Lynch Syndrome Colorectal Cancer Research Articles

Colorectal cancer in adolescents and young adults with Lynch syndrome: a Danish register-based study

ObjectiveTo assess clinicopathological predictors and prognosis in early-onset colorectal cancer (CRC) in Lynch syndrome with comparison to patients diagnosed from age 40 and up.DesignNational, retrospective register-based case–control study.SettingDanish national hereditary...

Classification and genetic counselling for a novel splicing mutation of the MLH1 intron associated with Lynch syndrome in colorectal cancer.

BackgroundLynch-syndrome-associated cancer is caused by germline pathogenic mutations in mismatch repair genes. The major challenge to Lynch-syndrome screening is the interpretation of variants found by diagnostic testing. This study aimed to classify the MLH1 c.1989 + 5G>A mutation, which was previously reported as a variant of uncertain significance, to describe its clinical phenotypes and characteristics, to enable detailed genetic counselling.MethodsWe reviewed the database of patients with Lynch-syndrome gene detection in our hospital. A novel variant of MLH1 c.1989 + 5G>A identified by next-generation sequencing was further investigated in this study. Immunohistochemical staining was carried out to assess the expression of MLH1 and PMS2 protein in tumour tissue. In silico analysis by Alamut software was used to predict the MLH1 c.1989 + 5G>A variant function. Reverse transcription-polymerase chain reaction and sequencing of RNA from whole blood were used to analyse the functional significance of this mutation.ResultsAmong affected family members in the suspected Lynch-syndrome pedigree, the patient suffered from late-stage colorectal cancer but had a good prognosis. We found the MLH1 c.1989 + 5G>A variant, which led to aberrant splicing and loss of MLH1 and PMS2 protein in the nuclei of tumour cells. An aberrant transcript was detectable and skipping of MLH1 exon 17 in carriers of MLH1 c.1989 + 5G>A was confirmed.Conclusions MLH1 c.1989 + 5G>A was detected in a cancer family pedigree and identified as a pathological variant in patients with Lynch syndrome. The mutation spectrum of Lynch syndrome was enriched through enhanced genetic testing and close surveillance might help future patients who are suspected of having Lynch syndrome to obtain a definitive early diagnosis.

P-167 Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients

Programmed death-1 (PD-1) blockade is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. LS patients with CRC who had evaluable tumors and received ≥2 cycles of PD-1 inhibitors were included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies including radiotherapy, chemotherapy, and targeted therapy. Polyps that remained after the treatment were sequenced. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analyzed. A total of 33 LS patients were included, with a median age of 37 years. The median duration of follow-up was 11.6 months (range, 1.4 to 36.3). The objective response rate (ORR) was 60.6% (n=20), including 21.2% (n=7) complete responses (CRs) and 39.4% (n=13) partial responses (PRs). Three cases of LS CRCs displaying pMMR/MSS or discordant MMR/MSI status were not responsive despite with a moderate/high tumor mutation burden (TMB). Patients carrying deletion/splice-site variants in germline MMR genes had a higher response rate than those with other mutations (100% vs 50.0%, P=0.027). Mucinous differentiation and TMB < 25/Mb were associated with a lower ORR. Four patients had pathologically confirmed remaining adenomas ranging from 8mm to 15mm after the treatment, which were found to be MSS and had a low TMB. PD-1 inhibitors are highly effective for dMMR/MSI-H LS CRCs, but not for pMMR/MSS LS CRCs or those displaying discordant MMR/MSI status. LS polyps that exhibit pMMR/MSS are insensitive to anti-PD-1 treatment.

