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Colorectal carcinomas that are mismatch repair (MMR)‐deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch‐like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000–2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer‐relevant genes. Among 107 MMR‐deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E‐negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP‐positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population‐based study design. Significantly more frequent CIMP‐positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1‐methylated colorectal carcinomas with CIMP‐positive phenotype. peerReviewed

Purpose\ud \ud There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.\ud \ud Methods\ud \ud Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.\ud \ud Results\ud \ud Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.\ud \ud Conclusion\ud \ud This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

The psychological impact of an unfavorable genetic test result for counselees at risk for hereditary cancer seems to be limited: only 10-20 % of counselees have psychological problems after testing positive for a known familial mutation. The objective of this study was to find prognostic factors that can predict which counselees are most likely to develop psychological problems after presymptomatic genetic testing. Counselees with a 50 % risk of BRCA1/2 or Lynch syndrome completed questionnaires at three time-points: after receiving a written invitation for a genetic counseling intake (T1), 2-3 days after receiving their DNA test result (T2), and 4-6 weeks later (T3). The psychological impact of the genetic test result was examined shortly and 4-6 weeks after learning their test result. Subsequently, the influence of various potentially prognostic factors on psychological impact were examined in the whole group. Data from 165 counselees were analyzed. Counselees with an unfavorable outcome did not have more emotional distress, but showed significantly more cancer worries 4-6 weeks after learning their test result. Prognostic factors for cancer worries after genetic testing were pre-existing cancer worries, being single, a high risk perception of getting cancer, and an unfavorable test result. Emotional distress was best predicted by pre-existing cancer worries and pre-existing emotional distress. The psychological impact of an unfavorable genetic test result appears considerable if it is measured as "worries about cancer." Genetic counselors should provide additional guidance to counselees with many cancer worries, emotional distress, a high risk perception or a weak social network.

Objective: The aim was to systematically review the characteristics of ovarian cancer in women with Lynch syndrome (LS) and evaluate the role of surveillance in detection of ovarian cancer in LS. Methods: All studies between 1979 and 2015 of women with ovarian cancer and LS or at 50% risk of LS were evaluated. Two reviewers independently evaluated eligible studies and extracted data on age at diagnosis, histological type, FIGO stage, and way of detection according to pre-specified criteria. The studies were assessed for quality using the Newcastle-Ottawa quality assessment scales. Results: The quality score of the 49 identified studies was at least 6 out of 8 and provide clinical information on 747 LS women with ovarian cancer. The mean age at diagnosis was 45.3 (range 19-82) years. Most frequent mutations were MSH2 (47%) and MLH1 (38%). Histopathological data were available for 445 women. The most frequently reported histological type was mixed type (mucinous/endometrioid/clear cell carcinomas) (n = 136; 31%). Most tumours (281, 65%) were diagnosed at an early stage (FIGO I/II). Six studies evaluating the effect of surveillance of ovarian cancer, reported that seven of 22 (32%) ovarian cancers were found during surveillance, 6/7 (86%) were detected at an early stage. Conclusion: This systematic review describes that ovarian cancer in women with LS has a wide age-range of onset, is often diagnosed at an early stage with frequently endometrioid/clear cell histology. Data about the role of surveillance in detection of ovarian cancer in women with LS are scarce however detection at an early stage seems possible. (C) 2015 Elsevier Ltd. All rights reserved.

Inherited mutations of the DNA Mismatch repair genes MLH1, MSH2, MSH6 and PMS2 can result in two hereditary tumor syndromes: the adult-onset autosomal dominant Lynch syndrome, previously referred to as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and the childhood-onset autosomal recessive Constitutional Mismatch Repair Deficiency syndrome. Both conditions are important to recognize clinically as their identification has direct consequences for clinical management and allows targeted preventive actions in mutation carriers. Lynch syndrome is one of the more common adult-onset hereditary tumor syndromes, with thousands of patients reported to date. Its tumor spectrum is well established and includes colorectal cancer, endometrial cancer and a range of other cancer types. However, surveillance for cancers other than colorectal cancer is still of uncertain value. Prophylactic surgery, especially for the uterus and its adnexa is an option in female mutation carriers. Chemoprevention of colorectal cancer with aspirin is actively being investigated in this syndrome and shows promising results. In contrast, the Constitutional Mismatch Repair Deficiency syndrome is rare, features a wide spectrum of childhood onset cancers, many of which are brain tumors with high mortality rates. Future studies are very much needed to improve the care for patients with this severe disorder. (C) 2016 Published by Elsevier B.V.

Familial risk of ovarian cancer is well-established but whether ovarian cancer clusters with other cancers and the clusters differ by histology remains uncertain. Using data from the Swedish Family-Cancer Database, we explored familial associations of ovarian cancer with other cancers with a novel approach; relative risk for (histology-specific) ovarian cancer was estimated in families with patients affected by other cancers, and conversely, risks for other cancers in families with (histology-specific) ovarian cancer patients. Eight discordant cancers were associated with ovarian cancer risk, of which family history of breast cancer showed a dose-response (P-trend

Ovarian cancer is a heterogeneous disease. Data regarding familial risks for specific proband, age at diagnosis and histology are limited. Such data can assist genetic counseling and help elucidate etiologic differences among various histologic types of ovarian malignancies. By using the Swedish Family-Cancer Database, we calculated relative risks (RRs) for detailed family histories using a two-way comparison, which implied e.g. estimation of RRs for overall ovarian cancer when family history was histology-specific ovarian cancer, and conversely, RRs for histology-specific ovarian cancer when family history was overall ovarian cancer. In families of only mother, only sisters or both mother and sisters diagnosed with ovarian cancer, cancer risks for ovary were 2.40, 2.59 and 10.40, respectively; and were higher for cases diagnosed before the age of 50 years. All histological types showed a familial risk in two-way analyses, except mucinous and sex cord-stromal tumors. RRs for concordant histology were found for serous (2.47), endometrioid (3.59) and mucinous ovarian cancers (6.91). Concordant familial risks were highest for mucinous cancer; for others, some discordant associations, such as endometrioid-undifferentiated (9.27) and serous-undifferentiated (4.80), showed the highest RRs. Familial risks are high for early-onset patients and for those with multiple affected relatives. Sharing of different histological types of ovarian cancer is likely an indication of the complexity of the underlying mechanisms.

