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Vasen H.F.A.,The Netherlands Foundation for the Detection of Hereditary Tumours | Vasen H.F.A.,Leiden University | Abdirahman M.,The Netherlands Foundation for the Detection of Hereditary Tumours | Abdirahman M.,Leiden University | And 23 more authors.
Gastroenterology | Year: 2010

Background & Aims: Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program. Methods: The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy. Results: After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without. Conclusions: With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended. © 2010 AGA Institute.


PubMed | University Utrecht, Netherlands Cancer Institute, Leiden University, University of Groningen and 5 more.
Type: Journal Article | Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | Year: 2014

We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk.This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum.All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 60 years by -3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09).Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers.The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60.


PubMed | University Utrecht, Netherlands Cancer Institute, Leiden University, University of Groningen and 5 more.
Type: | Journal: BMC research notes | Year: 2015

The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers.Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated.No significant association with pancreatic cancer was found for any of the seven SNPs.Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.


Cremers R.G.,Radboud University Nijmegen | Cremers R.G.,The Netherlands Foundation for the Detection of Hereditary Tumours | Aben K.K.,Radboud University Nijmegen | van Oort I.M.,Radboud University Nijmegen | And 4 more authors.
Prostate | Year: 2016

BACKGROUND: The definition of hereditary prostate cancer (HPC) is based on family history and age at onset. Intuitively, HPC is a serious subtype of prostate cancer but there are only limited data on the clinical phenotype of HPC. Here, we aimed to compare the prognosis of HPC to the sporadic form of prostate cancer (SPC). METHODS: HPC patients were identified through a national registry of HPC families in the Netherlands, selecting patients diagnosed from the year 2000 onward (n = 324). SPC patients were identified from the Netherlands Cancer Registry (NCR) between 2003 and 2006 for a population-based study into the genetic susceptibility of PC (n = 1,664). Detailed clinical data were collected by NCR-registrars, using a standardized registration form. Follow-up extended up to the end of 2013. Differences between the groups were evaluated by cross-tabulations and tested for statistical significance while accounting for familial dependency of observations by GEE. Differences in progression-free and overall survival were evaluated using χ2 testing with GEE in a proportional-hazards model. RESULTS: HPC patients were on average 3 years younger at diagnosis, had lower PSA values, lower Gleason scores, and more often locally confined disease. Of the HPC patients, 35% had high-risk disease (NICE-criteria) versus 51% of the SPC patients. HPC patients were less often treated with active surveillance. Kaplan–Meier 5-year progression-free survival after radical prostatectomy was comparable for HPC (78%) and SPC (74%; P = 0.30). The 5-year overall survival was 85% (95%CI 81–89%) for HPC versus 80% (95%CI 78–82%) for SPC (P = 0.03). CONCLUSIONS: HPC has a favorable clinical phenotype but patients more often underwent radical treatment. The major limitation of HPC is the absence of a genetics-based definition of HPC, which may lead to over-diagnosis of PC in men with a family history of prostate cancer. The HPC definition should, therefore, be re-evaluated, aiming at a reduction of over-diagnosis and overtreatment among men with multiple relatives diagnosed with PC. Prostate 76:897–904, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.


Gopie J.P.,Leiden University | Vasen H.F.A.,The Netherlands Foundation for the Detection of Hereditary Tumours | Vasen H.F.A.,Leiden University | Tibben A.,Leiden University | Tibben A.,Erasmus Medical Center
Critical Reviews in Oncology/Hematology | Year: 2012

Individuals at risk for developing hereditary cancer are offered surveillance in order to improve the prognosis. An important question is whether the benefit of surveillance outweighs the psychological burden. In this review, we evaluated all studies that investigated psychological distress and the quality of life in individuals under surveillance for hereditary cancer of the breast, ovarian, prostate, pancreas, colorectum, melanoma, and various rare syndromes such as familial adenomatous polyposis, Li-Fraumeni and Peutz-Jeghers syndrome.Thirty-two studies were identified. Surveillance for most hereditary cancers was associated with good psychological outcomes. However, surveillance of individuals at high risk for developing multiple tumors appeared to be associated with increased distress and a lower quality of life. Common factors associated with worse psychological outcomes included a personal history of cancer, female gender, having a first degree relative with cancer, negative illness perceptions and coping style. The use of a simple screening tool to identify distressed individuals is recommended. © 2012 Elsevier Ireland Ltd.


Douma K.F.L.,Netherlands Cancer Institute | Bleiker E.M.A.,Netherlands Cancer Institute | Aaronson N.K.,Netherlands Cancer Institute | Cats A.,Netherlands Cancer Institute | And 4 more authors.
Colorectal Disease | Year: 2010

Aim The study assessed compliance of patients with familial adenomatous polyposis (FAP) with endoscopic surveillance.Method In this nationwide, cross-sectional study, individuals from FAP families registered with the Netherlands Foundation for the Detection of Hereditary Tumours were invited to complete a questionnaire on endoscopic screening experiences.Results A total of 328 individuals were eligible for the study of whom 85 were at risk for FAP, 108 had an intact rectum after a colectomy with ileorectal anastomosis (IRA), and 135 had had a pouch following a proctocolectomy with ileoanal anastomosis (IPAA). Based on medical record data, 20% of the at-risk group and 26% of the IRA-group were found to be undercompliant with surveillance advice which was associated significantly with perceived self-efficacy, use of sedatives during surveillance, pain after surveillance and low perceived benefits of surveillance (P < 0.05).Conclusion One in five individuals at risk for FAP and one in four with a retained rectum are undercompliant with screening advice. We recommend that sedatives should be patient-tailored for FAP individuals undergoing surveillance and that adequate pain medication be provided after endoscopy. © 2010 The Authors. Colorectal Disease © 2010 The Association of Coloproctology of Great Britain and Ireland.