Abstract 1705: Identification and validation of neoantigens for developing a preventive vaccine for mismatch-repair deficient cancers

Abstract Background: Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC). LS arises when normal colorectal cells become DNA mismatch repair deficient (dMMR) upon acquiring a somatic hit in the alternative allele of the same MMR gene that harbors the germline mutation. This ‘second hit' manifests into insertion-deletion (indel) mutations in microsatellite sequences, which generates frameshift peptides (FSP) that become neoantigens (neoAg).Different system biology platforms have used next-generation sequencing (NGS) to rapidly screen the mutational landscape of LS cancers, which have identified a variety of nonsynonymous mutations that may be recognized as foreign antigens (neoantigens) to the host immune system. Putative neoantigens characterized by NGS data in LS patients provide the groundwork for developing immunoprevention strategies based on different neoantigen vaccination platforms. Methods: We utilized paired whole-exome sequencing and mRNAseq in LS CRC (stage I-III) and pre-cancers to catalog and identify the most frequently recurrent neoAg present in LS patients, and used in-silico metrics such as HLA genotype, mutational frequency, HLA binding affinity, and expression levels to predict immunogenicity. To validate our computational predictions, we harvested cytotoxic lymphocytes from a total of 3 LS patients and generated neoAg-loaded tetramers to mimic MHC-I presentation of 10 different neoAg from our prediction list. After neoAg-specific CTLs were enumerated and isolated using tetramer stains, ELISpots, and a 15-plex cytokine profiling ELISA assay were used to ascertain the immunogenic potential of each neoAg. Results: MHC-tetramer staining revealed that neoAg-specific CTLs comprised approximately 0.5-1% of total peripheral CTL population, which is consistent with previous studies. ELISpots performed using CTLs showed significant secretion of IFNγ (spot forming units) upon overnight stimulation with neoAg-loaded tetramers compared to controls. A 15-plex cytokine profile using CTLs from one patient identified significant activation of proinflammatory (IL-1a, IL-1b, IL-12, IL-17, IL-23) and proliferative (IL-2, IL-15) cytokines upon neoAg stimulation compared to the unstimulated control. Conclusion: Our results provide strong evidence to suggest our in silico computational pipelines accurately predict the immunogenicity of LS neoAg and that these neoAgs have the potential to mount an immune response consistent with previously published work performed in other cancers. Our study provides the foundation for developing an immunoprevention vaccine for LS carriers. Citation Format: Charles Bowen, Ana Bolivar, Kyle Chang, Wendy Wu, Laura Reyes-Uribe, Gregory A. Lizee, Krishna Sinha, Eduardo Vilar. Identification and validation of neoantigens for developing a preventive vaccine for mismatch-repair deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1705.

Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance.

Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols.

The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations.

Lynch syndrome (LS) is a hereditary cancer syndrome that accounts for 3% of all new colorectal cancer (CRC) cases. Patients carry a germline pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2), which encode proteins involved in a post-replicative proofreading and editing mechanism. The clinical presentation of LS is highly heterogeneous, showing high variability in age at onset and penetrance of cancer, which may be partly attributable to the molecular profiles of carcinomas. This review discusses the frequency of alterations in the WNT/B-CATENIN, RAF/MEK/ERK and PI3K/PTEN/AKT pathways identified in all four LS subgroups and how these changes may relate to the 'three pathway model' of carcinogenesis, in which LS CRCs develop from MMR-proficient adenomas, MMR-deficient adenomas or directly from MMR-deficient crypts. Understanding the specific differences in carcinogenesis for each LS subgroup will aid in the further optimization of guidelines for diagnosis, surveillance and treatment.

Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure.

Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.

Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer

It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes—people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P > .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.

Differential gain of chromosomal regions 20q or 13q with loss of 8p and 18q differentiates disease-free survival in colorectal cancer.