Objective. To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers.Methods. All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected.Results. A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%.Conclusion. Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance. (C) 2018 Published by Elsevier Inc.

To evaluate perceived pain during repetitive annual endometrial sampling at gynaecologic surveillance in asymptomatic women with Lynch syndrome (LS) over time and in addition to symptomatic women without LS, undergoing single endometrial sampling. In this prospective study, 52 women with LS or first degree relatives who underwent repetitive annual gynaecological surveillance including endometrial sampling of which 33 were evaluated twice or more and 50 symptomatic women without LS who had single endometrial sampling, were included. Pain intensity was registered with VAS scores. Differences in pain intensities between subsequent visits (in LS) and between the two groups were evaluated. The use of painkillers before endometrial sampling was registered. If women with LS decided for preventive surgery, the reason was recorded. The LS group reported a median VAS score of 5.0 (range 0-10) at the first surveillance (n = 52) and at the second visit (n = 24). Women who repeatedly underwent endometrial sampling more often used painkillers for this procedure. During the study period 7/52 (13 %) women with LS choose for preventive surgery, another 4/52 (8 %) refused further endometrial sampling. Painful endometrial sampling was mentioned as main reason to quit screening. The median VAS score of the 50 symptomatic women was 5.0 (range 1-9). Endometrial sampling, irrespective of indication, is a painful procedure, with a median VAS score of 5.0. During subsequent procedures in women with LS, the median pain score does not aggravate although one in five women chose an alternative for endometrial sampling.

ObjectiveEstimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.DesignWe undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affectingMLH1,MSH2,MSH6orPMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.Results1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards inMLH1andMSH2mutation carriers, and from about 40 years inMSH6andPMS2carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% forMLH1, MSH2, MSH6andPMS2mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.ConclusionsThe four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established athttp://LScarisk.orgenabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Despite colonoscopic surveillance, Lynch syndrome patients develop colorectal cancer (CRC). Identification of modifiable factors has the potential to improve outcome of surveillance. The aims of this study were to determine (1) characteristics of patients with CRC, (2) endoscopic and histological features of these cancers, and (3) quality of the previous colonoscopy.Approximately 2,200 medical reports from proven and obligate mutation carriers identified at the Dutch Lynch Syndrome Registry and two large hospitals were retrospectively analyzed for the presence of an interval cancer defined as CRC diagnosed within 24 months of previous colonoscopy.Thirty-one interval cancers were detected in 29 patients (median age of 52 [range 35-73]), after a median time of 17 months. All were MLH1 or MSH2 mutation carriers, and 39 % had a previous CRC. In patients without previous surgery for CRC, 84 % was proximally located. Of all interval cancers, 77 % were at local stage (T1-3N0Mx). In three patients (9 %) with an incomplete previous colonoscopy, CRC was located in the unexamined colon. In six of the nine patients with an adenoma during previous colonoscopy, the cancer was detected in the same colonic segment as the previously removed adenoma.Interval cancers were detected in MLH1 and MSH2 mutation carriers, especially in those with a history of previous CRC and between 40 and 60 years. Interval cancer could be related to incompleteness of previous endoscopy and possibly residual adenomatous tissue. Further reduction of the interval cancer risk may be achieved by optimizing endoscopy quality and individualization of surveillance guidelines.

Objective. Based on previous studies, standard gynecological screening consisting of annual transvaginal ultrasonography (TVU) was added with endometrial sampling in women with Lynch syndrome (LS). The aim of this study was to evaluate the additional value of endometrial sampling in detecting (pre)malignancies of the endometrial tissue in women with LS or first-degree relatives.Methods. All women above 30 years of age with LS or first-degree relatives at 50% risk of LS are offered annual gynecological screening in our family cancer clinic. Endometrial screening results from January 2003-December 2007 (period I: standard screening by transvaginal sonography and serum CA125) were compared with screening results from January 2008-June 2012 (period II: standard screening added with endometrial sampling).Results. Seventy five women (300 patient years) were screened annually. There were 266 screening visits, 117 in period I and 149 in period II. In period I, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II, two premalignancies were found. None of the lesions would have been missed without standard endometrial sampling. No interval endometrial cancers were detected in this study.Conclusion. In this study, annual endometrial screening seems an effective screening tool in the detection of premalignancies and early endometrial cancer in women with LS. Adding standard endometrial sampling to annual TVU has no additional value in the early detection of (pre)malignant endometrial lesions in women with LS in this study. (C) 2013 Published by Elsevier Inc.

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary condition predisposing for colorectal cancer. International guidelines recommend surveillance of the colorectum by colonoscopy every 1-2 years starting at the age of 20-25 years. This has been shown to reduce the incidence of, and mortality due to colorectal cancer. Aim of this review was to determine the current role of new endoscopic techniques, such as narrow-band imaging, autofluorescence endoscopy and chromoendoscopy in the surveillance of Lynch syndrome. So far, six studies have been published in which the new endoscopic techniques were investigated in Lynch syndrome: narrow-band imaging (n = 1), autofluorescence endoscopy (n = 1) and chromoendoscopy (n = 4). At this moment, none of the new endoscopic techniques have shown clear and convincing superiority over conventional white light colonoscopy in Lynch syndrome subjects. Of these three techniques, chromoendoscopy appears to be the most promising new endoscopic technique in aiding in the detection of neoplastic lesions in Lynch syndrome, although further prospective studies are needed.

