Family's History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10-18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families

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

An Italian prospective multicenter study on colonoscopy practice and quality: What has changed in the last 10 years

Background: A relevant number of adenomas can be missed during colonoscopy. Aims: Assess the current status of colonoscopy procedures in Italian centers. Methods: A prospective observational study involving 17 hospitals (34 endoscopists) included consecutive patients undergoing standard colonoscopy. In the first phase, endoscopists performed consecutive colonoscopies. In the second phase, retraining via an online learning platform was planned, while in the third phase data were collected analogously to phase 1. Results: A total of 3,504 patients were enrolled. Overall, a BBPS score ≥6 was obtained in 95.6% of cases (94.8% and 96.9% in the pre- and post-training phases, respectively). 88.4% of colonoscopies had a withdrawal time ≥6 min (88.2% and 88.7% in the pre- and post-training phases). Median adenoma detection rate (ADR) was 39.1%, with no significant differences between the pre- and post-training phases (40.1% vs 36.9%; P = 0.83). In total, 81% of endoscopists had a ADR performance above the 25% threshold. Conclusion: High colonoscopy quality standards are achieved by the Italian hospitals involved. Quality improvement initiatives and repeated module-based colonoscopy-training have been promoted in Italy during the last decade, which appear to have had a significant impact on quality colonoscopy metrics together with the activation of colorectal cancer screening programs

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