Douma K.F.L.,Netherlands Cancer Institute | Bleiker E.M.A.,Netherlands Cancer Institute | Vasen H.F.A.,The Netherlands Foundation for the Detection of Hereditary Tumours | Vasen H.F.A.,Leiden University | And 2 more authors.
Colorectal Disease | Year: 2011

Aim The study aimed to document the impact of familial adenomatous polyposis (FAP) on health-related quality of life (HRQOL) and several practical aspects of daily life, and to identify factors significantly associated with HRQOL. This study is the first to compare HRQOL between patients with FAP, at-risk individuals and noncarriers. Method A total of 525 individuals (response rate 64%) from 145 families at high risk for FAP completed a battery of self-report questionnaires assessing generic- and condition-specific HRQOL and the consequences of FAP for daily life. Results HRQOL was comparable to that of the general Dutch population. Surgically treated patients with FAP had significantly lower scores on several HRQOL domains compared with at-risk individuals, noncarriers and nonsurgically treated patients with FAP. Type of surgery was not significantly associated with HRQOL. Within the surgically treated group, postsurgical complications and comorbidity significantly affected HRQOL. Forty-one percent of patients reported that FAP had affected their working life. Conclusion Surgically treated patients with FAP have significantly poorer HRQOL than other groups. The type of surgery and age at time of first surgery were not associated with HRQOL but surgical complications and comorbidity were. Patients should be informed of the consequences of FAP for work and other life domains. © 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.


PubMed | The Netherlands Foundation for the Detection of Hereditary Tumours and Radboud University Nijmegen
Type: Journal Article | Journal: The Prostate | Year: 2016

The definition of hereditary prostate cancer (HPC) is based on family history and age at onset. Intuitively, HPC is a serious subtype of prostate cancer but there are only limited data on the clinical phenotype of HPC. Here, we aimed to compare the prognosis of HPC to the sporadic form of prostate cancer (SPC).HPC patients were identified through a national registry of HPC families in the Netherlands, selecting patients diagnosed from the year 2000 onward (n=324). SPC patients were identified from the Netherlands Cancer Registry (NCR) between 2003 and 2006 for a population-based study into the genetic susceptibility of PC (n=1,664). Detailed clinical data were collected by NCR-registrars, using a standardized registration form. Follow-up extended up to the end of 2013. Differences between the groups were evaluated by cross-tabulations and tested for statistical significance while accounting for familial dependency of observations by GEE. Differences in progression-free and overall survival were evaluated using (2) testing with GEE in a proportional-hazards model.HPC patients were on average 3 years younger at diagnosis, had lower PSA values, lower Gleason scores, and more often locally confined disease. Of the HPC patients, 35% had high-risk disease (NICE-criteria) versus 51% of the SPC patients. HPC patients were less often treated with active surveillance. Kaplan-Meier 5-year progression-free survival after radical prostatectomy was comparable for HPC (78%) and SPC (74%; P=0.30). The 5-year overall survival was 85% (95%CI 81-89%) for HPC versus 80% (95%CI 78-82%) for SPC (P=0.03).HPC has a favorable clinical phenotype but patients more often underwent radical treatment. The major limitation of HPC is the absence of a genetics-based definition of HPC, which may lead to over-diagnosis of PC in men with a family history of prostate cancer. The HPC definition should, therefore, be re-evaluated, aiming at a reduction of over-diagnosis and overtreatment among men with multiple relatives diagnosed with PC. Prostate 76:897-904, 2016. 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.


PubMed | Cancer Research UK Research Institute, Leiden University, The Netherlands Foundation for the Detection of Hereditary Tumours and Radboud University Nijmegen
Type: Journal Article | Journal: Urologic oncology | Year: 2015

To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers.Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level 3.0 ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate b iopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed.Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff 25; 34%) or 134 (cutoff 35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 ( 25; 28%) or 109 ( 35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff 25) or 43 (cutoff 35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated.The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels.


PubMed | The Netherlands Foundation for the Detection of Hereditary Tumours
Type: Journal Article | Journal: Gut | Year: 2012

MUTYH-associated polyposis (MAP) is an autosomal recessive inherited disorder characterised by the development of polyposis in the upper and lower gastrointestinal tract and a high risk of colorectal cancer (CRC). We evaluated the natural history of the disease and the outcome of colorectal surveillance and management.A large Western European dataset of biallelic MUTYH mutation carriers comprising 254 patients was used. Detailed information was collected on polyp and cancer development in the colorectum, and the outcome of surveillance and surgery. Survival methods were used to calculate the risk of CRC development.The mean follow-up was 9.8 years. Colorectal polyposis was diagnosed at a mean age of 44.8 years (range: 12-77 years). Most patients had <100 colorectal adenomas at diagnosis. CRC was diagnosed in 147 (58%) of the 254 patients (mean age at diagnosis: 48.5, range: 21-77 years). The cumulative lifetime risk of CRC was 63% at age 60 years. There was no correlation between the number of adenomas and the presence of CRC. The cumulative risk of CRC in patients presenting with polyps was 9% after 5 years of follow-up. Patients presenting with CRC had 11% risk of developing a metachronous CRC at 5 years after surgery. Thirty-seven per cent of patients with MAP with CRC who underwent partial colonic resection needed secondary surgery shortly afterwards.The high risk of developing CRC under surveillance in patients with MAP may suggest an accelerated carcinogenesis. Surveillance of these patients should therefore include colonoscopy at short intervals, for example, at 1-2-year intervals starting from the age of 18 to 20 years. If surgery for CRC is warranted, a (sub)total colectomy is recommended.

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