Purpose Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. Patients and Methods Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene–specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. Results The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. Conclusion The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.

Four main DNA mismatch repair (MMR) genes have been identified, MLH1, MSH2, MSH6, and PMS2, which when mutated cause susceptibility to Lynch syndrome (LS). LS is one of the most prevalent hereditary cancer syndromes in man and accounts for 1-3 % of unselected colorectal carcinomas and some 15 % of those with microsatellite instability and/or absent MMR protein. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) maintains a database for LS-associated mutations since 1996. The database was recently reorganized to efficiently gather published and unpublished data and to classify the variants according to a five-tiered scheme linked to clinical recommendations. This review provides an update of germline mutations causing susceptibility to LS based on information available in the InSiGHT database and the latest literature. MMR gene mutation profiles, correlations between genotype and phenotype, and possible mechanisms leading to the characteristic spectrum of tumors in LS are discussed in light of the different functions of MMR proteins, many of which directly serve cancer avoidance.

The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families.

PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype.METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally.RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC.CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med advance online publication 25 June 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.83.

Contains fulltext : 109239.pdf (Publisher’s version ) (Open Access) BACKGROUND: Lynch syndrome is a disorder caused by mismatch repair gene mutations. Mutation carriers have a high risk of developing colorectal cancer. In patients with Lynch syndrome in whom colon cancer has been diagnosed, in general, subtotal colectomy instead of partial colectomy is recommended because of the substantial risk of metachronous colorectal cancer. However, the effect of more extensive surgery on quality of life and functional outcome is unknown. OBJECTIVE: The aim of this study was to investigate quality of life and functional outcome in patients with Lynch syndrome after partial colectomy and subtotal colectomy. DESIGN: This is a nationwide cross-sectional study in the Netherlands. SETTINGS: Two quality-of-life questionnaires (Short Form-36 and The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module) and a functional outcome questionnaire (Colorectal Functional Outcome) were used. PATIENTS: Patients with Lynch syndrome who underwent surgery for colon cancer were included. MAIN OUTCOME MEASURES: The primary outcomes measured were quality of life and functional outcome. RESULTS: Questionnaires were sent to 192 patients with Lynch syndrome who underwent surgery for colorectal cancer. A total of 136 patients returned the questionnaire (response rate, 71%). Eighteen patients with rectal cancer, 9 patients with a permanent ileostomy, and 5 patients with an IPAA were excluded. Fifty-one patients underwent partial colectomy, and 53 underwent subtotal colectomy. None of the scales of the Short Form-36 survey showed a significant difference. Analysis of the Colorectal Functional Outcome questionnaire revealed that, after subtotal colectomy, patients have a significantly higher stool frequency (p

Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of duodenal polyposis, classically assessed by the Spigelman classification. For this reason, gastroduodenal surveillance with forward-viewing and side-viewing endoscopy is generally recommended. Studies using video capsule endoscopy and balloon-assisted enteroscopy in FAP patients have revealed that jejunal and ileal polyps occur frequently in FAP, especially in those with extensive duodenal polyposis. Nevertheless, the clinical relevance of small bowel polyps beyond the duodenum appears to be limited. Compared to FAP, little is known about the prevalence and natural history of small bowel neoplasia in Lynch syndrome. Surveillance of the small bowel is not recommended in Lynch syndrome, although recent data using capsule endoscopy provided promising results. (C) 2012 Elsevier Ltd. All rights reserved.

Purpose Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome, characterized by a high risk of developing cancer at various sites and ages. To date, limited clinical benefits of genetic testing for LFS have been demonstrated, and there are concerns about the potential adverse psychosocial impact of genetic testing for LFS. In this study, we evaluated the uptake of genetic testing and the psychosocial impact of undergoing or not undergoing a genetic test for LFS. Patients and Methods In total, 18 families with a p53 germline mutation in the Netherlands were identified. Eligible family members were invited to complete a self-report questionnaire assessing motives for undergoing or not undergoing genetic testing, LFS-related distress and worries, and health-related quality of life. Results Uptake of presymptomatic testing was 55% (65 of 119). Of the total group, 23% reported clinically relevant levels of LFS-related distress. Carriers were not significantly more distressed than noncarriers or than those with a 50% risk who did not undergo genetic testing. Those with a lack of social support were more prone to report clinically relevant levels of distress (odds ratio, 1.3; 95% CI, 1.0 to 1.5). Conclusion Although preventive and treatment options for LFS are limited, more than half of the family members from known LFS families choose to undergo presymptomatic testing. An unfavorable genetic test result, in general, does not cause adverse psychological effects. Nonetheless, it is important to note that a substantial proportion of individuals, irrespective of their carrier status, exhibit clinically relevant levels of distress which warrant psychological support.

Contains fulltext : 89461.pdf (Publisher’s version ) (Closed access) Li Fraumeni Syndrome (LFS) is a hereditary cancer syndrome characterized by a high risk of developing various types of cancer from birth through late adulthood. Clinical benefits of surveillance for LFS are limited. The aim of this study is to investigate which advice for regular surveillance, if any, is given to high risk LFS individuals, adherence to that advice, and any psychological gain or burden derived from surveillance. Fifty-five high risk individuals (proven carriers and those at 50% risk) from families with a p53 germline mutation were invited to participate, of whom 82% completed a self-report questionnaire assessing advice for regular surveillance, compliance, perceived benefits and barriers of screening and LFS-related distress (IES) and worries (CWS). In total, 71% of the high risk family members received advice to undergo regular surveillance for LFS. The majority (78%) reported adherence with the recommended advice. All high risk women aged 25 or older reported having been advised to undergo annual breast cancer surveillance (n = 11), of whom 64% (n = 7) in specific received advice to undergo a mammography. Seventy-eight percent of respondents indicated having received tailored surveillance advice based on family cancer history. The large majority of respondents believed in the value of surveillance to detect tumors at an early stage (90%) and reported that it gave them a sense of control (84%) and security (70%). Despite its limited clinical benefits, the majority of high risk LFS family are advised to undergo, and are adherent to, and report psychological benefit from, regular surveillance programs. 01 december 2010

