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Gastric cancer (GC) has long been a ‘Cinderella’ among hereditary cancers. Until recently, single-gene testing (SGT) was the only approach to identify high-risk individuals. With the spread of multigene panel testing (MGPT), a debate arose on the involvement of other genes, particularly those pertaining to homologous recombination (HR) repair. We report our mono-institutional experience in genetic counseling and SGT for 54 GC patients, with the detection of nine pathogenic variants (PVs) (9/54:16.7%). Seven out of fifty (14%) patients who underwent SGT for unknown mutations were carriers of a PV in CDH1 (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), and MSH2 (n = 1), while one patient (2%) carried two variants of unknown significance (VUSs). CDH1 and MSH2 emerged as genes involved in early-onset diffuse and later-onset intestinal GCs, respectively. We additionally conducted MGPT on 37 patients, identifying five PVs (13.5%), including three (3/5:60%) in an HR gene (BRCA2, ATM, RAD51D) and at least one VUS in 13 patients (35.1%). Comparing PV carriers and non-carriers, we observed a statistically significant difference in PVs between patients with and without family history of GC (p-value: 0.045) or Lynch-related tumors (p-value: 0.036). Genetic counseling remains central to GC risk assessment. MGPT appeared advantageous in patients with unspecific phenotypes, although it led to challenging results.

The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33–0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non–colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32–0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non–colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62–1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non–colorectal cancer cancers for patients with LS.Prevention Relevance:Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.See related Spotlight, p. 557

Perspective on This Article from A Randomized Placebo-Controlled Prevention Trial of Aspirin and/or Resistant Starch in Young People with Familial Adenomatous Polyposis

Supplementary Figure from Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

We recently read the article by Colletti et al. [...].

Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one of the most frequent hereditary syndromes; it is mainly associated with colorectal cancer (CRC). Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies, initially with contradictory results; however, longer follow-up confirmed a reduced CRC incidence and mortality. The CAPP2 study recruited 861 Lynch syndrome participants randomly assigned to 600 mg of aspirin versus placebo. Like sporadic CRCs, a significant CRC risk reduction was seen after an extended follow-up, with a median treatment time that was relatively short (2 years). The ongoing CAPP3 will address whether lower doses are equally effective. Based on pharmacology and clinical data on sporadic CRCs, the preventive effect should also be obtained with low-dose aspirin. The leading international guidelines suggest discussing with Lynch syndrome carriers the possibility of using low-dose aspirin for CRC prevention. We aim systematically promote this intervention with all Lynch syndrome carriers.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

There appears to be a sex-specific association between obesity and colorectal neoplasia in patients with Lynch Syndrome (LS). We meta-analyzed studies reporting on obesity and colorectal cancer (CRC) risk in LS patients to test whether obese subjects were at increased risk of cancer compared to those of normal weight. We explored also a possible sex-specific relationship between adiposity and CRC risk among patients with LS. The summary relative risk (SRR) and 95% confidence intervals (CI) were calculated through random effect models. We investigated the causes of between-study heterogeneity and assessed the presence of publication bias. We were able to retrieve suitable data from four independent studies. We found a twofold risk of CRC in obese men compared to nonobese men (SRR = 2.09, 95%CI: 1.23–3.55, I2 = 33%), and no indication of publication bias (p = 0.13). No significantly increased risk due to obesity was found for women. A 49% increased CRC risk for obesity was found for subjects with an MLH1 mutation (SRR = 1.49, 95%CI: 1.11–1.99, I2 = 0%). These results confirm the different effects of sex on obesity and CRC risk and also support the public measures to reduce overweight in people with LS, particularly for men.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

BACKGROUND: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population.METHODS: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [FINDINGS: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43-0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39-0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34-0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31-0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43-0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously.INTERPRETATION: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results.FUNDING: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

OBJECTIVE: Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers?DESIGN: Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants.RESULTS: 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%).CONCLUSIONS: Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

