Clonal origin and genomic diversity in Lynch syndrome-associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H.

Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent MLH1 loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.

Risk of metachronous colorectal cancer after colectomy for first colon cancer in Lynch syndrome: multicenter retrospective study in Japan.

BACKGROUND: We evaluated the risk of metachronous colorectal cancer (mCRC) and explored the optimal extent of colectomy in patients with Lynch syndrome (LS) and first colon cancer (fCC) in Japan, where the extent of colectomy for colon cancer (CC) is shorter than that in Western countries. METHODS: The clinicopathologic and survival data of patients with LS who developed CC were collected from a nationwide database and analyzed retrospectively. The cumulative incidence of mCRC after actual segmental colectomy was compared with that of mCRC when more extensive colectomy was assumed. RESULTS: There were 142 eligible patients (65 female). The median age at fCC surgery was 46.5 (range: 14-80) years. The cumulative incidence of 5-, 10-, and 20-year mCRC rate was 13.4%, 20.8%, and 53.6%, respectively. The incidence was higher in the left-sided group (splenic flexure to rectosigmoid colon, n = 54) than in the right-sided group (cecum to transvers colon, n = 88) (66.3% vs. 45.3% in 20 years, P < 0.01). Assuming that all patients would have undergone hemicolectomy or total colectomy, the estimated mCRC risk was 41.5% and 9.4% (P < 0.01, vs. actual procedures), respectively. The 20-year overall survival rate of all the patients was 83.3% without difference by fCC sidedness (P = 0.38). CONCLUSIONS: To reduce the incidence of mCRC, patients with genetically diagnosed LS and fCC, preferentially located in the left-sided colon, may need to undergo more extended colectomy than that usually performed in Japan. However, such extended colectomy should be counterbalanced with favorable overall survival and actual risk of mCRC development.

Primary and Secondary Prevention Interventions to Reduce Risk Factors Associated with Colorectal Cancer in High-Risk Groups: a Systematic Literature Review.

In the USA, colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths. Certain groups in the USA are at an increased risk of developing CRC, including those with a genetic risk and family history. The purpose of this project was to synthesize primary and secondary prevention interventions for individuals who are at high risk of CRC due to family history or genetic predisposition. This study systematically reviewed articles from PubMed, Google Scholar, and EBSCO using specific search terms to find relevant articles. Sixteen articles were identified for full-text review, which were categorized as non-drug interventions (n = 7) and drug interventions (n = 9). Non-drug interventions focused primarily on increasing screening in those with a first-degree relative (FDR) with CRC or those with Lynch syndrome (LS). Interventions that increased CRC screening often had a tailored component and were otherwise varied in study designs and intervention type. Drug interventions focused on the use of NSAIDs on patients with familial adenomatous polyposis (FAP). Studies showed very little racial and ethnic diversity. Findings suggest that tailored interventions are particularly effective in increasing CRC screening, and greater diversity of sample is needed with respect to race and ethnicity.

[Two Cases Suspected of Lynch Syndrome Caused by Juvenile Rectal Cancer].

Case 1: A 28-year-old man was admitted to our hospital because of bloody stools that persisted for several months. Colonoscopy showed a 1/2 circumferential type 2 tumor in the rectum. Laparoscopic high anterior resection(D3)was performed for rectal cancer cT3N0M0, cStage Ⅱa. The final diagnosis was pStage Ⅱa, and MSI-high. XELOX therapy was performed for 3 months to prevent recurrence, and the patient is alive without recurrence. Case 2: A 51-year-old man, father of case 1 patient, was admitted to our hospital because of anemia and dyspnea. Colonoscopy showed a circumferential type 2 tumor in the ascending colon. Laparoscopic right hemicolectomy(D3)was performed for ascending colon cancer cT4b N2aM0, cStage Ⅲc. The final diagnosis was pT3N0M0, pStage Ⅱa, and MSI-high. The patient is alive no recurrence without adjuvant chemotherapy. Both patients had a family history of colorectal cancer, were MSI-high, met the Amsterdam criteria Ⅱ and the revised Bethesda guidelines, and were suspected of having Lynch syndrome. A detailed family history and appropriate information provision were considered useful.

Endometrial cancer in Lynch syndrome.

Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS-EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS-EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR-immunohistochemistry (MMR-IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo-oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS-EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) EC.

Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X.

Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.

Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome.

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and pan-chromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

Determination of test performance of two contemporary screening tests for Lynch syndrome in endometrial cancer: A clinical trial.

