane (DBM) showed antitumorigenesis effects in several rodent carcinogenesis models. In this study, we investigated the cancer chemopreventive effects and the underlying molecular mechanisms of dietary administration of SFN and DBM alone or in combination in the ApcMin/+ mice model. Male ApcMin/+ mice (12 per group) at age of 5 weeks were given control AIN-76A diet, diets containing 600 ppm SFN and 1.0% DBM, or a combination of 300 ppm SFN and 0.5% DBM for 10 weeks. Mice were then sacrificed, and tumor numbers and size were examined. Microarray analysis, Western blotting, ELISA, and immunohistochemical staining were done to investigate the underlying molecular mechanisms of cancer chemopreventive effects of SFN and DBM. Dietary administrations of SFN and DBM alone or in combination significantly inhibited the development of intestinal adenomas by 48% (P=0.002), 50% (P=0.001), and 57% (P<0.001), respectively. Dietary administration of 600 ppm SFN and 1.0% DBM also reduced colon tumor numbers by 80% (P=0.016) and 60% (P=0.103), respectively, whereas the combination of SFN and DBM treatment blocked the colon tumor development (P=0.002). Both SFN and DBM treatments resulted in decreased levels of prostaglandin E2 or leukotriene B4 in intestinal polyps or apparently normal mucosa. Treatments also led to the inhibition of cell survival and growth-related signaling pathways (such as Akt and extracellular signal-regulated kinase) or biomarkers (such as cyclooxygenase-2, proliferating cell nuclear antigen, cleaved caspases, cyclin D1, and p21). In conclusion, our results showed that both SFN and DBM alone as well as their combination are potent natural dietary compounds for chemoprevention of gastrointestinal cancers.     

Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APCMin mice

Preclinical and clinical studies have established evidence that cyclooxygenase-2 (COX-2) inhibitors and statins [hydroxy-3-methylglutaryl CoA reductase (HMGR) inhibitors] inhibit colon carcinogenesis. Chronic use of high doses of COX-2 inhibitors may induce side effects, and combining the low doses of agents may be an effective way to increase their efficacy and minimize the side effects. We assessed the chemopreventive efficacy of atorvastatin (Lipitor) and celecoxib individually or in combination in an animal model of familial adenomatous polyposis. Six-week-old male C57BL/6J-APCmin/+ mice were either fed diets containing 0 or 100 ppm atorvastatin or 300 ppm celecoxib, or a combination of both for approximately 80 days. Mice were sacrificed, and their intestines were scored for tumors. Normal-seeming mucosa and intestinal tumors were harvested and assayed for apoptosis (terminal deoxynucleotidyl transferase-mediated nick-end labeling) and HMGR and COX-2 protein expression and activity. We observed that 100 ppm atorvastatin significantly (P < 0.002) suppressed intestinal polyp formation. As anticipated, 300 ppm celecoxib decreased the rate of formation of intestinal polyps by approximately 70% (P < 0.0001). Importantly, the combination of 100 ppm atorvastatin and 300 ppm celecoxib in the diet suppressed the colon polyps completely and small intestinal polyps by >86% (P < 0.0001) compared with the control group. The inhibition of tumor formation by the atorvastatin and celecoxib combination was significant (P < 0.005) when compared with tumor inhibition by celecoxib alone. In addition, increased rates of apoptosis in intestinal tumors (P < 0.01-0.0001) were observed in animals fed with atorvastatin and celecoxib and more so with the combinations. Tumors of animals fed atorvastatin showed a significant decrease in HMGR-R activity. Similarly, tumors of mice exposed to celecoxib showed significantly lower levels of COX-2 activity. These observations show that atorvastatin inhibits intestinal tumorigenesis and that, importantly, when given together with low doses of celecoxib, it significantly increases the chemopreventive efficacy in an APC(min) mice.