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.

Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade.

Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). The ability of ICB to prevent dMMR malignant or pre-malignant neoplasia development in patients with Lynch syndrome (LS) is unknown. Of 172 cancer-affected patients with LS who had received ≥1 ICB cycles, 21 (12%) developed subsequent malignancies after ICB exposure, 91% (29/32) of which were dMMR, with median time to development of 21 months (interquartile range, 6-38). Twenty-four of 61 (39%) ICB-treated patients who subsequently underwent surveillance colonoscopy had premalignant polyps. Within matched pre-ICB and post-ICB follow-up periods, the overall rate of tumor development was unchanged; however, on subgroup analysis, a decreased incidence of post-ICB visceral tumors was observed. These data suggest that ICB treatment of LS-associated tumors does not eliminate risk of new neoplasia development, and LS-specific surveillance strategies should continue. These data have implications for immunopreventative strategies and provide insight into the immunobiology of dMMR tumors.

Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study.

BACKGROUND: Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. METHODS: For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. FINDINGS: Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72). INTERPRETATION: The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. FUNDING: None.

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.

Small intestinal adenocarcinoma accompanied by lynch syndrome: A case report.

RATIONALE: Lynch syndrome is caused by germline mutations of DNA mismatch repair genes. A significant risk increase for several types of cancer is one of the characteristics of lynch syndrome. PATIENT CONCERNS: A 45-year-old female presented to the emergency department with abdominal pain that had persisted for a month. DIAGNOSES: The abdominal and pelvic computed tomography scan showed edematous and thickening of the proximal small bowel wall, as well as dilatation of the proximal bowel and stomach. INTERVENTIONS: Tumor resection of the small bowel was performed, and adenocarcinoma was confirmed pathologically. Microsatellite instability was also confirmed. OUTCOMES: Postoperative imaging revealed soft tissue lesions with potential for tumor seeding. Two months after the first surgery, a secondary surgery was performed as a result of cancer recurrence. The patient received chemotherapy with capecitabine. The latest computed tomography scan, performed 19 months after the cessation of chemotherapy, did not show any recurrence. LESSONS: In the rare incidence of small bowel cancer genetic mutation testing and detailed family history should be actively considered.

Methylated DNA Markers for Sporadic Colorectal and Endometrial Cancer Are Strongly Associated with Lynch Syndrome Cancers.

Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis.To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS.In a case-control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated.We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84-0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83-1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96-1.0).MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population. PREVENTION RELEVANCE: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS.

Recurrent Papillary Bladder Tumors in a Boy With Lynch Syndrome.

Lynch syndrome (LS) is an autosomal dominant genetic disorder defined by germline mutations in one of four mismatch repair genes including PMS2, MLH2, MSH1, MSH2, or deletion in the EPCAM gene.1 The most common urologic manifestation of LS is upper tract urothelial carcinoma, which occurs in up to 20% of patients with LS.2 While data are scarce, there is growing evidence of an increased relative risk of bladder malignancy in patients with LS.3,4 Bladder tumors in children are a rare entity and the link between pediatric bladder tumors and LS has not been previously reported to our knowledge.

Lung Cancer in Patients With Lynch Syndrome: Association or Coincidence?

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC) occurs due to microsatellite instability (MSI) caused by mutations in one of the mismatch repair genes leading to deficient mismatch repair proteins (dMMR). Although lung cancer is very common there is no established association between LS and lung cancer. In this manuscript we describe a case of lung cancer in a LS patient and then summarize available literature on this topic. Sixty seven y/o female patient with history of stage I colon and urothelial cancer, meeting the Amsterdam criteria, was diagnosed with LS on genetic testing. Sixteen years after the diagnosis of colon cancer, she was found to have adenocarcinoma of the lung with Next-generation sequencing (NGS) testing revealing the presence of germline mutation in MSH2 in the tumor cells indicating the possibility of LS driven lung cancer. However, subsequent immunohistochemistry (IHC) on tumor cells indicated proficient mismatch repair genes confirming the sporadic nature of lung cancer. On review of literature, we found that the coincidental presence of lung cancer in patients with LS can sometimes be mistaken for causation and may lead to confusion. Lynch syndrome associated tumors which are microsatellite instable (MSI) can be treated effectively with immunotherapy with durable responses, however, not all tumors in patient with LS are MSI impacting the choice of therapy.

Mismatch repair protein deficiency in endometriosis: Precursor of endometriosis-associated ovarian cancer in women with lynch syndrome.