BACKGROUND/PURPOSE: Published data on the performance of the immunohistochemistry (IHC) test for mismatch repair (MMR) protein expression to detect Lynch syndrome (LS) index cases suggests it is highly variable; its performance in our system was unknown. Moreover, a brief family history questionnaire (bFHQ) developed by Eiriksson and colleagues in Canada demonstrated 100% sensitivity for LS case identification thus was of interest to us, but its performance outside of its original setting was unknown. Determination of the performance of these tests requires complete LS case identification in the testing population. METHODS: Two hundred women were recruited during routine care for endometrial cancer (EC) to administer the bFHQ and perform genetic testing for the LS genes. Independently, the IHC test was performed to screen for presumptive LS cases. We determined the sensitivity, specificity, and positive and negative predictive values of the bFHQ and IHC test as well as simulating outcomes of the complete protocols. RESULTS: Genetic testing all participants identified 8 cases of LS out of 200 (4% prevalence), the bFHQ identified 5 of 8 of these cases (62.5%, CI: 31.5%-87.6%), and the IHC test identified 6 or 7 of 8 cases (mean of 75% or 87.5%) depending on interpretation of test results. The specificities of the bFHQ and IHC test were 56.8% (CI: 49.8%-63.7%) and 79.8% (CI: 73.6%-85.1%), respectively. CONCLUSIONS: This study is the first, to our knowledge, to test the effectiveness of the bFHQ in an EC population since its original reporting; our results are consistent with many reports of the challenges of collecting family health history. The performance of the IHC test as a screen falls within ranges reported in the literature but do not provide the confidence to drive a decision for or against continued use of this test as a LS screen.

Evaluation of Urinalysis-Based Screening for Urothelial Carcinoma in Patients With Lynch Syndrome.

BACKGROUND: Approximately 5% to 10% of patients with Lynch syndrome develop urothelial carcinoma. Current screening recommendations vary and are based on expert opinion. Practices need to be evaluated for clinical effectiveness. Our program utilizes urinalysis as a screening test, followed by additional evaluation of microscopic hematuria. OBJECTIVE: This study aimed to determine the clinical utility of a urinalysis-based screening approach for urothelial cancers in patients with Lynch syndrome. DESIGN: This is a retrospective review of a prospectively maintained cohort. SETTING: Patients with Lynch syndrome were managed at a tertiary referral center. PATIENTS: All patients with a Lynch syndrome diagnosis who had a screening urinalysis done as part of our institutional screening protocol (N = 204) were included. MAIN OUTCOME MEASURES: A single-institution hereditary colorectal cancer syndrome registry was queried for patients with Lynch syndrome who had been screened for urothelial carcinomas by urinalysis. Demographics, genotype, family history of urothelial carcinoma, urinalysis results, and subsequent screenings and final diagnosis were gathered for patients between 2008 and 2017. RESULTS: Two hundred four asymptomatic patients underwent screening by urinalysis. Nineteen patients (9.3%) had microscopic hematuria and were further evaluated with urine cytology, imaging, cystoscopy, and/or Urology consultation. None of the 19 patients with microscopic hematuria had urothelial carcinoma. During the same study period, 5 of 204 (2.4%) patients with Lynch syndrome were diagnosed with urothelial cancer, and all presented with symptoms between screening intervals. LIMITATIONS: This is a retrospective study, and not all patients underwent the same secondary evaluation. CONCLUSIONS: No urothelial carcinomas were detected by screening urinalysis in our cohort of asymptomatic patients with Lynch syndrome. False-positive testing led to extensive, mostly uninformative, workups. If urothelial cancer screening is to continue, more effective screening approaches need to be identified. See Video Abstract at http://links.lww.com/DCR/B702. EVALUACIN DEL CRIBADO BASADO EN ANLISIS DE ORINA PARA CARCINOMA UROTELIAL EN PACIENTES CON SNDROME DE LYNCH: ANTECEDENTES:Aproximadamente el 5-10% de los pacientes con síndrome de Lynch desarrollan carcinoma urotelial. Las recomendaciones actuales de detección varían y se basan en la opinión de expertos. Las prácticas deben evaluarse para determinar su eficacia clínica. Nuestro programa utiliza el análisis de orina como prueba de detección, seguido de una evaluación adicional con hematuria microscópica.OBJETIVO:Determinar la utilidad clínica desde un enfoque de cribado basado en análisis de orina, para cánceres uroteliales en pacientes con síndrome de Lynch.DISEÑO:Revisión retrospectiva de una cohorte mantenida prospectivamente.ENTORNO CLINICO:Pacientes con síndrome de Lynch atendidos en un centro de referencia terciario.PACIENTES:Criterios de inclusión fueron todos los pacientes con diagnóstico de síndrome de Lynch realizándoles un análisis de orina de detección como parte de nuestro protocolo de detección institucional (N = 204).PRINCIPALES MEDIDAS DE VALORACION:Solicitando un registro de síndrome de cáncer colorrectal hereditario de una sola institución para pacientes con síndrome de Lynch previamente evaluados para carcinomas uroteliales mediante análisis de orina. Se recopilaron para los pacientes entre 2008 y 2017, datos demográficos, genotipo, antecedentes familiares de carcinoma urotelial, resultados del análisis de orina, posteriores exámenes de detección posteriores y diagnóstico final.RESULTADOS:Doscientos cuatro pacientes asintomáticos fueron sometidos a cribado mediante análisis de orina. Diecinueve pacientes (9,3%) tenían hematuria microscópica y fueron investigados más a fondo con citología de orina, imágenes, cistoscopia y / o consulta de urología. Ninguno de los 19 pacientes con hematuria microscópica tenían carcinoma urotelial. Durante el mismo período de estudio, 5 de 204 (2,4%) pacientes con síndrome de Lynch fueron diagnosticados con cáncer urotelial y todos presentaron presentando síntomas entre los intervalos de detección.LIMITACIONES:Estudio retrospectivo y no todos los pacientes sometidos a la misma evaluación secundaria.CONCLUSIONES:No se detectaron carcinomas uroteliales mediante análisis de orina de detección en nuestra cohorte de pacientes asintomáticos con síndrome de Lynch. Las pruebas de falsos positivos. Condujeron a estudios exhaustivos y en su mayoría poco informativos. Si se desea continuar con la detección del cáncer de urotelio, es necesario identificar enfoques de detección más efectivos. Consulte Video Resumen en http://links.lww.com/DCR/B702.