It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene, PMS2, play a far more important role in Lynch syndrome than initially thought. To explore this further, we determined the prevalence of pathogenic germline PMS2 mutations in a series of Lynch syndrome-suspected patients. Ninety-seven patients who had early-onset microsatellite instable colorectal or endometrial cancer, or multiple Lynch syndrome-associated tumors and/or were from an Amsterdam Criteria II-positive family were selected for this study. These patients carried no pathogenic germline mutation in MLH1, MSH2, or MSH6. When available, tumors were investigated for immunohistochemical staining (IHC) for PMS2. PMS2 was screened in all patients by exon-by-exon sequencing. We identified four patients with a pathogenic PMS2 mutation (4%) among the 97 patients we selected. IHC of PMS2 was informative in one of the mutation carriers, and in this case, the tumor showed loss of PMS2 expression. In conclusion, our study confirms the finding of previous studies that PMS2 is more frequently involved in Lynch syndrome than originally expected. (C) 2009 Wiley-Liss, Inc.

Small-bowel cancer is part of the tumour spectrum of Lynch syndrome. Lynch syndrome, or hereditary non-polyposis colorectal cancer, is caused by germline mutations in one of the mismatch repair genes. Mutation carriers have an estimated lifetime risk for the development of small-bowel cancer of around 4%, corresponding to a relative risk of more than 100 compared with the general population. Patients with Lynch syndrome generally present with small-bowel cancer 10-20 years earlier than the general population, and small-bowel cancer might be the first clinical manifestation of Lynch syndrome. Tumours in patients with Lynch syndrome are evenly distributed within the small bowel. No specific risk factors, such as type of gene mutation, have been identified thus far. Screening for small-bowel cancer in Lynch syndrome has, until now, not been included in guidelines for surveillance, which might partly be due to the fact that, until recently, the possibilities for visualisation of the small bowel were limited. In view of the improved accessibility of the small bowel with the introduction of capsule endoscopy and double balloon enteroscopy, the question of whether patients should be screened for small-bowel neoplasia has regained attention. In this paper, we discuss the rationale for surveillance of small-bowel cancer in Lynch syndrome and highlight issues that need to be addressed in future studies before recommendations can be made.

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly MLH1, MSH2, and MSH6, underlie Hereditary non-polyposis colorectal cancer (HNPCC) and are mostly family-specific, with few reported founder mutations in MSH2 (Ashkenazim) MLH1 (Finnish). No mutations in colon cancer susceptibility genes have ever been reported in Druze individuals, a Moslem related faith encompassing similar to 1,000,000 individuals worldwide. A novel MSH2 mutation is described in a Druze HNPCC family: a multigenerational family with 10 members in 4 generations affected with colorectal cancer (mean age of diagnosis 46.5 years), two with gastric cancer and one-endometrial cancer. Mutational analysis of the MSH2 gene using denaturing gradient gel electrophoresis (DGGE) and direct sequencing revealed the c.702delA mutation in codon 234 of exon 4 of the MSH2 gene leading to a premature early stop in codon 245, p.Thr234fsX245. Analysis of mutation-carrying or presumed carriers individuals' offspring, revealed 11/42 asymptomatic mutation carriers, age range 17-50 years. The mutation was not present in two additional Druze HNPCC families and 20 Druze sporadic colon cancer patients. This is the first mutation ever reported in a colon cancer susceptibility gene in a Druze family and it appears not to be a founder mutation in Druze individuals with HNPCC.

BRCA1-associated cancers differ from non-hereditary cancers for many factors, including somatic mutation. It can be a subject of discussion that the natural history and response to treatment also may differ between the hereditary and sporadic subgroups. Three frequent BRCA1 mutations (5382insC, 4153delA, C61G) in the Baltic countries (Lithuania, Latvia, Byelorussia and Poland) open a way for the chip test to select a subgroup from women with breast cancer. These women with BRCA1 breast cancer have a chance to get adequate treatment, including neo-adjuvant chemotherapy. So far many retrospective studies of survival, that used the same gold standard treatment for women with BRCA1 breast cancer and for women without a mutation, have not found a difference between these groups. Some studies show a worse survival result in women with a BRCA1 mutation than women without the mutation.

Background: Despite the use of genetic services, counselees do not always share hereditary cancer information with at-risk relatives. Reasons for not informing relatives may be categorized as a lack of: knowledge, motivation, and/or self-efficacy.Purpose: This study aims to develop and test the psychometric properties of the Informing Relatives Inventory, a battery of instruments that intend to measure counselees’ knowledge, motivation, and self-efficacy regarding the disclosure of hereditary cancer risk information to at-risk relatives.Method: Guided by the proposed conceptual framework, existing instruments were selected and new instruments were developed. We tested the instruments’ acceptability, dimensionality, reliability, and criterion-related validity in consecutive index patients visiting the Clinical Genetics department with questions regarding hereditary breast and/or ovarian cancer or colon cancer.Results: Data of 211 index patients were included (response rate = 62 %). The Informing Relatives Inventory (IRI) assesses three barriers in disclosure representing seven domains. Instruments assessing index patients’ (positive) motivation and self-efficacy were acceptable and reliable and suggested good criterion-related validity. Psychometric properties of instruments assessing index patients knowledge were disputable. These items were moderately accepted by index patients and the criterion-related validity was weaker.Conclusion: This study presents a first conceptual framework and associated inventory (IRI) that improves insight into index patients’ barriers regarding the disclosure of genetic cancer information to at-risk relatives. Instruments assessing (positive) motivation and self-efficacy proved to be reliable measurements. Measuring index patients knowledge appeared to be more challenging. Further research is necessary to ensure IRI’s dimensionality and sensitivity to change.