Objective: To investigate the performance of tumor testing approaches in the identification of Lynch syndrome (LS) in a single-center cohort of people with colorectal cancer (CRC). Methods: A retrospective analysis of data stored in a dedicated database was carried out to identify patients with CRC suspected for LS who were referred to Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, between 1999 and 2014. The sensitivity and specificity of immunohistochemistry (IHC) for mismatch repair (MMR) proteins and microsatellite instability (MSI) analysis (alone or combined) were calculated with respect to the presence of causative MMR germline variants. Results: A total of 683 patients with CRC suspected for LS were identified. IHC results of MMR protein analysis and MSI were assessed in 593 and 525 CRCs, respectively, while germline analysis was performed in 418 patients based on the IHC or MSI test result and/or clinical features. Univariate and multivariate analysis revealed a significant correlation of pathogenic MMR germline variants with all clinicopathologic features including Amsterdam criteria, presence of endometrial cancer, CRC site, age at onset, stage, and grade. The highest odds ratio values were observed for IHC and MSI (17.1 and 8.8, respectively). The receiver operating characteristic curve and area under the curve values demonstrated that IHC alone or combined with other clinicopathologic parameters was an excellent test for LS identification. Conclusions: This study confirms the effectiveness of tumor testing to identify LS among patients with CRC. Although IHC and MSI analysis were similarly effective, IHC could be a better strategy for LS identification as it is less expensive and more feasible.

BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype. We investigated MBD4 variants in a large series of hereditary/familial and sporadic CRC cases. Whereas MBD4 frameshifts were only detected in tumors, missense variants were found in both normal and tumor DNA. In CRC with double-MBD4/MMR and single-MBD4 variants, transition mutation frequency was increased, indicating that MBD4 defects may affect the mutational landscape independently of MMR defect. Mbd4-deficient mice showed reduced survival when combined with Mlh1-/- genotype. Taken together, these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of MMR-deficient cancer phenotype.

Background We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval., published version, peerReviewed

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.

Background Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described. Case presentation Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers. Conclusions By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s40880-016-0115-1) contains supplementary material, which is available to authorized users.

Background and Aims It is not possible to accurately count adenomas in many patients with familial adenomatous polyposis (FAP). Nevertheless, polyp counts are critical in evaluating each patient's response to interventions. However, the U.S. Food and Drug Administration no longer recognizes the decrease in polyp burden as a sufficient chemoprevention trial treatment endpoint requiring a measure of "clinical benefit." To develop endpoints for future industry-sponsored chemopreventive trials, the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) developed an FAP staging and intervention classification scheme for lower-GI tract polyposis. Methods Twenty-four colonoscopy or sigmoidoscopy videos were reviewed by 26 clinicians familiar with diagnosis and treatment of FAP. The reviewers independently assigned a stage to a case by using the proposed system and chose a stage-specific intervention for each case. Our endpoint was the degree of concordance among reviewers staging and intervention assessments. Results The staging and intervention ratings of the 26 reviewers were highly concordant (ρ = 0.710; 95% credible interval, 0.651-0.759). Sixty-two percent of reviewers agreed on the FAP stage, and 90% of scores were within ±1 stage of the mode. Sixty percent of reviewers agreed on the intervention, and 86% chose an intervention within ±1 level of the mode. Conclusions The proposed FAP colon polyposis staging system and stage-specific intervention are based on a high degree of agreement on the part of experts in the review of individual cases of polyposis. Therefore, reliable and clinically relevant means for measuring trial outcomes can be developed. Outlier cases showing wide scatter in stage assignment call for individualized attention and may be inappropriate for enrollment in clinical trials for this reason.

Background: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers. Methods: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided. Results: Mutations were detected in 539 of 2304 (23%) individuals from the clinic- based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%. Conclusions: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in the family.

