Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome.

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.

Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis.

BACKGROUND: Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. METHODS: We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). RESULTS: We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. CONCLUSIONS: These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.

Surgical management for advanced duodenal adenomatosis and duodenal cancer in Dutch patients with familial adenomatous polyposis: a nationwide retrospective cohort study.

BACKGROUND: Duodenal cancer is a major cause of mortality in patients with familial adenomatous polyposis (FAP). The clinical challenge is to perform duodenectomy before cancer develops; however, procedures are associated with complications. Our aim was to gain insight into the pros and cons of prophylactic duodenectomy. METHODS: Patients with FAP from the nationwide Dutch polyposis registry who underwent prophylactic duodenectomy or were diagnosed with duodenal cancer were identified and classified as having benign disease or cancer at preoperative endoscopy. Surveillance, clinical presentation, surgical management, outcome, survival, and recurrence were compared. RESULTS: Of 1,066 patients with FAP in the registry, 52 (5%; 25 males) were included: 36 with benign adenomatosis (median: 48 years old; including two (6%) cancer cases diagnosed after operation), and 16 with cancer (median: 53 years old). Cancer cases had been diagnosed with colorectal cancer more often (6% vs 44%; P < .01). Forty-three patients underwent duodenectomy (35 benign/eight cancer): 30-day mortality was 4.7% (n = 2), and in-hospital morbidity occurred in 21 patients (49%), without differences between patients with benign adenomatosis and cancer. Adenomas recurred in reconstructed proximal small bowel in 14 of 28 patients (50%, median time to recurrence: 75 months), and one patient developed cancer. Median survival of all 18 cancer cases in the registry (1.7%; 12 ampullary/six duodenal) was 11 months. CONCLUSION: Prognosis of duodenal cancer in patients with FAP is poor, which justifies an aggressive approach to advanced benign adenomatosis. Strict adherence to recommended surveillance intervals is essential for a well-timed intervention. Given the substantial morbidity and mortality of duodenectomy, patients' individual characteristics are to be critically evaluated preoperatively. As adenomas recur, postoperative endoscopic surveillance is mandatory.

Family history, surgery, and APC mutation are risk factors for desmoid tumors in familial adenomatous polyposis: an international cohort study.

BACKGROUND: Ability to identify patients with familial adenomatous polyposis who have a high risk of developing desmoid tumors may affect decisions in clinical practice. OBJECTIVES: Our aim was to assess several risk factors for desmoid tumor development in an international cohort of patients with familial adenomatous polyposis and to evaluate the clinical relevance of risk factors. DESIGN: This was a retrospective cohort study. SETTING AND PATIENTS: Polyposis registries in The Netherlands, France, Denmark, Finland, and Italy provided information on familial adenomatous polyposis patients with desmoid tumors. MAIN OUTCOME MEASURES: We used univariate and multivariable analyses of data from registries in The Netherlands, France, Denmark, and Finland to test whether gender, APC mutation site, previous colorectal surgery, colorectal cancer, and family history for desmoid tumors contribute to risk of developing desmoid tumors at any location, or specifically at an intra-abdominal location. The effect of family history was tested with a generalized linear mixed model. RESULTS: : Of 2260 patients with familial adenomatous polyposis from 912 families in The Netherlands, France, Denmark, and Finland, 220 patients (10%) had desmoid tumors (101 men). In 387 patients with desmoid tumors (including 167 patients from the Italian registry), the median age at diagnosis of the first desmoid tumor was 31 years (range, 4 months-74 years). Desmoid locations were intra-abdominal (53%), abdominal wall (24%), extremities (9%), and unknown sites or combinations of sites (14%). Multivariable analysis of risk factors for desmoids at any location showed surgery (OR, 2.58; P = .0004), an APC mutation 3' of codon 1444 (OR, 3.0; P < .0001), and a positive family history (P < .0001) to be independently associated with desmoid development. When only intra-abdominal location was analyzed, APC mutation site was not associated with desmoid development. LIMITATIONS: Selection bias may have occurred. CONCLUSIONS: A positive family history for desmoid tumors, abdominal surgery, and APC mutation site are significant risk factors for development of desmoid tumors. The results may have implications for determining the optimal management of FAP patients and guide future studies.

A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses.

Desmoid-type fibromatoses are neoplasms of fibroblastic origin, occurring sporadically or associated with familial adenomatous polyposis (FAP) coli. By comparing sporadic and FAP-associated desmoid-type fibromatoses, we tried to identify clinical characteristics, which may indicate FAP. Histopathology data of all Dutch patients with desmoid-type fibromatoses diagnosed between 1999 and 2009 were retrieved from PALGA, the nation-wide network and registry of histopathology in the Netherlands. For calculation of incidence rates, person-years from the general matched population were used. Based on polyp counts in pathological records, the cohort was divided into a FAP group and a non-FAP group. Patient- and tumor characteristics were compared between the two groups. A total number of 519 patients older than 10 years with a confirmed diagnosis of desmoid-type fibromatoses were included. Thirty-nine (7.5%) desmoid patients were documented of having FAP. The incidences of sporadic and FAP-related desmoid-type fibromatoses were 3.42 and 2,784 per million person-years, respectively. The majority of FAP patients developed desmoid-type fibromatoses after the diagnosis of FAP. Having FAP was associated with male gender [odds ratio (OR) 2.0, p = 0.034], desmoid diagnosis at an earlier age (mean 36 vs. 42 years, p = 0.031), and desmoid localization intra-abdominally (OR 18.9, p ≤ 0.001) or in the abdominal wall (OR 4.8, p ≤ 0.001), compared to extra-abdominal desmoid localization. In conclusion, patients with desmoid-type fibromatoses are at risk of underlying FAP. Especially cases with desmoid localization intra-abdominal or in the abdominal wall, and all patients younger than 60 years, have a substantial increased risk and should be referred for colonoscopy.