Purpose The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Methods Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome–associated cancers. Results The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis. Conclusion CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.

Contains fulltext : 49187.pdf (Publisher’s version ) (Closed access) BACKGROUND: Distinguishing hereditary non-polyposis colorectal cancer (HNPCC) from non-hereditary colorectal cancer (CRC) can increase the life expectancy of HNPCC patients and their close relatives. AIM: To determine the effectiveness, efficiency, and feasibility of a new strategy for the detection of HNPCC, using simple criteria for microsatellite instability (MSI) analysis of newly detected tumours that can be applied by pathologists. Criteria for MSI analysis are: (1) CRC before age 50 years; (2) second CRC; (3) CRC and HNPCC associated cancer; or (4) adenoma before age 40 years. METHODS: The efficacy and cost effectiveness of the new strategy was evaluated against current practice. Decision analytic models were constructed to estimate the number of extra HNPCC mutation carriers and the costs of this strategy. The incremental costs and gain in life expectancy for a HNPCC mutation carrier were evaluated by Markov modelling. Feasibility was explored in five hospitals. RESULTS: Using the new strategy, 2.2 times more HNPCC patients can be identified among a CRC population compared with current practice. This new strategy was found to be cost effective with an expected cost effectiveness ratio of 3801 per life year gained. When including the group of siblings and children, the cost effectiveness ratio became 2184 per life year gained. Sensitivity analysis showed these findings to be robust. CONCLUSIONS: MSI testing in a selection of newly diagnosed CRC patients was shown to be cost effective and a feasible method to identify patients at risk for HNPCC who are not recognised by family history.

Purpose: To determine the frequency of mismatch repair (MMR) gene germline mutations in endometrial cancer patients who were diagnosed at less than 50 years of age; to relate the presence of mutations to family history, histopathologic data, presence of tumor microsatellite instability (MSI), and immunostaining; and to formulate criteria for genetic testing in these patients.Patients and Methods: Endometrial cancer patients (N = 58), who were diagnosed at less than 50 years of age, were included and questioned about their family history. Mutation analysis of the MLH1, MSH2, and MSH6 genes was performed (denaturing gradient gel electrophoresis and sequence analysis to detect small mutations and multiplex ligation-dependent probe amplification to detect large deletions or duplications). For MSI analysis, five consensus markers were used, and immunostaining of the three MMR proteins was performed.Results: In five of 22 patients with a positive first-degree family history for hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, pathogenic germline mutations were found (one MLH1, three MSH2, and one MSH6). Four mutation carriers belonged to families fulfilling the revised Amsterdam criteria. No mutations were found in the 35 patients without such family history (P = .006). MSI was detected in 20 of 57 cancers, among which four were from mutation carriers. In 23 of 51 cancers, one or more MMR protein was absent; in all five mutation carriers, immunostaining indicated the involved MMR gene.Conclusion: In 23% of the young endometrial cancer patients with at least one first-degree relative with an HNPCC-related cancer, an MMR gene mutation was detected. Therefore, presence of an HNPCC-related cancer in a first-degree relative seems to be an important selection criterion for mutation analysis. Subsequent immunostaining of MMR proteins will point to the gene(s) that should be analyzed. (C) 2003 by American Society of Clinical Oncology.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6. The MSH2 mutation, I145M, is the same in both families, whereas the MSH6 mutations are different (R1095H and L1354Q). The families do not fulfil the international criteria for HNPCC, one family comprising two and the other family four colon cancer patients, all in one generation, resembling a recessive rather than dominant inheritance characteristic of HNPCC. The tumors of the index patients showed microsatellite instability. Functional analysis was performed to determine which one of the mutations could primarily underlie the cancer susceptibility in the families. MSH2 and MSH6 are known to form a heterodimeric complex (MutSalpha) responsible for mismatch recognition. The interaction of each mutated protein with its wild-type partner and with its mutated partner present in the colon cancer patient, and the MMR function of the mutated MutSalpha complexes were determined. Since none of the three mutations affected the MSH2-MSH6 interaction or the function of MutSalpha in an in-vitro MMR assay, our results suggest that alone the mutations do not cause MMR deficiency typical of HNPCC. However, our results do not exclude the possible compound pathogenicity of the two mutations.

A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as I of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. Copyright (C) 2000 by W.B. Saunders Company.

Lynch syndrome (LS) is characterised by the\ud development of colorectal cancer, endometrial cancer\ud and various other cancers, and is caused by a mutation\ud in one of the mismatch repair genes: MLH1, MSH2,\ud MSH6 or PMS2. In 2007, a group of European experts\ud (the Mallorca group) published guidelines for the clinical\ud management of LS. Since then substantial new\ud information has become available necessitating an\ud update of the guidelines. In 2011 and 2012 workshops\ud were organised in Palma de Mallorca. A total of 35\ud specialists from 13 countries participated in the\ud meetings. The first step was to formulate important\ud clinical questions. Then a systematic literature search\ud was performed using the Pubmed database and manual\ud searches of relevant articles. During the workshops the\ud outcome of the literature search was discussed in detail.\ud The guidelines described in this paper may be helpful for\ud the appropriate management of families with LS.\ud Prospective controlled studies should be undertaken to\ud improve further the care of these families.

Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five-class classification system was developed and applied to 143MMRmissense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align-Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [ MAPP], MutPred, PolyPhen-2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen-2.1 provided the best-combined model (R-2 = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen-2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions. Hum Mutat 34: 255-265, 2013. (C) 2012 Wiley Periodicals, Inc.

