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The aim of this study was to determine the pan-cancer landscape of MUTYH alterations and the relationship between MUTYH mutations and potentially actionable biomarkers such as specific genomic alterations, tumor mutational burden, and mutational signatures. We used a large pan-cancer comprehensive genomic dataset from patients profiled (tissue next generation sequencing) during routine clinical care. Overall, 2.8% of 229 120 solid tumors had MUTYH alterations, of which 55% were predicted germline. Thirty tumor types had a 2% or greater MUTYH mutation rate. MUTYH-altered versus -WT cancers had significantly higher tumor mutational burden and more frequent alterations in KRAS G12C, but not in KRAS in general; these observations were statistically significant, especially in colorectal cancers. Across cancers, PD-L1 expression levels (immunohistochemistry) were not associated with MUTYH alteration status. In silico computation demonstrated that MUTYH mutational signatures are associated with higher levels of hydrophobicity (which may reflect higher immunogenicity of neoantigens) relative to several other signature types such as microsatellite instability. Survival of patients with MUTYH-altered versus -WT tumors was similar. In conclusion, comprehensive genomic profiling suggests that several features of MUTYH-altered cancers may be pharmacologically targetable. Drugs such as sotorasib (targeting KRAS G12C) and immune checkpoint inhibitors, targeting the increased mutational load and higher neo-antigen hydrophobicity/immunogenicity merit investigation in MUTYH-mutated malignancies. This study aimed to determine the pan-cancer landscape of MUTYH alterations and the relationship between MUTYH mutations and potentially actionable biomarkers, such as specific genomic alterations, tumor mutational burden, and mutational signatures.

The genome—the source of life and platform of evolution—is continuously exposed to harmful factors, both extra- and intra-cellular. Their activity causes different types of DNA damage, with approximately 80 different types of lesions having been identified so far. In this paper, the influence of a clustered DNA damage site containing imidazolone (Iz) or oxazolone (Oz) and 7,8-dihydro-8-oxo-2′-deoxyguanosine ([sup.OXO]dG) on the charge transfer through the double helix as well as their electronic properties were investigated. To this end, the structures of oligo-Iz, d[A[sub.1]Iz[sub.2]A[sub.3] [sup.OXO]G[sub.4]A[sub.5]]*d[T[sub.5]C[sub.4]T[sub.3]C[sub.2]T[sub.1]], and oligo-Oz, d[A[sub.1]Oz[sub.2]A[sub.3] [sup.OXO]G[sub.4]A[sub.5]]*d[T[sub.5]C[sub.4]T[sub.3]C[sub.2]T[sub.1]], were optimized at the M06-2X/6-D95**//M06-2X/sto-3G level of theory in the aqueous phase using the ONIOM methodology; all the discussed energies were obtained at the M06-2X/6-31++G** level of theory. The non-equilibrated and equilibrated solvent–solute interactions were taken into consideration. The following results were found: (A) In all the discussed cases, [sup.OXO]dG showed a higher predisposition to radical cation formation, and B) the excess electron migration toward Iz and Oz was preferred. However, in the case of oligo-Oz, the electron transfer from Oz[sub.2] to complementary C[sub.4] was noted during vertical to adiabatic anion relaxation, while for oligo-Iz, it was settled exclusively on the Iz[sub.2] moiety. The above was reflected in the charge transfer rate constant, vertical/adiabatic ionization potential, and electron affinity energy values, as well as the charge and spin distribution. It can be postulated that imidazolone moiety formation within the CDL ds-oligo structure and its conversion to oxazolone can significantly influence the charge migration process, depending on the C2 carbon hybridization sp2 or sp3. The above can confuse the single DNA damage recognition and removal processes, cause an increase in mutagenesis, and harm the effectiveness of anticancer therapy.

Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with mutations is -associated polyposis, a form of familial colorectal cancer syndrome. may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way. Most available data on mutations are on Caucasian patients. We analyzed a small cohort of non-Caucasian, Colombian cancer patients with germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without -associated polyposis. With this case series, we intended to provide important data for the understanding of as a possible driver of familial cancer, even when only heterozygous mutations are found.