Initial screening by immunohistochemistry is effective in universal screening for Lynch syndrome in endometrial cancer patients: a prospective observational study.

BACKGROUND: Few prospective reports of universal screening for Lynch syndrome exist for patients with endometrial cancer. In this study, we performed immunohistochemical staining for DNA mismatch repair-related genes (MLH1, MSH2, MSH6 and PMS2), to determine the extent to which Lynch syndrome can be diagnosed in endometrial cancer patients through universal screening. METHODS: We recruited 116 consecutive patients assumed to have uterine corpus malignancy from October 2019 to February 2021 in a prospective observational study. We performed immunohistochemical for mismatch repair-related proteins on samples from 100 patients who had surgicopathologically confirmed diagnoses of endometrial cancer. Samples with missing immunohistochemical results for any of the proteins had subsequent universal screening tests for microsatellite instability, DNA methylation of the MLH1 promoter region and mismatch repair genetics. RESULTS: We identified 19 (19.0%) patients with lost results for any of the proteins. All 19 patient samples had subsequent screening tests. We identified the microsatellite instability-high phenotype in 84.2% (16/19) of these patients and MLH1 methylation in 57.9% (11/19). Mismatch repair genetic testing detected two pathological variants, in MSH2 and MSH6, which indicated that the prevalence of Lynch syndrome was 2.0% in our cohort. Two cases of unclassified variant (MSH6) and one case of benign variant (PMS2) were also detected. CONCLUSIONS: Initial screening by immunohistochemical is an effective method in universal screening for Lynch syndrome in endometrial cancer patients.

Risk of first onset of colorectal cancer associated with alcohol consumption in Lynch syndrome: a multicenter cohort study.

BACKGROUND: Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site. METHODS: Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC. RESULTS: Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer). CONCLUSIONS: Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.

The clinical features and management of Lynch syndrome-associated ovarian cancer.

AIM: Lynch syndrome (LS) is one of the most common hereditary cancer syndromes, characterized by mutations in mismatch repair genes and autosomal dominant inheritance. Women with LS have an additional increased risk of gynecologic malignancies, including endometrial cancer (EC) and ovarian cancer (OC). Compared with EC, OC is relatively under investigation. This review thoroughly summarizes the current clinical evidence of surveillance, screening, and prevention strategies, and describes the molecular and clinical characteristics of LS-associated OC. METHODS: An electronic search from databases of PubMed and Google Scholar was carried out using key words pertaining to Lynch syndrome and ovarian cancer. A review of the literatures including review articles, experimental, and observational studies published between 2000 and 2021 was conducted. RESULTS: The lifetime risk of OC in women with LS of MLH1, MSH2, and MSH6 mutations is approximately 7%, with the median age at onset being 46 years, 10-15 years earlier than that in sporadic cases. Histologically, LS-associated OCs are primarily endometrioid (40%), high-grade (25%), and low-grade (11%) serous, or clear cell (6%) in nature. Eighty-five percent of patients are diagnosed at an early stage, presenting with a good prognosis at 84% 5-year survival. Optimal screening strategies for OC in LS are controversial; combined screening of patients' clinical and family history, immunohistochemical analysis, and microsatellite instability testing for mismatch repair deficiency have been proven efficient. CONCLUSION: The clinical features were different between ovarian cancer in Lynch syndrome and sporadic cases. More research are needed for a greater understanding of the prevention and medical treatment of LS-associated OC.