Vascular cyclooxygenase (COX)-2-dependent prostacyclin (PGI(2)) may affect angiogenesis by preventing endothelial activation and platelet release of angiogenic factors present in platelet α-granules. Thus, a profound inhibition of COX-2-dependent PGI(2) might be associated with changes in circulating markers of angiogenesis. We aimed to address this issue by performing a clinical study with celecoxib in familial adenomatous polyposis (FAP). In nine patients with FAP and healthy controls, pair-matched for gender and age, we compared systemic biosynthesis of PGI(2), thromboxane (TX) A(2), and prostaglandin (PG) E(2), assessing their urinary enzymatic metabolites, 2,3-dinor-6-keto PGF(1α) (PGI-M), 11-dehydro-TXB(2) (TX-M), and 11-α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), respectively. The impact of celecoxib (400 mg b.i.d. for 7 days) on prostanoid biosynthesis and 14 circulating biomarkers of angiogenesis was evaluated in FAP. Intestinal tumorigenesis was associated with enhanced urinary TX-M levels, but unaffected by celecoxib, suggesting the involvement of a COX-1-dependent pathway, presumably from platelets. This was supported by the finding that in cocultures of a human colon adenocarcinoma cell line (HT-29) and platelets enhanced TXA(2) generation was almost completely inhibited by pretreatment of platelets with aspirin, a preferential inhibitor of COX-1. In FAP, celecoxib profoundly suppressed PGE(2) and PGI(2) biosynthesis that was associated with a significant increase in circulating levels of most proangiogenesis proteins but also the antiangiogenic tissue inhibitor of metalloproteinase 2. Urinary PGI-M, but not PGE-M, was negatively correlated with circulating levels of fibroblast growth factor 2 and angiogenin. In conclusion, inhibition of tumor COX-2-dependent PGE(2) by celecoxib may reduce tumor progression. However, the coincident depression of vascular PGI(2), in a context of enhanced TXA(2) biosynthesis, may modulate the attendant angiogenesis, contributing to variability in the chemopreventive efficacy of COX-2 inhibitors such as celecoxib.

Purpose To determine the prevalence of adenomatous and hyperplastic polyps in a large cohort of individuals with a germline mutation in a mismatch repair (MMR) gene, the major genetic determinant of hereditary nonpolyposis colorectal cancer (HNPCC). These prevalences have been estimated previously in smaller studies, and the results have been found to be variable. Patients and Methods Colorectal Adenoma/Carcinoma Prevention Programme 2 trial is a chemoprevention trial in people classified as having HNPCC. The 695 patients with a proven germline MMR mutation and documented screening history before the chemoprevention study were the focus of this study. The number, histology, size, and location of polyps found at the participants' first ever colonoscopy were analyzed in a cross-sectional study. Results Seventy-four patients (10.6%) were found to have at least one adenoma at first colonoscopy, whereas 37 (5.3%) had at least one hyperplastic polyp. The frequency of an adenoma at first colonoscopy increased from 5.0% (95% CI, 2.8% to 8.3%) in patients younger than 35 years old to 18.9% (95% CI, 9.4% to 32.0%) in patients age at least 55 years (P = .0001 for trend). No such trend was observed for hyperplastic polyps. No sex differences were found for either type of polyp. A marginal association was found between the co-occurrence of adenomas and hyperplastic polyps. Adenomas tended to be more proximally distributed through the colon, whereas hyperplastic polyps tended to be located in the distal colon. Conclusion Adenoma prevalence increases with age among MMR mutation carriers, whereas hyperplastic polyp prevalence is consistent. No sex differences were observed for either type of lesion.

Background: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. Methods: In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. Results: Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. Conclusions: The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.).

Knowledge about hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome clearly evolved during the last 10 to 15 years much more rapidly than in the past century. Consequently, long-established concepts and attitudes that held for many years should now be changed or updated. With regard to classification, we suggest maintaining the eponym "Lynch syndrome" for families that have a well-documented deficiency of the DNA mismatch repair system, whereas "clinical hereditary nonpolyposis colorectal cancer" should be reserved for those families that meet the Amsterdam criteria but without evidence of mismatch repair impairment. Any family (or individual) meeting one or more of the Bethesda criteria can be considered as suspected HNPCC. For the identification of hereditary colorectal cancer molecular screening or the pedigree analysis show advantages and disadvantages; the ideal would be to combine the two approaches. Diffusion of the microsatellite instability test and of immunohistochemistry in the pathology laboratories might render in the immediate future molecular screening more realistic. Strict endoscopic surveillance of family members at risk (with first colonoscopy at age 20-25 years and then every 2-3 years) is needed only in families with documented alterations of the DNA mismatch repair. To a certain extent, our conclusions were similar to the recently proposed "European guidelines for the clinical management of HNPCC," although we prefer the term "clinical hereditary nonpolyposis colorectal cancer," instead of familial colorectal cancer, for families meeting the Amsterdam criteria but not having evidence of mismatch repair impairment.

