Gliosarcoma is a rare subtype of glioblastoma (GBM) with a shorter medical history and a worse prognosis compared to other Grade 4 gliomas. Most gliosarcomas are sporadic, but it is undeniable that a small percentage are linked to germline mutations and several inherited cancer susceptibility syndromes, including Lynch Syndrome (LS). The authors present a case of a primary mismatch repair-deficient gliosarcoma in LS. A 54-year-old Chinese male patient was admitted to the hospital with a history of facial asymmetry for over 1 month and right temporo-occipital pain for 5 days. Head MRI revealed a complex mass lesion in the right frontoparietal region, consisting of cystic and solid components. The patient\'s history of colon malignancy and family history of rectal carcinoma were noteworthy. Postoperative pathology indicated the presence of gliosarcoma with high-frequency microsatellite instability (MSI-H) and mismatch repair deficiency (MMRD). Further genetic testing results confirmed a germline heterozygous mutation in MSH2, which is considered the gold standard for diagnosing LS. This case report enriches the existing literature on germline MSH2 mutations and gliosarcomas. It highlights the importance for neurosurgeons to consider possible hereditary disorders when treating patients with a history of concurrent tumors outside the nervous system. Genetic testing is crucial for further identification of such disorders.

The Lynch syndrome (LS) is an autosomal dominant condition usually characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes. Despite the guidelines now available, determining the pathogenicity of rare variants remains challenging, as the clinical significance of a genetic variant could be uncertain, but it may represent a disease-associated variation in the aforementioned genes. In this case report we will describe the case of a 47 years-old female affected by endometrial cancer (EC) with an extremely rare germline heterozygous variant in the MSH2 gene (c.562G > T p. (Glu188Ter), exon 3) that is likely pathogenic, and a family history consistent with LS.

Lynch syndrome (LS) is a genetic disorder mainly caused by germline mutations in mismatched repair (MMR) genes (MSH2, MLH1, MSH6, and PMS2) or deletions of the epithelial cell adhesion molecule gene (EPCAM). A 43-year-old Chinese male patient underwent radical surgery and was pathologically confirmed to have stage IIIB colon adenocarcinoma. After four cycles of standard adjuvant chemotherapy, the tumor reoccurred in situ with intestinal obstruction. The patient received secondary colectomy. Immunohistochemistry analysis revealed a loss of MSH2 protein expression in the surgical specimen. Noticing that the patient\'s mother and grandfather all were diagnosed with LS-related cancers, we collected the patient\'s and his mother\'s peripheral blood for genetic testing, and the result showed a six-base deletion of MSH2. Thus, we concluded that our patient had LS. Subsequently, the patient accepted pembrolizumab as the first-line systemic therapy after liver metastases. He achieved clinical complete response (cCR) within 2 months and remained progression-free for more than 2 years. The case report showed that MSH2 mutation (c.489_494deTGGGTA) is a likely pathogenic mutation, and immunotherapy (pembrolizumab) is effective for this patient.

UNASSIGNED: Patients with Lynch syndrome are at an increased risk of developing simultaneous or metachronous tumors, while sarcomas have been occasionally reported. Sarcomas are generally not considered part of the common Lynch syndrome tumor spectrum. However, more and more studies and case reports suggested that sarcoma could be a rare clinical manifestation of Lynch syndrome, leading to new treatment strategies for sarcoma.
UNASSIGNED: We report the case of a 74-year-old male patient with Lynch syndrome who had rectal mucinous adenocarcinoma and prostate adenocarcinoma and then developed undifferentiated sarcoma of the left neck two years later. Mismatch repair deficiency (dMMR) was confirmed by immunohistochemical staining for the mismatch repair proteins MSH2, MSH6, MLH1 and PMS2. The result of polymerase chain reaction (PCR) microsatellite instability (MSI) testing of sarcoma showed high-level microsatellite instability (MSI-H). Additionally, a pathogenic germline mutation in MSH2 (c.2459-12A>G) was detected by next-generation sequencing (NGS). Taking into account HE morphology, immunohistochemical phenotype, MSI status, NGS result, medical history and germline MSH2 gene mutation, the pathological diagnosis of left neck biopsy tissue was Lynch syndrome related undifferentiated sarcoma with epithelioid morphology. The patient has been receiving immunotherapy (sintilimab) combined with chemotherapy (tegafur, gimeracil and oteracil potassium capsules) and currently has stable disease. We also reviewed the literature to understand the association between sarcoma and Lynch syndrome.
UNASSIGNED: Sarcoma may now be considered a rare clinical manifestation of Lynch syndrome. Attention and awareness about the association between Lynch syndrome and sarcoma need to be increased. Therefore, timely detection of MMR proteins and validation at the gene level for suspicious patients are the keys to avoiding missed or delayed diagnosis and to identifying patients suited for immunotherapy, which may also help to provide appropriate genetic counseling and follow-up management for patients.

Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case “JI-021”, which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G>A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G>T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.