[A Case of Suspected Lynch Syndrome Due to Radical Resection for Descending Colon Cancer and Renal Pelvic Cancer].

A 60-year-old woman was admitted on account of presenting with bloody stools. She had a history of endometrial cancer surgery. Family history revealed 3 colorectal cancer cases among the first or second relatives. Colonoscopy and contrast- enhanced computed tomography revealed descending colon cancer and left renal pelvic cancer. We performed partial resection of the descending/transverse colon with D3 lymph node dissection and total resection of the left kidney and ureter with curative intent. Postoperative pathological diagnosis revealed descending colon cancer(pT4bN0M1c, pStage Ⅳc)and left renal pelvic cancer (T1N0M0, Stage Ⅰ). In this case, Lynch syndrome was suspected based on the family history and medical history. The clinical findings were consistent with Amsterdam Criteria Ⅱ. The microsatellite instability(MSI)test result was MSI-H and the BRAF genetic test result showed a wild type. Immunohistochemical staining of descending colon cancer tissue showed loss of expression of MSH2 and MSH6 proteins. Genetic counseling was provided because Lynch syndrome was strongly suspected. Capecitabine plus oxaliplatin therapy was performed for 6 months for descending colon cancer. Nine months postoperatively, the patient remained recurrence-free for both colon cancer and renal pelvic cancer. We report a case of suspected Lynch syndrome triggered by double cancer of the descending colon and renal pelvis.

Early detection of duodenal cancer by upper gastrointestinal-endoscopy in Lynch syndrome.

Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DCs), therefore being accessible by esophago-gastro-duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance group) were compared to those who did not (nonsurveillance group) regarding tumor stage at diagnosis. Union for International Cancer Control stages I-IIA were defined as early stage disease and IIB-IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch-repair-gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance group and 14 in the nonsurveillance group. Early detection was possible for 71% of patients in the surveillance group and 29% of patients in the nonsurveillance group (P = .021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.

White-Light Endoscopy Is Adequate for Lynch Syndrome Surveillance in a Randomized and Noninferiority Study.

BACKGROUND & AIMS: Dye-based pancolonic chromoendoscopy is recommended for colorectal cancer surveillance in patients with Lynch syndrome. However, there is scarce evidence to support its superiority to high-definition white-light endoscopy. We performed a prospective study assess whether in the hands of high detecting colonoscopists, high-definition, white-light endoscopy is noninferior to pancolonic chromoendoscopy for detection of adenomas in patients with Lynch syndrome. METHODS: We conducted a parallel controlled study, from July 2016 through January 2018 at 14 centers in Spain of adults with pathogenic germline variants in mismatch repair genes (60% women; mean age, 47 ± 14 years) under surveillance. Patients were randomly assigned to groups that underwent high-definition white-light endoscopy (n = 128) or pancolonic chromoendoscopy (n = 128) evaluations by 24 colonoscopists who specialized in detection of colorectal lesions in high-risk patients for colorectal cancer. Adenoma detection rates (defined as the proportion of patients with at least 1 adenoma) were compared between groups, with a noninferiority margin (relative difference) of 15%. RESULTS: We found an important overlap of confidence intervals (CIs) and no significant difference in adenoma detection rates by pancolonic chromoendoscopy (34.4%; 95% CI 26.4%-43.3%) vs white-light endoscopy (28.1%; 95% CI 21.1%-36.4%; P = .28). However, pancolonic chromoendoscopy detected serrated lesions in a significantly higher proportion of patients (37.5%; 95% CI 29.5-46.1) than white-light endoscopy (23.4%; 95% CI 16.9-31.4; P = .01). However, there were no significant differences between groups in proportions of patients found to have serrated lesions of 5 mm or larger (9.4% vs 7.0%; P = .49), of proximal location (11.7% vs 10.2%; P = .68), or sessile serrated lesions (3.9% vs 5.5%; P = .55), respectively. Total procedure and withdrawal times with pancolonic chromoendoscopy (30.7 ± 12.8 minutes and 18.3 ± 7.6 minutes, respectively) were significantly longer than with white-light endoscopy (22.4 ± 8.7 minutes and 13.5 ± 5.6 minutes; P < .001). CONCLUSIONS: In a randomized parallel trial, we found that for Lynch syndrome surveillance, high-definition white-light endoscopy is not inferior to pancolonic chromoendoscopy if performed by experienced and dedicated endoscopists. ClinicalTrials.gov no: NCT02951390.