Purpose In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS). Patients and Methods Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2 × 2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months. Results During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41× (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m2 increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96; P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75; 95% CI, 1.12 to 6.79; P = .03). Conclusion Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.

BACKGROUND: Germline mutations in the STK11/LKB1 gene cause Peutz-Jeghers syndrome, an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyposis, and an increased risk for various malignancies. We here report the results of the first Italian collaborative study on Peutz-Jeghers syndrome. AIMS: To assess cancer risks in a large homogenous cohort of patients with Peutz-Jeghers syndrome, carrying, in large majority, an identified STK11/LKB1 mutation. METHODS: One-hundred and nineteen patients with Peutz-Jeghers syndrome, ascertained in sixteen different Italian centres, were enrolled in a retrospective cohort study. Relative and cumulative cancer risks and genotype-phenotype correlations were evaluated. RESULTS: 36 malignant tumours were found in 31/119 (29 STK11/LKB1 mutation carriers) patients. The mean age at first cancer diagnosis was 41 years. The relative overall cancer risk was 15.1 with a significantly higher risk (p

We describe a new approach to investigate alterations in the human MLH1 mismatch repair (MMR) gene. This is based on complementation of the phenotype of a MLH1-defective subclone of the ovarian carcinoma A2780 cells by transfection of vectors encoding altered MLH1 proteins. Measurements of resistance (tolerance) to methylating agents, mutation rate at HPRT, microsatellite instability (MSI), and steady-state levels of DNA 8-oxoguanine were used to define the MMR status of transfected clones. The approach was validated by transfecting cDNA of wild-type (WT) MLH1, cDNAs bearing two previously identified polymorphisms (I219V and I219L) and two with confirmed hereditary nonpolyposis colorectal cancer (HNPCC) syndrome mutations (G224D and G67R). A low-level expression of two MLH1 polymorphisms partially reversed methylation tolerance and the mutator phenotype, including MSI. Higher levels of I219V resulted in full restoration of these properties to WT. Increased expression of I129L did not fully complement the MLH1 defect, because there was a simultaneous escalation in the level of oxidative DNA damage. The findings confirmed the important relationship between deficient MMR and increased levels of oxidative DNA damage. Mutations from Italian HNPCC families (G224D, G67R, N635S, and K618A) were all ineffective at reversing the phenotype of the MLH1-defective A2780 cells. One (K618A) was identified as a low penetrance mutation based on clinical and genetic observations. (Cancer Res 2006; 66(18): 9036-44)

Background & Aims: MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. There are only few immunohistochemical studies of the MYH protein. We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene. Methods: The expression of MYH, MSH2, MLH1, and MSH6 proteins was studied by immunohistochemistry in 20 samples (colorectal adenomas or cancer) from 18 patients with biallelic MYH mutation, in 11 samples from patients with germline adenomatous polyposis coli (APC) mutations, in 20 samples from patients with sporadic colorectal cancers, and in 10 samples from patients with normal colonic mucosa without malignancies. Results: In all cases the mismatch repair proteins were expressed normally. Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations. Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression. The same immunophenotype was observed in the surrounding normal mucosa. Conclusions: Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa. Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis.