In predictive DNA testing for hereditary cancer, test results should traditionally be disclosed face-to-face. Increasingly, however, counselees ask to receive their test result at home by letter. To compare the quality of genetic counselling in the traditional way to a procedure in which counselees are offered a choice on how to get their test result. Counselees from families with a known BRCA1/ 2 or Lynch syndrome mutation were randomised into two groups. The control group was given the DNA test result in a face-to-face consultation. In the intervention group people could choose to learn their test result face-to-face or by letter. The quality of genetic counselling was assessed through questionnaires at three different moments. Data of 198 counselees were analysed. The quality of genetic counselling and psychological functioning were equally good in both groups. The majority of cases chose for disclosure by letter. The counselees with a good test result in the intervention group were the most satisfied. Our results indicate that in predictive DNA testing for BRCA1/ 2 and Lynch syndrome, a choice protocol is equally safe and more satisfying. Moreover, it is more efficient for both counsellor and counselee.

Lynch syndrome (LS) is an autosomal dominant disorder that predisposes to colon, endometrial, and other cancers. LS is caused by a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. A significant proportion of all mutations found in suspected LS patients comprises single amino acid alterations. The pathogenicity of these variants of uncertain significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell-free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the MSH6 VUS appears MMR proficient. We anticipate that this assay will be an important tool in the development of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS. Hum Mutat 33:488494, 2012. (C) 2011 Wiley Periodicals, Inc.

Background and aimsPancreatic cancer risk is increased in Lynch syndrome (LS) patients with mismatch repair gene defects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI). However, the frequency of MSI pancreatic cancers has never been ascertained in consecutive, unselected clinical series, and their contribution to the sporadic and inherited burden of pancreatic cancer remains to be established. Aims of the study were to determine the prevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess the occurrence of pancreatic cancer in LS.MethodsMS-status was screened by a panel of 5 mononucleotide repeats (Bat26, Bat25, NR-21, NR-24 and NR-27) in 338 consecutive pancreatic ductal adenocarcinoma (PDAC), resected at two Italian and one German referral centres. The personal history of pancreatic cancer was assessed in an independent set of 58 probands with LS and in 138 first degree relatives who had cancers.ResultsOnly one PDAC (0.3%) showed MSI. This was a medullary type cancer, with hMLH1-deficiency, and no identified germ-line mutation but methylation of hMLH1. Pancreatic cancer occurred in 5 (2.5%) LS patients. Histological sampling was available for 2 cases, revealing PDAC in one case and an ampullary cancer in the other one.ConclusionsMSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is 2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancer should be advised in LS mutation carriers at referral centers.

Background Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2 , cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening. Methods and Results The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression. Conclusions Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8.

Contains fulltext : 96266.pdf (Publisher’s version ) (Closed access) Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like families for the presence of EPCAM deletions. We identified 27 novel independent MSH2-deficient families from multiple geographical origins with varying deletions all encompassing the 3' end of EPCAM, but leaving the MSH2 gene intact. Within The Netherlands and Germany, EPCAM deletions appeared to represent at least 2.8% and 1.1% of the confirmed Lynch syndrome families, respectively. MSH2 promoter methylation was observed in epithelial tissues of all deletion carriers tested, thus confirming silencing of MSH2 as the causative defect. In a total of 45 families, 19 different deletions were found, all including the last two exons and the transcription termination signal of EPCAM. All deletions appeared to originate from Alu-repeat mediated recombination events. In 17 cases regions of microhomology around the breakpoints were found, suggesting nonallelic homologous recombination as the most likely mechanism. We conclude that 3' end EPCAM deletions are a recurrent cause of Lynch syndrome, which should be implemented in routine Lynch syndrome diagnostics.

In this review we present an overview of recent developments in the management of hereditary ovarian cancer. Until recently, intensive screening of the ovaries was recommended to mutation carriers and their first-degree female relatives. However, since screening is not effective in detecting early-stage ovarian cancer, women are counselled for a prophylactic bilateral salpingo-oophorectomy (pBSO) shortly after child-bearing age (>35 years). Many mutation carriers already choose to undergo pBSO to reduce their cancer risks; however, the age of prophylactic surgery may interfere with reproductive and other important (psychosexual) issues in life. Due to the protective effect of oral contraceptives regarding ovarian cancer, we advise women at increased risk of ovarian cancer to use oral contraceptive pills for 3–5 years early in life (

Contains fulltext : 80583.pdf (Publisher’s version ) (Closed access) It was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3' region of EPCAM cause transcriptional read-through which results in silencing of MSH2 by hypermethylation. We wanted to determine the prevalence of germline MLH1 promoter hypermethylation and of germline and somatic MSH2 promoter hypermethylation in a large group of Lynch syndrome-suspected patients. From a group of 331 Lynch Syndrome-suspected patients we selected cases, who had no germline MLH1, MSH2, or MSH6 mutation and whose tumors showed loss of MLH1 or MSH2, or, if staining was unavailable, had a tumor with microsatellite instability. Methylation assays were performed to test these patients for germline MLH1 and/or MSH2 promoter hypermethylation. Two patients with germline MLH1 promoter hypermethylation and no patients with germline MSH2 promoter hypermethylation were identified. In the subgroup screened for germline MSH2 promoter hypermethylation, we identified 3 patients with somatic MSH2 promoter hypermethylation in their tumors, which was caused by a germline EPCAM deletion. In the group of 331 Lynch Syndrome-suspected patients, the frequencies of germline MLH1 promoter hypermethylation and somatic MSH2 promoter hypermethylation caused by germline EPCAM deletions are 0.6 and 0.9%, respectively. These mutations, therefore, seem to be rather infrequent. However, the contribution of germline MLH1 hypermethylation and EPCAM deletions to the genetically proven Lynch syndrome cases in this cohort is very high. Previously 27 pathogenic mutations were identified; the newly identified mutations now represent 16% of all mutations.

Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2-3% of all colorectal cancers. Lynch syndrome is also associated with a high risk of extracolonic cancers, including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinary tract, brain, and skin cancer. In this Review, we discuss the risks, surveillance tests, and guidelines for the management of extracolonic tumours associated with Lynch syndrome. For all types of extracolonic cancer, evidence supporting surveillance is scarce. A benefit of surveillance is evident only for endometrial cancer, where transvaginal ultrasound and endometrial sampling detect tumours in early stages. Surveillance is generally recommended for urinary tract and gastric cancer, especially in families with more than one member with these types of cancer. For the other types of cancer, surveillance is typically not recommended. Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be considered for women with Lynch syndrome who are past childbearing age, especially during surgery for colorectal cancer. No data show efficacy of chemopreventive drugs in reducing the risk of extracolonic cancers for patients with Lynch syndrome.

So far 18 MLH3 germline mutations/variants have been identified in familial colorectal cancer cases. Sixteen of these variants are amino acid substitutions of which the pathogenic nature is still unclear. These substitutions are known as unclassified variants or UVs. To clarify a possible role for eight of these MLH3 UVs identified in suspected Lynch syndrome patients, we performed several biochemical tests. We determined the protein expression and stability, protein localization and interaction of the mutant MLH3 proteins with wildtype MLH1. All eight MLH3 UVs gave protein expression levels comparable with wildtype MLH3. Furthermore, the UV-containing proteins, in contrast to previous studies, were all localized normally in the nucleus and they interacted normally with wildtype MLH1. Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary colorectal cancer, including Lynch syndrome. (C) 2009 Wiley-Liss, Inc.

Microsatellite instability (MSI) is present in hereditary conditions due to mismatch repair (MMR) gene mutations. Following MSI analysis, tumor samples are classified into MSS (stable), MSI-L (low instability), and MSI-H (high instability) based on the fraction of unstable loci. Another MSI-based classification takes into account the size difference between mutant alleles in tumor DNA compared to wild-type alleles; two types of MSI, A and B, are recognized using this approach, type A being characterized by smaller, more subtle allelic shifts compared to type B. Biallelic mutations of MMR genes are associated with pediatric cancers, including glial tumors, in Turcot syndrome type 1 (TS1). However, most TS1-associated gliomas so far analyzed did not display MSI. We investigated the frequency of MSI in a series of 34 pediatric gliomas of different grade using a panel of five mononucleotide quasimonomorphic markers. Subtle qualitative changes were observed for the majority of markers in two glioblastomas (5.9% of the total series and 33.3% of glioblastomas). In both cases, family histories were compatible with TS1, and mutations of the PMS2 and MLH1 genes were identified. In one family, the MSI patterns were compared between the glioblastoma and a colon cancer from an affected relative, showing a clear qualitative difference, with the former displaying type A and the latter type B instability, respectively. These results were confirmed using additional microsatellite markers, indicating that knowledge of the association between TS1-related glial tumors and subtle type A MSI is important for full ascertainment of TS1 patients and appropriate counselling.

Hereditary non-polyposis colorectal cancer (HNPCC) is a common autosomal dominant condition characterized by early onset colorectal cancer as well as other tumour types at different anatomical sites1. HNPCC tumours often display a high level of genomic instability, characterized by changes in repeat numbers of simple repetitive sequences (microsatellite instability, MSI), which reflects the malfunction of the DNA mismatch repair machinery2, 3. Accordingly, HNPCC was shown to be caused by germline mutations in the DNA mismatch repair genes (MMR) MSH2, MLH1, PMS1, PMS2 and MSH6 (refs 3, 4, 5, 6). So far, more than 220 predisposing mutations have been identified, most in MSH2 and MLH1 and in families complying with the clinical Amsterdam criteria3, 7, 8 (AMS+). Many HNPCC families, however, do not fully comply with these criteria, and in most cases the causative mutations are unknown.

DNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated Mlh3−/−;Apc1638N and Mlh3−/−;Pms2−/−;Apc1638N (MPA) mice. Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. Combined Mlh3;Pms2 nullizygosity further increased Apc base-substitution mutations. The spectrum of MPA tumor mutations was distinct from that observed in Mlh1−/−;Apc1638N mice, implicating the first potential role for MLH1/PMS1 in tumor suppression. Because Mlh3;Pms2 deficiency also increased gastrointestinal tumor progression, we used array-CGH to identify a recurrent tumor amplicon. This amplicon contained a previously uncharacterized Transducin enhancer of Split (Tle) family gene, Tle6-like. Expression of Tle6-like, or the similar human TLE6D splice isoform in colon cancer cells increased cell proliferation, colony-formation, cell migration, and xenograft tumorgenicity. Tle6-like;TLE6D directly interact with the gastrointestinal tumor suppressor RUNX3 and antagonize RUNX3 target transactivation. TLE6D is recurrently overexpressed in human colorectal cancers and TLE6D expression correlates with RUNX3 expression. Collectively, these findings provide important insights into the molecular mechanisms of individual MutL homologue tumor suppression and demonstrate an association between TLE mediated antagonism of RUNX3 and accelerated human colorectal cancer progression., Author Summary Approximately one million people every year are diagnosed with colorectal cancer worldwide, and about five hundred thousand of these people subsequently perish from the disease. Colorectal cancer is thought to develop through a series of early and later stages (called cancer initiation and progression, respectively). Deaths from colorectal cancer are particularly tragic because the disease can usually be cured if discovered before full-blown progression. However, our knowledge of how these tumors progress remains very limited. DNA mismatch repair is known to be an important process in preventing ∼15% of colorectal cancer initiation. In this study we describe how two of these genes (Mlh3 and Pms2) that have partial functional redundancy and therefore individually are rarely mutated are also important in preventing colorectal cancer progression. Additionally, we describe a new gene (Tle6-like) that, when overactive, makes these cancers progress more rapidly. The overall goal of this study is to understand colorectal cancer progression better so that we can come up with new ways to block it at the later stage.