8-Oxoguanine, a major oxidized base lesion formed by reactive oxygen species, causes G to T transversion mutations or leads to cell death in mammals if it accumulates in DNA. 8-Oxoguanine can originate as 8-oxo-dGTP, formed in the nucleotide pool, or by direct oxidation of the DNA guanine base. MTH1, also known as NUDT1, with 8-oxo-dGTP hydrolyzing activity, 8-oxoguanine DNA glycosylase (OGG1) an 8-oxoG DNA glycosylase, and MutY homolog (MUTYH) with adenine DNA glycosylase activity, minimize the accumulation of 8-oxoG in DNA; deficiencies in these enzymes increase spontaneous and induced tumorigenesis susceptibility. However, different tissue types have different tumorigenesis susceptibilities. These can be reversed by combined deficiencies in the defense systems, because cell death induced by accumulation of 8-oxoG in DNA is dependent on MUTYH, which can be suppressed by MTH1 and OGG1. In cancer cells encountering high oxidative stress levels, a high level of 8-oxo-dGTP accumulates in the nucleotide pool, and cells therefore express increased levels of MTH1 in order to eliminate 8-oxo-dGTP. Suppression of MTH1 may be an efficient strategy for killing cancer cells; however, because MTH1 and OGG1 protect normal tissues from oxidative-stress-induced cell death, it is important that MTH1 inhibition does not increase the risk of healthy tissue degeneration.

ObjectiveFamilial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum that will inevitably progress to adenocarcinomas if left untreated. Here, we investigated the genetic alterations and transcriptomic transitions from precancerous adenoma to carcinoma.DesignWhole-exome sequencing, whole-genome sequencing and single-cell RNA sequencing were performed on matched adjacent normal tissues, multiregionally sampled adenomas at different stages and carcinomas from six patients with FAP and one patient with MUTYH-associated polyposis (n=56 exomes, n=56 genomes and n=8,757 single cells). Genomic alterations (including copy number alterations and somatic mutations), clonal architectures and transcriptome dynamics during adenocarcinoma carcinogenesis were comprehensively investigated.ResultsGenomic evolutionary analysis showed that adjacent lesions from the same patient with FAP can originate from the same cancer-primed cell. In addition, the tricarboxylic acid cycle pathway was strongly repressed in adenomas and was then slightly alleviated in carcinomas. Cells from the ‘normal’ colon epithelium of patients with FAP already showed metabolic reprogramming compared with cells from the normal colon epithelium of patients with sporadic colorectal cancer.ConclusionsThe process described in the previously reported field cancerisation model also occurs in patients with FAP and can contribute to the formation of adjacent lesions in patients with FAP. Reprogramming of carbohydrate metabolism has already occurred at the precancerous adenoma stage. Our study provides an accurate picture of the genomic and transcriptomic landscapes during the initiation and progression of carcinogenesis, especially during the transition from adenoma to carcinoma.

Purpose Breast cancer patients referred to genetic counseling often undergo genetic testing with broad panels that include both breast cancer susceptibility genes as well as genes more specific for extramammary sites. As a result, patients are often incidentally found to have germline mutations in genes that are not necessarily related to breast cancer risk. One such gene is MUTYH . To understand the role MUTYH may play in breast cancer, the clinicopathological features of patients with monoallelic MUTYH germline mutation and breast cancer were examined. Methods The clinicopathological characteristics of the breast cancers from patients with monoallelic MUTYH mutation were compared to breast cancer patients with other germline mutations in known breast cancer susceptibility genes, including ATM , BRCA1/2 , CHEK2 , and PALB2 . The breast cancer patients who received genetic counseling but tested negative for the aforementioned gene mutations were used as a control group. Results Histologic characteristics of the breast cancers arising in monoallelic MUTYH mutation carriers had significantly larger tumor size, higher tumor grade, and more high-risk biomarker profiles (i.e., Her2-positive and triple-negative) than breast cancer patients with susceptibility genes, except for BRCA1 . MUTYH mutation carriers also showed a trend of more frequent intratumoral divergency in terms of tumor grade and biomarker profiles. Conclusion Although germline monoallelic MUTYH mutation is not thought to confer a meaningfully increased risk of breast cancer development, it may contribute to pathological aggressiveness and diversity of breast cancers when they sporadically arise in MUTYH carriers.

Whether monoallelic MUTYH mutations increase female breast cancer risk remains controversial. This study aimed to determine if monoallelic MUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelic MUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that included MUTYH. We tested breast cancer associations with MUTYH alleles using Fisher’s exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were compared independently between the breast cancer cases and MGPT controls, as well as the healthy UK10K control population (n = 2640). Comparing cases to MGPT controls, no association was observed between female breast cancer and any monoallelic MUTYH carrier status (OR 0.86–1.36, p = 0.21–0.96). Similarly, comparisons to UK10K controls revealed no significant increase in breast cancer risk associated with p.G396D (OR 1.20, p = 0.44) or p.Y179C (OR 1.71, p = 0.24). This study did not find a significant increase in breast cancer risk associated with monoallelic MUTYH mutations.