OBJECTIVE: We aimed to elucidate the pathogenesis of ovarian cancer through the loss of mismatch repair (MMR) proteins in women with Lynch syndrome (LS) in this report. CASE REPORT: Two women with LS underwent surgery for synchronous endometrial cancer and ovarian cancer. In both cases, immunohistochemical examination showed concomitant MMR protein deficiency in endometrial cancer, ovarian cancer, and contiguous ovarian endometriosis. In Case 1, the macroscopically normal ovary included multiple endometrioses with MSH2 and MSH6 expression, and FIGO grade 1 endometrioid carcinoma and contiguous endometriosis without MSH2 and MSH6 expression. In Case 2, all endometriotic cells contiguous with carcinoma in the lumen of the ovarian cyst showed loss of the expression of MSH2 and MSH6. CONCLUSION: Ovarian endometriosis with MMR protein deficiency may progress to endometriosis-associated ovarian cancer in women with LS. Diagnosing endometriosis in women with LS during surveillance is important.

Biology of Precancers and Opportunities for Cancer Interception: Lesson from Colorectal Cancer Susceptibility Syndromes.

Hereditary gastrointestinal cancer is associated with molecular and neoplastic precursors which have revealed much about sporadic carcinogenesis. Therefore, an appreciation of constitutional and somatic events linked to these syndromes have provided a useful model for the development of risk models and preventative strategies. In this review, we focus of two of the best characterized syndromes, Lynch syndrome (LS) and familial adenomatous polyposis (FAP). Our understanding of the neoplasia-immune interaction in LS has contributed to the development of immune mediated therapies including cancer preventing vaccines and immunotherapy for cancer precursors. Chemoprevention in LS with aspirin and nonsteroidal anti-inflammatory drugs has also translated into clinical cancer, however the efficacy of such agents in FAP remains elusive when cancer is applied as an endpoint in trials rather than the use of 'indirect' endpoints such as polyp burden, and requires further elucidation of biological mechanisms in FAP. Finally, we review controversies in gastrointestinal surveillance for LS and FAP, including limitations and opportunities of upper and lower gastrointestinal endoscopy in the prevention and early detection of cancer.

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.

Prevalence and risk factors of barrett's esophagus in lynch syndrome.

Lynch syndrome (LS), the most common hereditary cause of colorectal cancer, predisposes to upper gastrointestinal neoplasia. The prevalence of Barrett's esophagus (BE) is elevated in some hereditary gastrointestinal cancer syndromes but has not been systematically evaluated in LS. We assessed the prevalence of BE, BE-related dysplasia, esophageal adenocarcinoma (EAC), and factors associated with BE in LS. Asymptomatic patients with a germline pathogenic variant (PV) in the DNA mismatch repair (MMR) genes undergoing EGD for LS surveillance were identified from a hereditary colorectal cancer registry. We assessed the prevalence of BE and compared demographic, clinical, and endoscopic factors in LS patients with and without BE by logistic regression analysis. 323 patients were included. 21 patients (6.5%) were diagnosed with BE including 38% of females and 33% without gastroesophageal reflux disease (GERD). Dysplasia was diagnosed in two patients (9.5%) and EAC in one (4.8%) patient. Factors associated with BE included male gender (OR 3.00, 1.21-7.46), age at last LS EGD (OR 1.04, 1.01-1.08), presence of hiatal hernia (OR 20.09, 4.57-88.23), hiatal hernia > 3 cm (OR 11.25, 2.41-51.94), and GERD (OR 3.39, 1.32-8.67). No MMR PV was associated with BE. BE was diagnosed in 1 of 15 patients undergoing EGD surveillance for LS and nearly 10% had dysplasia including one EAC. Risk factors associated with BE in LS are similar to those established for BE in the general population. More studies are needed to evaluate if an association between BE and LS exists.

Two Cases of Thymic Cancer in Patients with Lynch Syndrome.

We herein report two cases of thymic cancer with Lynch syndrome showing a high frequency of microsatellite instability and loss of mismatch repair protein expression without MLH1 promoter hyper-methylation. In Case 1, a 71-year-old man had a pathogenic germline variant in MLH1 and underwent tumor resection. No relapse has been reported thus far. In Case 2, a 43-year-old man underwent genetic testing that also showed a pathogenic germline variant in MLH1. Since these two cases had MLH variants, we suspect a possible association between thymic cancer with Lynch syndrome and germline pathogenic variants in MLH1.

Paraneoplastic Neuromyelitis Optica Spectrum Disorder Related to Glucose-regulated Protein 78 (GRP78) Autoantibodies in a Patient with Lynch Syndrome-associated Colorectal Cancer.

Neuromyelitis optica spectrum disorders have been previously reported in a paraneoplastic context, although there is no clear consensus on their pathogenesis. We herein report a case of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder in a 64-year-old woman with colorectal cancer. She underwent tumor resection, resulting in serum aquaporin-4 antibody titers subsequently becoming negative. Serum samples were also positive for glucose-regulated protein 78 antibody, which has recently been suggested to be a novel factor in the disruption of the blood-brain barrier. Serological and pathological investigations in this case highlight the role and involvement of aquaporin-4 and glucose-regulated protein 78 antibodies in paraneoplastic conditions.