126 Background: In microsatellite stable (MSS) colorectal cancer (CRC) cases, frequent amplifications in 13q and 20q regions have been reported with limited understanding of their potential role for prognosis and treatment. Based on an internal research molecular tumor board case analysis of a KRAS WT, MSS left-sided (LS), metastatic CRC patient, we noted 50% of the 11 listed variants of unknown significance were on 20q. This study aims to investigate the potential prognostic role for gain of 20q chromosomal regions relative to other chromosomal imbalances using a retrospective cohort. Methods: We performed a genome-wide CN cluster analysis using the TCGA data with resulting patient clusters compared based on Kaplan-Meier estimated disease-free interval (DFI) in months (mos) using a log-rank. We examined associations between CN-derived clusters and CRC phenotypes. Results: Using TCGA data, we identified four CN-derived patient clusters of which two had significantly different DFI’s. One longer DFI cluster (n = 83; median DFI = 28mos) was defined by a signature of copy neutral genes along Chr8p and 18q regions. The shorter DFI cluster (n = 46; median DFI = 20mos) was defined by a signature of Chr8p and 18q regions of loss. The two clusters significantly differed in terms of site (85% right-sided in the shorter vs. 85% LS in the longer DFI cluster) and MS status (81% MSS in the shorter vs. 72% MSI in the longer DFI cluster) with no significant differences in age (mean of 70 years at diagnosis) and KRAS status (around 50% WT) between clusters. The shorter DFI was able to be further differentiated based on gain of chromosomal regions 20q (n = 26; median DFI = 24mos) and 13q (n = 20; median DFI = 18mos). No significant differences in mean age, tumor stage, site, and MS status between the shorter DFI subgroups were noted. Enriched pathways in the Chr20q gain sub-cluster include cell differentiation (Hippo, Rap1, VEGF), whereas metabolic signaling pathways via AGE-RAGE and AMPK, as well as cell growth and malignant transformation via RAS are enriched in the Chr13q gain sub-cluster. Conclusions: Clinical sequencing is able to identify regions of gain in Chr20q and Chr13q as part of VUS’s. Gain of Chr20q has been reported with better survival in mCRC patients. Gain of chromosomal region 20q and loss of 18q has been reported to discriminate between Lynch Syndrome and familial colorectal cancer. Herein, we show that gain of the 20q region with 18q and 8p regions of loss is associated with shorter DFI and gain of 13q region with loss of 8p even worse prognosis.

Comparison of oncologic outcomes between patients with Lynch syndrome and sporadic microsatellite instability-high colorectal cancer.

PurposeLong-term oncologic differences in outcome between groups of patients with Lynch syndrome (LS) colorectal cancer (CRC) and sporadic CRC with microsatellite instability-high (MSI-H) are the focus of investigation in the current study.MethodsPatients registered in the Korean Hereditary Tumor Registry and 2 tertiary referral hospitals treated for stage I–III CRC between 2005 and 2015 were retrospectively analyzed. Detection for both groups was performed using pedigree, microsatellite instability, and mismatch repair (MMR) gene testing. Multivariate analyses for overall survival (OS) and disease-free survival (DFS) were conducted.ResultsCases of LS (n = 77) and sporadic CRC with MSI-H (n = 96) were identified. LS CRC patients were younger in age and displayed tumor sidedness, typically involving left-sided colon and rectum, compared to patients with sporadic CRC with MSI-H. OS and DFS were lower for LS CRC relative to CRC with MSI-H (OS, 72.7% vs. 93.8%, P = 0.001; DFS, 71.4% vs. 88.5%, P = 0.001). In multivariate analyses, tumor sidedness, stage, and chemotherapy were independent factors for OS and DFS. LS CRC was a prognostic factor for poorer OS (hazard ratio, 2.740; 95% confidence interval, 1.003–7.487; P = 0.049), but not DFS.ConclusionOur findings indicate that LS CRC is associated with poorer outcomes compared to sporadic CRC with MSI-H, presenting distinct clinical features. In view of the current lack of knowledge on genetic and molecular mechanisms, appropriate management taking into consideration the difficulty of identification of CRC with hypermutable tumors harboring heterogeneity is essential.

A practical screening strategy for Lynch syndrome and Lynch syndrome mimics in colorectal cancer.

