Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.

OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

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 [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. 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.

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

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.

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Risk factors for metachronous colorectal cancer in Lynch syndrome patients: a registry-based observational mono-institutional study cohort.

BACKGROUND: Risk factors for metachronous colorectal cancer (mCRC) in Lynch Syndrome (LS) patients are essential for colorectal cancer (CRC) treatment strategy to perform not only a curative but also preventive surgery. The aim of this study was to evaluate the risk factors for mCRC development in LS patients to define the patient subset that may benefit an extended curative and preventive surgical resection. METHODS: Patient's clinical history, oncological, molecular and follow-up were collected retrospectively from the Hereditary Digestive Tumors Registry at the National Cancer Institute of Milan. The age-related cumulative risk of mCRC was calculated using the Kaplan-Meier method. Factors significantly associated with mCRC were analyzed with a Cox regression model. Overall and specific competitive risks were also calculated. RESULTS: In a total of 1346 CRC patients, 159 (11.8%) developed a mCRC after a mean follow-up of 138 months from the primary tumor. The independent risk factors reported by a multivariate analysis were: pathogenetic variants in MLH1 and MSH2 (HR 2.96 and 1.91, respectively) and history of colorectal adenomas (HR 1.54); whereas female sex and extended surgery were protective (HR 0.59 and 0.79, respectively). CONCLUSIONS: Among a high-risk population for CRC, in particular LS, an extended surgery may be considered in CRC patients with specific risk factors (MLH1 or MSH2 germline pathogenic variants, history of colorectal adenomas) to reduce the risk of mCRC development.

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.

BACKGROUND: Most 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 DESIGN: This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. RESULTS: 3119 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. CONCLUSION: Carriers 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.

Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.

OBJECTIVE: Estimates 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. DESIGN: We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. RESULTS: 1942 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 in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation 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. CONCLUSIONS: The 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 at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database.

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.

Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.

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.

A proposed staging system and stage-specific interventions for familial adenomatous polyposis.

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.

Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.

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

Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability.

Early detection of cancer-associated genomic instability is crucial, particularly in tumour types in which this instability represents the essential underlying mechanism of tumourigenesis. Currently used methods require the presence of already established neoplastic cells because they only detect clonal mutations. In principle, parallel sequencing of single DNA filaments could reveal the early phases of tumour initiation by detecting low-frequency mutations, provided an adequate depth of coverage and an effective control of the experimental error. We applied ultradeep sequencing to estimate the genomic instability of individuals with hereditary non-polyposis colorectal cancer (HNPCC). To overcome the experimental error, we used an ultraconserved region (UCR) of the human genome as an internal control. By comparing the mutability outside and inside the UCR, we observed a tendency of the ultraconserved element to accumulate significantly fewer mutations than the flanking segments in both neoplastic and nonneoplastic HNPCC samples. No difference between the two regions was detectable in cells from healthy donors, indicating that all three HNPCC samples have mutation rates higher than the healthy genome. This is the first, to our knowledge, direct evidence of an intrinsic genomic instability of individuals with heterozygous mutations in mismatch repair genes, and constitutes the proof of principle for the development of a more sensitive molecular assay of genomic instability.

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND: Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the effect of resistant starch on the incidence of colorectal cancer. METHODS: In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990. FINDINGS: 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9-78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78-2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66-2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55-2·19, p=0·80) and an IRR of 0·98 (0·51-1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up. INTERPRETATION: Resistant starch had no detectable effect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective effect of diets rich in dietary fibre against colorectal cancer. FUNDING: European Union, Cancer Research UK, Bayer Corporation, National Starch and Chemical Co, UK Medical Research Council, Newcastle Hospitals Trustees, Cancer Council of Victoria Australia, THRIPP South Africa, The Finnish Cancer Foundation, SIAK Switzerland, and Bayer Pharma.

Editorial for the Special Issue "Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment".

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Microsatellite instability evaluation: which test to use for endometrial cancer?

AIMS: Analysis of microsatellite instability (MSI) is strongly recommended in endometrial cancer (EC) and colorectal cancer to screen for Lynch syndrome, to predict prognosis and to determine optimal treatment and follow-up. In a large monoinstitutional series of ECs, we evaluated the reliability and accuracy of Idylla assay, a rapid, fully automated system to detect MSI, and we compared its performance with two routine reference methods. METHODS: We evaluated MSI status in 174 formalin-fixed, paraffin-embedded EC tissue samples using immunohistochemistry (IHC) for mismatch repair (MMR) proteins and Idylla assay. Samples with discordant or equivocal results were analysed with a third technique, the Promega MSI kit. RESULTS: Idylla MSI assay and IHC were highly concordant (overall agreement: 154/170=90.59%, 95% CI 85.26% to 94.12%). However, in four samples, MMR-IHC staining was equivocal; moreover, 16 cases showed discordant results, that is, MMR deficient using IHC and microsatellite stable using Idylla. These 20 samples were reanalysed using the MSI-Promega kit, which showed the same results of Idylla assay in 18/20 cases (overall agreement: 90%, 95% CI 69.90% to 97.21%). CONCLUSIONS: Our results suggest that IHC is an efficient method to determine MMR status in ECs. However, the Idylla MSI assay is a rapid and reliable tool to define MSI status, and it could represent a valuable alternative to conventional MSI-PCR methods.

Hereditary Gastric Cancer: Single-Gene or Multigene Panel Testing? A Mono-Institutional Experience.

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.

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.

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.

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND: Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS: In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS: 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35-1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32-0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19-0·86, p=0·02) and an IRR of 0·37 (0·18-0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION: 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING: European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.