Valentina D'Angelo

Background: Colorectal cancer (CRC) is the third most diagnosed type of cancer and the second leading cause of cancer-related death. However, the increase in CRC incidence observed over the last 50 years has been accompanied by an overall reduction in mortality thanks to improved diagnostic strategies, patient follow-up, and more targeted therapies. Gastrointestinal adenomatous polyposis syndromes are a group of hereditary syndromes that predispose individuals to gastrointestinal tumors. These syndromes, characterized by the onset of gastrointestinal adenomas, are genetically heterogeneous. Methods: We analyzed 60 subjects with clinical suspicion or diagnosis of polyposis using next-generation sequencing (NGS). An additional 20 healthy individuals, all negative for pathogenic variants, were included in the study as a control population. We also performed bioinformatic analyses to investigate the hypothesis that benign variants could still be partially destructive, even though they cannot, by themselves, be responsible for the onset of disease. Results: Germline pathogenic variants were identified in 55% (33/60) of affected patients (MUT⁺), while variants of uncertain significance (VUS) were identified in 18.3% of affected patients (11/60). No variants were detected in the remaining 26.7% (16/60) of patients (MUT⁻). A genotype-phenotype correlation emerged from this study: MUT⁺ patients exhibited a significantly earlier age of onset and a higher number of polyps compared to VUS or MUT⁻ patients. Furthermore, Mendelian inheritance was significatively more frequent in MUT⁺ and VUS patients than in MUT⁻ individuals. Finally, the investigation of benign variants identified an SNP (single nucleotide polymorphism) of the APC gene promoter and a cluster of variants in POLD1, in which bioinformatic analysis predicted altered gene expression. Conclusions: These results suggest that, although MUT⁻ patients may develop multiple gastrointestinal adenomatous polyps, they are likely to have a familial predisposition rather than a Mendelian disorder. Furthermore, we propose that certain benign variants may be partially deleterious, potentially contributing to disease onset and/or act as phenotypic modifiers, likely through additive effects.

The history of Lynch syndrome changed definitively in 2000, when a study published in Gastroenterology demonstrated a significant reduction in mortality among individuals with Lynch syndrome who undergo regular endoscopic surveillance. As a consequence of this clinical evidence, all scientific societies developed guidelines, which highlighted the role of colonoscopy in the management of Lynch syndrome, especially for individuals at high risk of colorectal cancer. Over the years, these guidelines were modified and updated. Specialized networks were developed in order to standardize endoscopic surveillance programs and evaluate all the clinical data retrieved by the results of colonoscopies performed for both the screening and the surveillance of individuals with Lynch syndrome. Recent data show that the impact of colonoscopy (with polypectomy) on the prevention of colorectal cancer in individuals with Lynch syndrome is less significant than previously thought. This narrative review summarizes the current discussion, the hypotheses elaborated and the algorithms depicted for the management of individuals with Lynch Syndrome on the basis of the recent data published in the literature.

Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual’s risk of developing cancer.

Multimodal treatments for rectal cancer, along with significant research on predictors to response to therapy, have led to more conservative surgical strategies. We describe our experience of the rectal sparing approach in rectal cancer patients with clinical complete response (cCR) after neoadjuvant treatment. We also specifically highlight our clinical and imaging criteria to select patients for the watch and wait strategy (w&w). Data came from 39 out of 670 patients treated for locally advanced rectal cancer between January 2016 until February 2020. The selection criteria were a clinical complete response after neoadjuvant chemotherapy managed with a watch and wait (w&w) strategy. A strict follow-up period was adopted in these selected patients and follow-ups were performed every three months during the first two years and every six months after that. The median follow-up time was 28 months. Six patients had a local recurrence (15.3%); all were salvageable by total mesorectal excision (TME). Five patients had a distant metastasis (12.8%). There was no local unsalvageable disease after w&w strategy. The rectal sparing approach in patients with clinical complete response after neoadjuvant treatment is the best possible treatment and is appropriate to analyze from this perspective. The watch and wait approach after neoadjuvant treatment for rectal cancer can be successfully explored after inflexible and strict patient selection.

Intestinal‑type gastric adenocarcinomas are preceded by precancerous lesions, which begin with chronic atrophic gastritis. Over the last few years, multiple serological screening techniques have been performed and commercialized for the diagnosis of chronic atrophic gastritis. In the present study, 123 patients were recruited at the International Cancer Institute 'G. Pascale' Foundation (Naples, Italy) to test commercial kits for the serological determination of chronic atrophic gastritis, supported by histological analysis, according to the International Group of Gastroenterologists 'Operative Link for Gastritis Assessment Staging System'. The results revealed a significant discrepancy between serological screening and histological evaluation in 10.6% of patients, which highlighted the dubious positive predictive value of commercial serological screening kits.

Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target.