Hereditary Colorectal Tumor Registry, Istituto NazionaleTumori, Milan, ItalyCommunicated by Jing ChengLarge genomic rearrangements are recognized as playing a pathogenic role in an increasing number of humangenetic diseases. It is important to develop efficient methods for the routine detection and confirmation of thesegermline defects. Multiplex ligation-dependent probe amplification (MLPA) is considered an early step formolecular diagnosis of several genetic disorders. However, artifacts might hamper the interpretation of MLPAanalysis, especially when rearrangements involve a single exon. Therefore, rearrangements must be verifiedby two independent methods. In this study, we developed nonfluorescent multiplex-PCR coupled to high-performance liquid chromatography (NFMP-HPLC) andanalyzed whetherthe use of this method combined withMLPA could be helpful in the detection and confirmation of gross MSH2 and MLH1 genomic rearrangements.A total of nine nonfluorescent multiplex-PCRs were developed to analyze the 16 MSH2 and 19 MLH1 exons.Reliable multiplex amplifications and nonfluorescent peak quantitation were obtained with a limited number ofcycles (r25) using a denaturing HPLC (DHPLC) instrument under nondenaturing conditions. The resultsobtained by NFMP-HPLC were highly reproducible. The combined use of MLPA and NFMP-HPLC identifiedand independently confirmed putative MLH1 and MSH2 deletions in eight out of 50 unrelated patients withhereditary nonpolyposis colorectal cancer (HNPCC). In five cases, the deletions affected a single exon and inthree cases multiple contiguous exons. These results were in agreement with breakpoint and complementaryDNA (cDNA) analyses. Considering that MLPA and NFMP-HPLC are unlikely to be affected by the sameartifacts, their combined use could also provide a robust and cost-effective strategy for routine screening andconfirmation of putative rearrangements in other genes, especially when a single exon is involved or a precisecharacterization of breakpoints is not achieved. Hum Mutat 27(10), 1047–1056, 2006.

Familial adenomatous polyposis (FAP) is an autosomal condition caused by inherited mutations in the adenomatous polyposis coli (APC) or in the MYH genes. Clinical trials have established that nonsteroidal anti-inflammatory drugs (NSAID) are effective in preventing the development as well as reducing the size and decreasing the number of adenomas in FAP patients. Our aim was to evaluate the cyclooxygenase-2 (COX-2) expression in surgical specimens from patients with no evidence of germ line APC mutations but carrying germ line MYH mutations. COX-2 expression was evaluated through immunohistochemical and mRNA analysis in carcinomas, adenomas, and healthy mucosa from six patients carrying germ line biallelic MYH mutations. A modulation of COX-2 expression from adenoma (lower level) to carcinoma (higher level) was observed in all patients by both immunohistochemical and mRNA analysis. Moreover, patients with MYH mutations showed a weak COX-2 expression in the whole colorectal mucosa, as for classic FAP patients carrying germ line APC mutations. All together, our data suggest that biallelic MYH patients might benefit from NSAID treatment, because in these patients COX-2 is overexpressed in the whole colorectal mucosa, a finding possibly related to the interplay between COX-2 and APC protein being the APC gene a common target of mutations in MYH patients.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

BACKGROUND, Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients. METHODS. A questionnaire was mailed to the members of International Collaborative Group on HNPCC (ICG-HNPCC) requesting clinicopathologic data in their registries on HNPCC patients with small bowel carcinoma. Survival was estimated utilizing the Kaplan-Meier method. RESULTS. Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors. There were 46 adenocarcinomas and 3 carcinoid tumors. The median age at diagnosis of the index small bowel tumor was 49 years. Mismatch repair gene mutations were present in 15 of 42 patients (36%). There were nine hMLH1 and six hMSH2 mutations. The small bowel was the first site of carcinoma in 24 patients (57%). The median survival for the 42 patients was 47 months (range, 0-447 months). The overall 5- and 10-year survival rates were 44% and 33%, respectively. CONCLUSIONS. Small bowel tumors can be the presenting neoplasms in HNPCC patients. Similar to colorectal carcinoma in HNPCC, small bowel adenocarcinomas in HNPCC patients occur at an earlier age and appear to have a better prognosis than those occurring in the general population.

ObjectiveThe authors analyzed the incidence of rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) after an abdominal colectomy.Summary Background DataThe treatment of choice for a newly diagnosed patient with HNPCC with colon cancer is an abdominal colectomy. The in

Background Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. Methods The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. Results A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0–516) months in the open group and 60 (12–108) months in the laparoscopic group, 98 patients (16·3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13·0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0·042). In multivariable analysis, female sex (hazard ratio (HR) 2·18, 95 per cent confidence interval 1·40 to 3·39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3·85, 1·90 to 7·80), proctocolectomy (HR 1·67, 1·06 to 2·61), open colectomy (HR 6·84, 1·96 to 23·98) and year of surgery (HR 1·04, 1·01 to 1·07) were independent risk factors for the diagnosis of DT after prophylactic surgery. Conclusion Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP.