Application of targeted nanopore sequencing for the screening and determination of structural variants in patients with Lynch syndrome.

Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.

Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.

The coding microsatellite mutation profile of PMS2-deficient colorectal cancer.

Lynch syndrome (LS) is caused by a pathogenic heterozygous germline variant in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. LS-associated colorectal carcinomas (CRCs) are characterized by MMR deficiency and by accumulation of multiple insertions/deletions at coding microsatellites (cMS). MMR deficiency-induced variants at defined cMS loci have a driver function and promote tumorigenesis. Notably, PMS2 variant carriers face only a slightly increased risk of developing CRC. Here, we investigate whether this lower penetrance is also reflected by differences in molecular features and cMS variant patterns. Tumor DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue cores or sections (n = 90). Tumors originated from genetically proven germline pathogenic MMR variant carriers (including 14 PMS2-deficient tumors). The mutational spectrum was analyzed using fluorescently labeled primers specific for 18 cMS previously described as mutational targets in MMR-deficient tumors. Immune cell infiltration was analyzed by immunohistochemical detection of T-cells on FFPE tissue sections. The cMS spectrum of PMS2-deficient CRCs did not show any significant differences from MLH1/MSH2-deficient CRCs. PMS2-deficient tumors, however, displayed lower CD3-positive T-cell infiltration compared to other MMR-deficient cancers (28.00 vs. 55.00 per 0.1 mm2, p = 0.0025). Our study demonstrates that the spectrum of potentially immunogenic cMS variants in CRCs from PMS2 gene variant carriers is similar to that observed in CRCs from other MMR gene variant carriers. Lower immune cell infiltration observed in PMS2-deficient CRCs could be the result of alternative mechanisms of immune evasion or immune cell exclusion, similar to those seen in MMR-proficient tumors.

Deficient DNA mismatch repair and persistence of SARS-CoV-2 RNA shedding: a case report of hereditary nonpolyposis colorectal cancer with COVID-19 infection.

BACKGROUND: Several independent risk factors have been reported to influence viral shedding following COVID-19 infection, but the influence of host-related molecular factors has not yet been described. We report a case of a cancer patient with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) who manifested SARS-CoV-2 PCR (polymerase chain reaction) positivity for at least 54 days after contracting mild COVID-19 illness. We propose that deficient mismatch repair (MMR) may play a role in the prolonged SARS-CoV-2 RNA shedding. CASE PRESENTATION: A patient with Lynch syndrome was under surveillance for metastatic adenocarcinoma after completing palliative chemotherapy in October 2019. Between the period of April 2020 to June 2020, he was admitted multiple times to address several clinical needs mainly related to his underlying malignancy. These included progressive disease observed in the aortocaval lymph nodes leading to recurrent episodes of upper gastrointestinal bleeding, dehydration resulting in acute kidney injury and a short-lived episode of pyrexia. A SARS-CoV-2 PCR of the nasopharyngeal swab (NPS) was positive at his initial admission with mild COVID-19 symptoms. He remained positive on subsequent admissions when tested routinely for SARS-CoV-2 without demonstrating any apparent clinical features of COVID-19 infection. The MMR pathway, a component of DNA damage response (DDR), is impaired in Lynch syndrome due to an inherited genetic mutation. This pathway is also required for viral clearance from the host cells following certain RNA viral infections like influenza virus and other coronaviridae. Here we provide a current understanding of the importance of DDR deficiencies in the clearance of RNA virus and suggest how this may play a similar role in the clearance of COVID-19, as evident in our case that demonstrated persistent positivity. CONCLUSION: The importance of understanding the scientific basis of extended viral shedding during the COVID-19 pandemic is now centre-stage in the establishment of robust track and trace services to allow the recovery and function of societies and economies. This patient with Lynch syndrome recovered from infection but had prolonged viral positivity, which might merit further investigation to better understand the effect of this condition on infection duration and outcome.