Germline mutations in the DNA repair gene E. coli MutY homolog ( MUTYH ) are established predisposing factors for colorectal polyposis, colorectal carcinoma, and various extracolonic malignancies. Nevertheless, the association between MUTYH mutations and central nervous system (CNS) tumorigenesis remains poorly characterized. In this study, we reported the first identification of a novel c.467G > A (p.W156∗) MUTYH variant in two patients with high‐grade astrocytoma, IDH mutant , which was classified as pathogenic. Histopathological evaluation revealed tumor morphologies consistent with either diffuse glioma or giant cell glioblastoma. Comparative analysis with mismatch repair (MMR)–deficient tumors demonstrated that patients carrying MUTYH mutations exhibited microsatellite stability, relatively low tumor mutation burden (TMB), and an immunosuppressive microenvironment, indicating difficulties in benefiting from immunotherapy. Fortunately, gain of Chromosome 7, in association with amplification of the MET gene, was detected, underscoring the possible application of targeted drugs. Integrating previous studies, we summarized germline MUTYH mutations in 11 cases of high‐grade neuroepithelial tumors (eight gliomas and three medulloblastomas). This cohort demonstrated a predilection for pediatric and young adult populations without significant gender predominance. Our findings suggested a potential association between germline MUTYH mutations and CNS tumor susceptibility.

The genome—the source of life and platform of evolution—is continuously exposed to harmful factors, both extra- and intra-cellular. Their activity causes different types of DNA damage, with approximately 80 different types of lesions having been identified so far. In this paper, the influence of a clustered DNA damage site containing imidazolone (Iz) or oxazolone (Oz) and 7,8-dihydro-8-oxo-2′-deoxyguanosine (OXOdG) on the charge transfer through the double helix as well as their electronic properties were investigated. To this end, the structures of oligo-Iz, d[A1Iz2A3OXOG4A5]*d[T5C4T3C2T1], and oligo-Oz, d[A1Oz2A3OXOG4A5]*d[T5C4T3C2T1], were optimized at the M06-2X/6-D95**//M06-2X/sto-3G level of theory in the aqueous phase using the ONIOM methodology; all the discussed energies were obtained at the M06-2X/6-31++G** level of theory. The non-equilibrated and equilibrated solvent–solute interactions were taken into consideration. The following results were found: (A) In all the discussed cases, OXOdG showed a higher predisposition to radical cation formation, and B) the excess electron migration toward Iz and Oz was preferred. However, in the case of oligo-Oz, the electron transfer from Oz2 to complementary C4 was noted during vertical to adiabatic anion relaxation, while for oligo-Iz, it was settled exclusively on the Iz2 moiety. The above was reflected in the charge transfer rate constant, vertical/adiabatic ionization potential, and electron affinity energy values, as well as the charge and spin distribution. It can be postulated that imidazolone moiety formation within the CDL ds-oligo structure and its conversion to oxazolone can significantly influence the charge migration process, depending on the C2 carbon hybridization sp2 or sp3. The above can confuse the single DNA damage recognition and removal processes, cause an increase in mutagenesis, and harm the effectiveness of anticancer therapy.

Background: MUTYH has been implicated in hereditary colonic polyposis and colorectal carcinoma. However, there are conflicting data refgarding its relationship to hereditary breast cancer. Therefore, we aimed to assess if MUTYH mutations contribute to breast cancer susceptibility. Methods: We retrospectively reviewed 3598 patients evaluated from June 2018 to June 2023 at the Hereditary Cancer Unit of La Paz University Hospital, focusing on those with detected MUTYH variants. Results: Variants of MUTYH were detected in 56 patients (1.6%, 95%CI: 1.2–2.0). Of the 766 patients with breast cancer, 14 patients were carriers of MUTYH mutations (1.8%, 95%CI: 0.5–3.0). The prevalence of MUTYH mutation was significantly higher in the subpopulation with colonic polyposis (11.3% vs. 1.1%, p < 0.00001, OR = 11.2, 95%CI: 6.2–22.3). However, there was no significant difference in the prevalence within the subpopulation with breast cancer (1.8% vs. 1.5%, p = 0.49, OR = 1.2, 95%CI: 0.7–2.3). Conclusion: In our population, we could not establish a relationship between MUTYH and breast cancer. These findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in breast cancer risk.