[Desmoid tumour as indication of familial adenomatous polyposis]. / Desmoïdtumoren als aanwijzing voor familiaire adenomateuze polyposis.

In two patients, a man aged 43 and a woman aged 40 years, who presented with a desmoid tumour, familial adenomatous polyposis (FAP) was diagnosed three and six years later, respectively. The second patient had developed metastatic rectal cancer. Desmoid-type fibromatoses usually develop sporadically, but may also be an extracolonic manifestation of FAP. All patients with desmoids diagnosed who are under age 60, or with desmoids located intra-abdominally or in the abdominal wall, should be referred for colonic and genetic evaluation. In all further patients with a desmoid tumour, the possibility of FAP should be considered and patient data and the family history should be evaluated thoroughly. If FAP is suspected, patients should be referred for colonoscopic examination and genetic evaluation.

Female fertility after colorectal surgery for familial adenomatous polyposis: a nationwide cross-sectional study.

BACKGROUND: Information on postoperative fertility problems in female patients with familial adenomatous polyposis (FAP) is scarce. Previous studies in FAP or colitis patients almost uniformly describe a reduction in fertility after ileal pouch-anal anastomosis, compared with ileorectal anastomosis. OBJECTIVE: To describe fertility problems in female FAP patients after colectomy and to investigate the relationship between self-reported fertility problems and the type of operation and other surgery-related factors (eg, comorbid conditions). METHODS: A questionnaire addressing surgery, fertility problems, and desire to have children was sent to a nationwide sample of FAP patients. Medical data were verified in the FAP-registry of the Netherlands Foundation for the Detection of Hereditary Tumors. Differences between women with and without fertility problems were investigated. RESULTS: Of 138 patients, 23 (17%) reported current or past fertility problems. The prevalence of fertility problems was similar among those who had undergone ileorectal anastomosis, ileal pouch-anal anastomosis, and proctocolectomy with ileostomy. None of the other surgery-related factors, nor desmoid tumors or cancer were associated significantly with the development of fertility problems. Patients reporting fertility problems were significantly younger at diagnosis of FAP (mean, 20 vs. 27 years, P < 0.05) and at the time of the first surgical procedure (mean, 22 vs. 28 years, P < 0.05). CONCLUSIONS: The risk of developing postoperative fertility problems is not associated significantly with the type of surgery, indication for surgery, complications, or other comorbid conditions. Postoperative fertility problems are more common among women who had their first surgical procedure at a younger age.

Genotype predicting phenotype in familial adenomatous polyposis: a practical application to the choice of surgery.

PURPOSE: Genetic information may help preoperatively select patients with familial adenomatous polyposis for either colectomy with ileorectal anastomosis or proctocolectomy with ileal pouch-anal anastomosis. Although complicated, the latter procedure has a low long-term risk of rectal cancer. METHODS: Data were obtained from four national polyposis registries. On the basis of previously described genotype-phenotype correlations, patients were divided into three genotype groups predicting attenuated, intermediate, and severe polyposis phenotypes. Cumulative risks of secondary proctectomy and rectal cancer after primary colectomy were calculated using the Kaplan-Meier method. RESULTS: Four hundred and seventy-five polyposis patients with a previous colectomy were included. Cumulative risks of secondary proctectomy 20 years after primary colectomy were 10%, 39%, and 61% in the attenuated, intermediate, and severe genotype groups, respectively (P < 0.05, groups compared separately). Cumulative risks of rectal cancer after primary colectomy were 3.7%, 9.3%, and 8.3%, respectively, in the three groups (P > 0.05, groups compared separately). CONCLUSION: Mutation analysis may be used to predict the risk of secondary proctectomy after primary colectomy in familial adenomatous polyposis. Patients with severe genotypes have a high risk of reoperation after primary colectomy and will benefit from primary proctocolectomy with ileal pouch-anal anastomosis. The risk of rectal cancer after primary colectomy was not significantly different between the three groups.

Desmoid tumors in a dutch cohort of patients with familial adenomatous polyposis.

BACKGROUND & AIMS: Desmoid tumors are a severe extracolonic manifestation in familial adenomatous polyposis (FAP). Identification of risk factors might be helpful in the management of FAP patients with such tumors. The aim of this study was to assess potential risk factors for the development of desmoids in a cohort of Dutch FAP patients. METHODS: The medical records of 735 FAP patients were analyzed for the occurrence of desmoids. Relative risks and survival times were calculated to assess the influence of potential risk factors (female sex, family history, mutation site, abdominal surgery, and pregnancy) on desmoid development. RESULTS: Desmoid tumors were identified in 66 of the 735 patients (9%). The cumulative risk of developing desmoids was 14%. No correlation was found between specific adenomatous polyposis coli mutation sites and desmoid development. Patients with a positive family history for desmoids had a significant increased risk to develop this tumor (30% vs 6.7%, P < .001). No association was found between female sex or pregnancy and desmoid development. Most desmoid patients (95%) had undergone previous abdominal surgery. In a substantial proportion of patients with an ileorectal anastomosis, it was impossible to convert the ileorectal anastomosis to an ileal pouch-anal anastomosis as a result of desmoid development. CONCLUSIONS: A positive family history of desmoids is an evident risk factor for developing desmoids. Most desmoids develop after colectomy. No correlation was found between desmoids and the adenomatous polyposis coli gene mutation site, female sex, and pregnancy. Ileal pouch-anal anastomosis is the appropriate type of surgery in FAP patients with a positive family history for desmoids.