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common genetic disorder predisposing to colorectal cancer. As regular colonoscopic surveillance has been shown to reduce the incidence of colorectal cancer, this strategy is recommended worldwide. Recently, several advances in colonoscopic techniques have improved detection rates of neoplasia in Lynch syndrome. In this nationwide survey, we evaluated current surveillance colonoscopy practices for Lynch syndrome in the Netherlands and the extent to which advanced techniques have been adopted in routine clinical practice. (c) 2007 WJG. All rights reserved.

Item does not contain fulltext BACKGROUND: Small bowel cancer (SBC) is one of the tumours associated with Lynch syndrome (LS). To advise on screening for this tumour it is paramount to be informed about the lifetime risk. The aim of this study was to calculate the lifetime risk of SBC in LS and to identify possible risk factors. METHODS: Clinical and pathological data were collected on 1496 proven or putative carriers of a mismatch repair gene mutation from 189 families. Kaplan-Meier survival analysis was used to calculate the lifetime risk and to assess potential risk factors. RESULTS: 28 (1.9%) of the 1496 (putative) mutation carriers were identified with SBC. The median age at diagnosis was 52 years (range 23-69 years). The lifetime risk of developing SBC was 4.2%. There was no difference in risk between males and females (log rank: p = 0.2470), or between MLH1 and MSH2 mutation carriers (log rank: p = 0.2754). SBC was not observed in MSH6 mutation carriers (n = 203). The previous occurrence of colorectal cancer and a family history of SBC did not increase the risk significantly. CONCLUSIONS: Approximately, one out of 25 mutation carriers will develop SBC during life. No specific risk factors were identified. The risk appeared to be too low to advise screening by means of an invasive burdensome procedure like double balloon enteroscopy. However, screening by a non-invasive procedure (videocapsule endoscopy) might be considered if future studies will show its cost effectiveness. In patients with unexplained abdominal complaints and/or unexplained iron deficiency anaemia SBC should be considered.

This prospective study explored the contribution of illness representations and coping to cancer-related distress in unaffected individuals undergoing predictive genetic testing for an identified mutation in BRCA1/2 (BReast CAncer) or an HNPCC (Hereditary Nonpolyposis Colorectal Cancer)-related gene, based on the common sense model of self-regulation.Coping with hereditary cancer (UCL), illness representations (IPQ-R) and risk perception were assessed in 235 unaffected applicants for genetic testing before test result disclosure. Hereditary cancer distress (IES) and cancer worry (CWS) were assessed before, 2 weeks after and 6 months after result disclosure.Timeline (r = 0.30), consequences (r = 0.25), illness coherence (r = 0.21) and risk perception (r = 0.20) were significantly correlated to passive coping. Passive coping predicted hereditary cancer distress and cancer worry from pre-test (beta= 0.46 and 0.42, respectively) up to 6 months after result disclosure (beta= 0.32 and 0.19, respectively). Illness coherence predicted hereditary cancer distress up to 6 months after result disclosure (beta= 0.24), too.The self-regulatory model may be useful to predict the cognitive and emotional reactions to genetic cancer susceptibility testing. Identifying unhelpful representations and cognitive restructuring may be appropriate interventions to help distressed individuals undergoing genetic susceptibility testing for a BRCA1/2 or a HNPCC-related mutation. Copyright (c) 2007 John Wiley & Sons, Ltd.

This study assessed the impact of genetic testing for cancer susceptibility on family relationships and determinants of adverse consequences for family relationships. Applicants for genetic testing of a known familial pathogenic mutation in BRCA1/2 or a HNPCC related gene (N = 271) rated the prevalence and nature of changes in family relationships, familial difficulties and conflicts due to genetic testing 6 months after receiving the test result. The level of family functioning, differentiation from parents, support and familial communication style regarding hereditary cancer were assessed before receiving the test result. Genetic testing affected some family relationships in a positive way (37%), i.e. by feeling closer, improved communication and support, more appreciation of the relative and relief of negative test result. A minority reported unwanted changes in relationships (19%), problematic situations (13%) or conflicts (4%). Adverse effects comprised feelings of guilt towards children and carrier siblings, imposed secrecy and communication problems. Predictors of adverse consequences on family relationships were reluctance to communicate about hereditary cancer with relatives and disengaged-rigid or enmeshed-chaotic family functioning. Open communication between relatives should be stimulated because a lack of open communication may be an important determinant of familial adverse effects. Copyright (c) 2006 John Wiley & Sons, Ltd.

Objective: To study differences between individuals opting for genetic cancer susceptibility testing of a known familial BRCA1/2 and HNPCC related germline mutation.Methods: Coping, illness perceptions, experiences with cancer in relatives and family system characteristics were assessed in 271 applicants for genetic testing before test result disclosure. Hereditary cancer distress, worry and cancer risk perception were assessed before, 1 week after, and 6 months after disclosure.Results: Individuals from BRCA1/2 and HNPCC mutation families did not differ with regard to the number of experiences with cancer in relatives, grief symptoms, the course of cancer distress, worry and risk perception through time and most illness perceptions, coping responses and family characteristics. Individuals from BRCA1/2 families perceived hereditary cancer as more serious. They reported more frequently a passive coping style, cancer worry and a less open communication with their partner and children.Conclusion: Besides subtle differences, psychological mechanisms maybe mainly identical in individuals opting for BRCA1/2 and HNPCC susceptibility testing.Practice implications: Based on our findings, using a similar counseling approach for individuals opting for BRCA1/2 or HNPCC genetic susceptibility testing is justified. In this approach, attention should be directed more to individual aspects than to the type of disorder. (c) 2006 Elsevier Ireland Ltd. All rights reserved.