The objective of the study is to provide an efficient and practical screening strategy to distinguish a broader spectrum of Lynch syndrome (LS) and LS mimics-associated colorectal cancer (CRC), including Lynch-like syndrome (LLS), constitutional mismatch repair-deficiency, familial CRC type X (FCCTX), and polymerase proofreading-associated polyposis syndrome. 1294 cases of CRC samples were detected mismatch repair (MMR) status using immunohistochemistry (IHC) staining, in which the cases with MLH1-deficient CRC underwent BRAF mutation analysis by IHC. Following the personal and/or family history survey, next-generation sequencing (NGS) was used to detect gene variants. 1294 CRC patients were dichotomized into tumors caused by a deficient MMR (dMMR) system and a proficient MMR (pMMR) system after MMR status analysis. 45 patients with suspected sporadic dMMR CRC were then separated from MLH1-deficient CRC though BRAF mutation status analysis by IHC. Following the personal and/or family history survey for 1294 patients, as well as germline genetic testing by NGS, 34 patients were diagnosed as LS (8 cases), SLS (13 cases), LLS ( 6 cases), FCCTX (3 cases), and sporadic CRC (4 cases). Our screening strategy, which consists of clinical and molecular analyses, is expected to improve the screening efficiency and management for the LS and LS mimics.

The "unnatural" history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance.

Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.

On Hereditary Colorectal Cancer: What Is the Appropriate Surgical Technique?

Explore the pathogenesis, unique features, and various prophylactic as well as therapeutic surgical techniques used in the two most common types of hereditary colorectal cancer Lynch syndrome (LS) and familial adenomatous polyposis (FAP). In LS patients, it is important to determine the genetic risk panel before undergoing surgery. In practice, 22% of surgeons prefer to perform a subtotal colectomy at diagnosis of LS, and more than a half recommend a subtotal colectomy at diagnosis of CRC. In FAP patients, most surgeons would choose proctocolectomy + ileal pouch-anal anastomosis (IPAA) rather than total colectomy + ileorectal anastomosis (IRA), as the remaining rectum might harbor disease and will require surveillance. The role of laparoscopy and robotics has been introduced in the management of these operations over the past few years. Different surgical techniques are used as prophylactic or therapeutic measures in patients with LS and FAP. The main question is to determine how extensive the surgery should be, rather than deciding on the need or on the timing of intervention. Regardless of the surgical technique options, all decisions need to be individualized and best undertaken with the patient, patient’s family, and a multi-disciplinary team.

Underutilization of Lynch Syndrome Screening at Two Large Veterans Affairs Medical Centers.

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, yet is grossly under-recognized. Multiple professional societies recommend screening all CRCs for LS by performing tumor testing. The veterans affairs system has not adopted universal tumor testing as a national performance metric and leaves screening for LS to clinical care at individual sites. Describe adherence to LS screening in the VA system. Dual-center, retrospective review of all CRCs diagnosed between 2010 and 2016. Rates of tumor testing, personal and family history of cancer were extracted from the medical record. Univariate and multivariate regression analysis was performed to determine predictors of tumor-based screening for LS. A total of 421 cancers were reviewed. 15.1% of all cancers underwent either MSI and/or IHC for LS screening over the study period. There was improvement in LS screening from 3% of all CRCs in 2010 to 45% of all CRCs in 2016. 34% and 70% of patients did not have documentation of CRC in first- and second-degree relatives, respectively. Of the 73 patients who met one of the Revised Bethesda Criteria or had a PREMM1,2,6 score of ≥ 5, 34% and 56% underwent tumor testing, respectively. Younger age, non-Caucasian race, meeting Bethesda or PREMM1,2,6 criteria and right-sided tumor location were predictors of undergoing tumor testing. CRC tumor screening for LS is grossly inadequate when left to routine clinical care. Our results lend support to implementation of reflexive universal tumor testing within the VA system.

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

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. 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. In a total of 1346 CRC patients, 159 (11.8%) developed a mCRC after a mean follow-up of 138months 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). 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.