The identification of germline variants predisposing to hereditary nonpolyposis colorectal cancer (HNPCC) is crucial for clinical management of carriers, but several probands remain negative for such variants or bear variants of uncertain significance (VUS). Here we describe the results of integrative molecular analyses in 132 HNPCC patients providing evidences for improved genetic testing of HNPCC with traditional or next generation methods. Patients were screened for: germline allele-specific expression (ASE), nucleotide variants, rearrangements and promoter methylation of mismatch repair (MMR) genes; germline EPCAM rearrangements; tumor microsatellite instability (MSI) and immunohistochemical (IHC) MMR protein expression. Probands negative for pathogenic variants of MMR genes were screened for germline APC and MUTYH sequence variants. Most germline defects identified were sequence variants and rearrangements of MMR genes. Remarkably, altered germline ASE of MMR genes was detected in 8/22 (36.5%) probands analyzed, including 3 cases negative at other screenings. Moreover, ASE provided evidence for the pathogenic role and guided the characterization of a VUS shared by 2 additional probands. No germline MMR gene promoter methylation was observed and only one EPCAM rearrangement was detected. In several cases, tumor IHC and MSI diverged from germline screening results. Notably, APC or biallelic MUTYH germline defects were identified in 2/19 probands negative for pathogenic variants of MMR genes. Our results show that ASE complements gDNA-based analyses in the identification of MMR defects and in the characterization of VUS affecting gene expression, increasing the number of germline alterations detected. An appreciable fraction of probands negative for MMR gene variants harbors APC or MUTYH variants. These results indicate that germline ASE analysis and screening for APC and MUTYH defects should be included in HNPCC diagnostic algorithms.

Item does not contain fulltext Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis. 01 juli 2010

A biomarker, according to a generally accepted definition, is a substance or a manifestation used as indicator of a biologic state. It has the characteristic to be objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological responses to therapeutic interventions. Biomarkers are important tools available to the clinicians with escalating perspectives in oncologic field. Clinical and genetic biomarkers are essential to properly individuate the disease, to address patients to specific surveillance programs and therapeutic strategies. An ideal biomarker should be absent in normal tissue/condition but present in precancerous lesions like dysplasia and so able to recognize early cancer. Coming from these considerations, several of the known genetic pathways in cancer pathogenesis could be considerate potential candidate biomarkers. In this review, we have reported clinical and molecular biomarkers helpful to manage the Familial Adenomatous Polyposis (FAP), a dominantly inherited colorectal cancer predisposition syndrome. Biomarkers, both clinical and molecular, are essential to reduce the high potential morbidity of FAP giving the opportunity to develop innovative diagnostic and therapeutic protocols.

Background Women with a germline mutation in one of the MMR genes MLH1 , MSH2 or MSH6 reportedly have 4–12% lifetime risk of ovarian cancer, but there is limited knowledge on survival. Prophylactic bilateral salpingo-oophorectomy (PBSO) has been suggested for preventing this condition. Aim The purpose of this retrospective multicentre study was to describe survival in carriers of pathogenic mutations in one of the MMR genes, and who had contracted ovarian cancer. Methods Women who had ovarian cancer, and who tested positive for or were obligate carriers of an MMR mutation, were included from 11 European centres for hereditary cancer. Most women had not attended for gynaecological screening. Crude and disease specific survival was calculated by the Kaplan–Meier algorithm. Results Among the 144 women included, 81.5% had FIGO stage 1 or 2 at diagnosis. 10 year ovarian cancer specific survival independent of staging was 80.6%, compared to less than 40% that is reported both in population based series and in BRCA mutation carriers. Disease specific 30 year survival for ovarian cancer was 71.5%, and for all hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome related cancers including ovarian cancer it was 47.3%. Conclusions In the series examined, infiltrating ovarian cancer in Lynch syndrome had a better prognosis than infiltrating ovarian cancer in BRCA1/2 mutation carriers or in the general population. Lifetime risk of ovarian cancer of about 10% and a risk of dying of ovarian cancer of 20% gave a lifetime risk of dying of ovarian cancer of about 2% in female MMR mutation carriers.