An Exceptional Response to Dostarlimab in Mismatch Repair Deficient, Microsatellite Instability-High and Platinum Refractory Endometrial Cancer

Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer.

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs

Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families

Caratterizzazione istochimica del carcinoma squamoso della mammella nella cagna Atti VIII Congresso Nazionale S.I.Di.L.V., 323-324, 2006.

Squamous cell carcinoma of the mammary gland is a rare entity both in veterinary and human medicine. In this latter metaplastic and squamous variants are known. Aim of this study was to ascertain the presence of such entities in canine mammary tumours and the differential diagnosis from epidermal squamous tumours. A panel of antibodies (anti-cytokeratin (CK) 19, -CK 14, -CK 5/6, -Pan-cytokeratin, -vimentin, -S-100) was used on a series of mammary gland and skin tumours. The panel employed proved useful to discriminate primary epidermal squamous tumours from mammary squamous neoplasms. However, the panel does not allow a discrimination between primary mammary and other squamous tumours of glandular origin

Twelve years of endoscopic surveillance in a family carrying biallelic Y165C MYH defect: Report of a case

PURPOSE: We report the case of two siblings, clinically and endoscopically followed for 12 years, who displayed an attenuated adenomatous polyposis coli phenotype. METHODS: On workup for rectal bleeding with colonoscopy, we found multiple adenomas mainly right- sided in a 21-year-old female and the same colonic phenotype was observed in her 27-year-old brother. We made a clinical diagnosis of attenuated adenomatous polyposis coli and performed APC gene testing. Because they had refused the proposed ileorectal anastomosis surgical option, we planned a periodic, endoscopic follow- up. RESULTS: Gene testing did not confirm the clinical suspicion of attenuated adenomatous polyposis coli. Actually, we did not find any pathogenic mutation in APC gene and we recently identified a biallelic Y125C MYH defect. During the endoscopic follow- up, a progressive reduction of adenomas was seen. CONCLUSIONS: New insight colorectal cancer genetics have allowed definition of a new class of polyposis that applies to some patients with attenuated adenomatous polyposis coli phenotype as in the siblings we have described. To prevent colorectal cancer without recurring to surgery, colonoscopic polypectomy may be a suitable tool in controlling MYH polyposis

Toward a better definition of EPCAM deletions in Lynch Syndrome: Report of new variants in Italy and the associated molecular phenotype

Background: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%–3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination. Methods: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS). Results: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae. Conclusion: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients

SERRATED ADENOMAS OF THE COLORECTUM: PREVALENCE IN ROUTINARY ENDOSCOPY PRACTICE

5nonenoneMaiero, S; Fornasarig, M; Cannizzaro, R; Benevento, G; Canzonieri,