Abstract A08: Tumor microbiome in subtypes of mismatch repair-deficient colorectal cancer

Abstract Background: Colorectal cancer (CRC) comprises different molecular subtypes, including those tumors that develop defective DNA mismatch repair (MMR) evidenced by microsatellite instability (MSI) and/or loss of MMR protein expression (MMR-deficiency). Tumor MMR-deficiency can result from inherited causes, namely germline mutations in the MMR genes (Lynch syndrome) or from somatic inactivation resulting from hypermethylation of the MLH1 gene promoter or from biallelic somatic mutations. Little is known about the etiologies of these cancers or the avenues for risk amelioration. We hypothesized that dysbiosis of the gut microbiome is a risk factor for the development of MMR-deficient subtypes of CRC and that the microbiome composition differs between inherited and somatic MMR-deficient CRC. Materials and Methods: The microbiome composition was determined by 16S rRNA sequencing of the V3-V4 regions in DNA extracted from 94 FFPE-derived tumor specimens comprised of 14 MMR-proficient CRCs and 80 MMR-deficient CRCs from the Australasian Colorectal Cancer Family Registry. The MMR-deficient CRCs comprised three subtypes: 35 people with germline MMR gene mutations (Lynch syndrome), 13 people with sporadic MLH1 hypermethylated CRCs, and 32 people with suspected Lynch syndrome (no germline or MLH1 methylation). LEfse analyses were used to identify differential abundance in taxa between groups. Results: In all tumor samples, Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria were most abundant. Of these, the Firmicute population was significantly higher in the MMR-proficient than MMR-deficient CRCs (0.33 v 0.19, P &amp;lt; 0.05). When compared with the Lynch syndrome-related CRCs, we found 22 bacterial species, including Corynebacteriaceae, that were significantly more abundant in MLH1 hypermethylated tumors (P &amp;lt; 0.05), whereas we found 4 species significantly more abundant, including Enterobacter, in suspected Lynch syndrome group. Although the microbial diversity was notably smaller compared with the sporadic groups, several species of the family Comamanadaceae including Acidovorax were abundant in Lynch syndrome tumors (P &amp;lt; 0.05). Fusobacterium nucleatum was detected in 11/35 (31.4%) Lynch syndrome-related CRCs, 5/13 (38.5%) MLH1 hypermethylated CRCs, 13/32 (40.6%) suspected Lynch syndrome CRCs, and 4/14 (28.6%) sporadic MMR-proficient CRCs. Conclusions: Inherited and somatic subtypes of MMR-deficient CRC show significant differences in their tumor microbiome composition where Lynch syndrome-related MMR-deficient CRC showed a reduced microbiome diversity compared with somatic MMR-deficient CRC. Further validation of these findings will improve our understanding of MMR-deficient CRC tumorigenesis and aid in CRC prevention through the identification of modifiable microbial risk factors. Citation Format: Jihoon E. Joo, Mark Clendenning, Khalid Mahmood, Christophe Rosty, Ingrid M. Winship, Mark A. Jenkins, Daniel D. Buchanan. Tumor microbiome in subtypes of mismatch repair-deficient colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A08.

Incident colorectal cancer in Lynch syndrome is usually not preceded by compromised quality of colonoscopy

