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.

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a "sporadic" subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the "sporadic" subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this "sporadic" early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.

IntroductionSeveral studies evaluated the prevalence of Lynch Syndrome (LS) in young onset colorectal cancer (CRC) patients and the results were extremely variable (5%-20%). Immunohistochemistry (IHC) for MMR proteins and/or MSI analysis are screening tests that are done, either by themselves or in conjunction, on colon cancer tissue to identify individuals at risk for LS. The primary aim of our study was to evaluate the prevalence of LS in a large series of early-onset CRC without family history compared with those with family history. The secondary aim was to assess the diagnostic accuracy of IHC and MSI analysis as pre-screening tools for LS.MethodsEarly-onset CRC patients (≤ 50 years) were prospectively recruited in the study. IHC and MSI analysis were performed in all the patients. Germ-line mutation analysis (GMA) was carried out in all MMR deficient tumors. A logistic regression model was performed to identify clinical features predictive of MSI-H.Results117 early onset CRC cases were categorized in three groups (A, B, C) according with family history of CRC. IHC and MSI analysis showed MMR deficiency in 6/70 patients (8.6%) of group A, 24/40 patients (60%) of group B and none of group C. GMA showed a deleterious mutation in 19 (47.5%) patients of group B. MSI analysis had a diagnostic accuracy of 95.7% (CI 92.1-99.4) and IHC of 83.8% (CI 77.1-90.4). The logistic regression model revealed that by using a combination of the two features “No Amsterdam Criteria” and ”left sided CRC” to exclude MSI-H, accuracy was 89.7% (84.2-95.2).ConclusionsEarly-onset CRC patients, with left sided CRC and without family history are “at very low risk” for Lynch syndrome. The two simple criteria of family history and CRC site could be used as a pre-screening tool to evaluate whether or not patients should undergo tissue molecular screening. In the few cases of suspected LS (right sided CRC and/or Amsterdam Criteria), a reasonable approach could be to perform MSI analysis first and IHC afterwards only in MSI-H patients.

(1) Background: desmoid tumors (DTs) are common in patients with familial adenomatous polyposis (FAP). An active surveillance approach has been recently proposed as a valuable alternative to immediate treatment in some patients. However, no clear indication exists on which patients are suitable for active surveillance, how to establish the cut-off for an active treatment, and which imaging technique or predictive factors should be used during the surveillance period. (2) Results: we retrospectively analyzed 13 FAP patients with DTs. A surveillance protocol consisting of scheduled follow-up evaluations depending on tumor location and tissue thickening, abdominal computed tomography (CT) scan/Magnetic resonance imaging (MRI) allowed prompt intervention in 3/11 aggressive intra-abdominal DTs, while sparing further interventions in the remaining cases, despite worrisome features detected in three patients. Moreover, we identified a possible predictive marker of tumor aggressiveness, i.e., the “average monthly growth rate” (AMGR), which could distinguish patients with very aggressive/life-threatening tumor behavior (AMGR > 0.5) who need immediate active treatment, from those with stable DTs (AMGR < 0.1) in whom follow-up assessments could be delayed. (3) Conclusion: surveillance protocols may be a useful approach for DTs. Further studies on larger series are needed to confirm the usefulness of periodic CT scan/MRI and the value of AMGR as a prognostic tool to guide treatment strategies.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and its incidence is correlated with infections, chronic inflammation, diet, and genetic factors. An emerging aspect is that microbial dysbiosis and chronic infections triggered by certain bacteria can be risk factors for tumor progression. Recent data suggest that certain bacterial toxins implicated in DNA attack or in proliferation, replication, and death can be risk factors for insurgence and progression of CRC. In this study, we recruited more than 300 biopsy specimens from people undergoing colonoscopy, and we analyzed to determine whether a correlation exists between the presence of bacterial genes coding for toxins possibly involved in CRC onset and progression and the different stages of CRC. We also analyzed to determine whether CRC-predisposing genetic factors could contribute to bacterial toxins response. Our results showed that CIF toxin is associated with polyps or adenomas, whereas pks+ seems to be a predisposing factor for CRC. Toxins from Escherichia coli as a whole have a higher incidence rate in adenocarcinoma patients compared to controls, whereas Bacteroides fragilis toxin does not seem to be associated with pre-cancerous nor with cancerous lesions. These results have been obtained irrespectively of the presence of CRC-risk loci.