UNASSIGNED: Lynch syndrome (LS), an autosomal dominant disorder, is characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes like MSH2. EPCAM deletions cause a minority (3%) of LS cases. However, there are only a few reports of LS-associated endometrial cancer (LS-EC) induced by the inactivation of the MSH2 gene due to EPCAM deletions.
UNASSIGNED: We present the case of a 45-years old woman diagnosed with endometrial cancer (EC). Definitive surgery revealed meso-differentiated endometrioid adenocarcinoma, stage IA without lymph-vascular space invasion. Four months later, she received radiation therapy (125I radioactive seeds implantation), and platinum-containing regimen combined chemotherapy because of vaginal stump metastasis of EC. After five years, we performed immunohistochemistry (IHC) on pelvic mass because of presacral metastatic lymph node. IHC showed the absence of MSH2 and MSH6 protein expression in the pelvic mass tissue. Peripheral blood was used for genetic testing based on her cancer diagnosis and family history of cancer in close relatives. Genetic testing revealed deletions of exon 8 and 9 in EPCAM and deletions of exon 1 and 8 in MSH2; thus, we diagnosed the presence of LS. The patient underwent interstitial brachytherapy (BT) of the presacral metastatic lymph node.
UNASSIGNED: This case highlights that patients with LS-EC who are carriers of combined EPCAM-MSH2 deletion might experience better oncologic outcomes even with early recurrence.

Synovial sarcoma is a high-grade soft tissue sarcoma that occurs primarily in the deep soft tissue of extremities, and primary colorectal synovial sarcoma is extremely rare. In this report, we present a synovial sarcoma mostly located within the mucosa of the sigmoid colon. The patient was a man in his forties with a germline deletion in the MSH2 gene. He had experienced undifferentiated pleomorphic sarcoma of the left forearm 7 years before and adenocarcinoma of the transverse colon 6 years before, both of which were successfully treated and exhibited no recurrence to date. A surveillance colonoscopy for Lynch syndrome revealed the tumor which had a submucosal tumor-like appearance with central erosion and endoscopic resection was performed. Histologically, it was composed of monotonous proliferation of spindle cells arranged in cellular fascicles; these findings were compatible with monophasic fibrous synovial sarcoma. In the tumor cells, the presence of the SS18-SSX1 fusion gene was confirmed. Protein expression of mismatch repair genes was intact in the tumor cells, indicating the association between microsatellite instability and synovial sarcoma was weak. The present case highlights a rare primary site of synovial sarcoma in a patient with Lynch syndrome.

Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome. We proposed that Lynch Syndrome-related germline mutations (LS-mutations) are associated with breast cancer (BC). In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes MLH1, MSH2, MSH6, EPCAM, and PMS2 in a cohort of 711 patients with hereditary BC, 60 patients with sporadic BC, and 492 healthy donors. Sixty-nine patients (9.7%) with hereditary BC harbored at least one germline mutation in the MMR pathway genes, of them 32 patients (4.5%) harbored mutations in MMR pathway genes which we define as pathogenic or likely pathogenic, and of them 26 patients (3.6%) did not have any pathogenic mutations in DDR pathway genes, compared to two mutations in MMR pathway genes (0.4%) detected in a group of 492 healthy donors [p = 0.00013, OR = 8.9 (CI 95% 2.2-78.4)]. Our study demonstrates that LS-mutations are present in patients with hereditary BC more frequently than in healthy donors, and that there is an association of hereditary BC and mutations c.1321G>A in MLH1, c.260C>G and c.2178G>C in MSH2, c.3217C>T in MSH6, c.1268C>G and c.86G>C in PMS2 genes. This finding provides a rationale for including pathogenic LS-mutations into genetic counseling tests for patients with hereditary BC.

The aims of the Prospective Lynch Syndrome Database (PLSD) are to provide empirical prospectively observed data on the incidences of cancer in different organs, survival following cancer and the effects of interventions in carriers of pathogenic variants of the mismatch repair genes (path_MMR) categorized by age, gene and gender. Although PLSD is assumption-free, as with any study the ascertainment procedures used to identify the study cohort will introduce selection biases which have to be declared and considered in detail in order to provide robust and valid results. This paper provides a commentary on the methods used and considers how results from the PLSD reports should be interpreted. A number of the results from PLSD were novel and some in conflict with previous assumptions. Notably, colonoscopic surveillance did not prevent colo-rectal cancer, survival after colo-rectal, endometrial and ovarian cancer was good, no survival gain was observed with more frequent colonoscopy, new causes of cancer-related death were observed in survivors of first cancers due to later cancers in other organs, variants in the different MMR genes caused distinct multi-cancer syndromes characterized by different penetrance and phenotypes. The www.PLSD.eu website together with the InSiGHT database website (https://www.insight-group.org/variants/databases/) now facilitate evidence-based personalized precision health care for individual carriers at increased risk of cancer. The arguments are summarized in a final discussion on how to conceptualize current knowledge for the different practical purposes of treating cancers, genetic counselling and prevention, and for understanding /research on carcinogenetic mechanisms.

BACKGROUND: The tumor spectrum in the Lynch syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch syndrome spectrum. Hence, the real link between Lynch syndrome, or Muir-Torre syndrome, and these tumors remains difficult to assess.
METHODS: We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma.
CONCLUSIONS: Squamous cell carcinomas have been described in Lynch syndrome and Muir-Torre syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch syndrome and squamous cell carcinoma.