Background: Lifetime incidence of colorectal cancer (CRC) especially in carriers of MLH1 and MSH2 pathogenic germline variants in mismatch repair genes is high despite ongoing colonoscopy surveillance. Lynch syndrome (LS) registries have been criticized for not reporting colonoscopy quality adequately.Methods: Prospective follow-up data from the national registry were combined with a retrospective assessment of the colonoscopy reports from Helsinki University Hospital electronic patients records in 2004–2019.Results: Total of 366 MLH1, MSH2 and MSH6 carriers underwent 1564 colorectal endoscopies (mean 4.3 per patient, range 1–10) at a single unit. At least one subsequent examination was performed on 336 patients.Bowel preparation was suboptimal (Boston Bowel Preparation Scale 0–2) on either right or left side of the colon in 12.9% of planned surveillance examinations. Caecal intubation rate for full-length colonoscopies was 98.9%. Adenoma detection rate (ADR) was 15.8% in 2004–2014 but substantially increased (21.9%) after introduction of high-definition (HD) technology in 2015–2019 (p = .004; 18.7% across all examinations).CRCs were detected in 23 cases. Nineteen cancers were detected after 977 optimal quality colonoscopies and 4 after 151 compromised quality (BBPS <3 or non-complete examination; p = .16). Advanced neoplasias were not more frequently reported after compromised quality examinations.Conclusion: The majority of LS-associated incident CRCs were detected after colonoscopies with proper bowel preparation and complete examination. There is a considerable time trend towards higher ADR after introducing HD technology of endoscopes. The effect of time trend in ADR to CRC incidence in LS needs to be studied in larger, prospective settings.

Endoscopic Management of Patients with Lynch Syndrome or Familial Colorectal Cancer Risk

Sponsoring Organization: European Society of Gastrointestinal Endoscopy (ESGE)Background and ObjectiveBecause of the increased risk for cancer in

The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.

ObjectivesTo evaluate the health impact and cost‐effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia.Design, setting, participantsWe investigated the impact of LS testing strategies in a micro‐simulation model (Policy1–Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at‐risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance.Main outcome measuresCost‐effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost‐effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years).ResultsThe cost‐effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life‐year saved (LYS) (indicative willingness‐to‐pay threshold: $30 000–$50 000/LYS). These strategies could avert 184–189 CRC deaths with an additional 30 597–31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164–166 additional colonoscopies/death averted). The most cost‐effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost‐effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost‐effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost‐effective at all age limits when paired with 2‐yearly colonoscopic surveillance (ICER, $11 525–$32 153/LYS), and required 4778–15 860 additional colonoscopies to avert 46–181 CRC deaths (88–103 additional colonoscopies/death averted).ConclusionsUniversal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost‐effective compared with no testing. Universal germline gene panel testing would not currently be cost‐effective.

Single-center study of Lynch syndrome screening in colorectal polyps

BackgroundLynch syndrome is the most common hereditary colorectal cancer syndrome, and adenoma is one of the important premalignant lesions to colorectal cancer in Lynch syndrome. The first objective of this study was to calculate the detection rate of Lynch syndrome in colorectal polyps by using mismatch repair immunohistochemistry as the initial screening strategy. The second objective of this study was to optimize screening strategies for adenoma associated with Lynch syndrome by integrating polyp and/or patient characteristics such as polyp size, location, dysplasia, age of onset and/or family history of cancer.MethodsFrom June 2014 to May 2016, immunohistochemistry was performed for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) using endoscopically resected specimens obtained from newly diagnosed colorectal adenomas. Gene analysis was performed in patients with missing expression of mismatched repair protein.ResultsFive hundred and ten patients underwent colorectal polyp resection, with a total of 718 polyps. Five hundred and eight resected adenomas underwent mismatch repair protein immunohistochemical testing. Loss of mismatch repair protein expression was observed in six adenomas, accounting for 1.18% of all adenomas. Five patients then underwent genetic tests to identify two pathogenic mutations from different individuals, while another patient was suspected to have a pathogenic mutation. Three patients were younger than 50 years old. Two patients had advanced histology (high-grade dysplasia and malignant components) and one patient had a family history of cancer.ConclusionImmunohistochemical detection of colorectal polyp mismatch repair protein as Lynch syndrome screening efficiency is low. Effective screening strategies may be improved by optimizing patient/polyp selection, such as focusing on young adenoma patients with a family history of cancer, or patients who present with high-risk features (large size, villous, high-grade dysplasia and malignant components).