A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America.

MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics. Patients were identified from eight high-risk genetic cancer centers of five Latin American countries. Statistical analysis was performed using the two-sided P test using the Vassarstats statistical tools. Statistical significance was set at a p value ≤ 0.05. Of the 105 unrelated patients with cancer or colorectal polyposis, 84.8% and 15.2% carried pathogenic monoallelic and biallelic MUTYH variants, respectively. The most common pathogenic variants were p.Gly396Asp and p.Tyr179Cys (55% and 23%, respectively). The mean age at first diagnosis was 48.29 years (range 31-71) and 49.90 years (range 27-87) in biallelic and monoallelic MUTYH patients, respectively. CRC was the only cancer diagnosed in patients with biallelic MUTYH pathogenic variants (75%), while breast cancer (46.1%) was more common than CRC (24.7%) in individuals with monoallelic MUTYH pathogenic variants. We reported a high frequency of European founder variants in our diverse population. Some phenotypic differences from current studies were identified, such as a higher breast cancer burden in monoallelic carriers and a complete absence of extra-colon tumors in biallelic patients.

Complete Response to Immunotherapy in a Patient with MUTYH-Associated Polyposis and Gastric Cancer: A Case Report.

MUTYH-associated polyposis syndrome is an uncommon, autosomal recessive colorectal polyposis syndrome caused by biallelic inactivation of MUTYH. Most patients present with multiple colorectal polyps. However, other primary tumor sites have been described as less frequent. In this report, we describe the case of a young patient with a germline biallelic pathogenic MUTYH mutation with three different primary tumors. We focused on a metastatic gastric adenocarcinoma that presented with complete bowel obstruction secondary to extensive peritoneal carcinomatosis and achieved complete response upon treatment with immunotherapy. The patient's tumor presented with a high tumor mutational burden and a 100% combined positive score, which certainly contributed to the complete response to immunotherapy. To date, no studies have described the association of MUTYH-related tumors with high PD-L1 expression, but we hypothesized that it may be linked to the increased antigenicity of these cancers.

The Unique Spectrum of MUTYH Germline Mutations in Colombian Patients with Extracolonic Carcinomas.

Background: 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 MUTYH mutations is MUTYH-associated polyposis, a form of familial colorectal cancer syndrome. MUTYH 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 MUTYH mutations are on Caucasian patients. Material and Methods: We analyzed a small cohort of non-Caucasian, Colombian cancer patients with MUTYH germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without MUTYH-associated polyposis. Conclusion: With this case series, we intended to provide important data for the understanding of MUTYH as a possible driver of familial cancer, even when only heterozygous mutations are found.

Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes.

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis.

MUTYH encodes a glycosylase involved in the base excision repair of DNA. Biallelic pathogenic germline variants in MUTYH cause an autosomal recessive condition known as MUTYH-associated adenomatous polyposis and consequently increase the risk of colorectal cancer. However, reports of increased cancer risk in individuals carrying only one defective MUTYH allele are controversial and based on studies involving few individuals. Here, we describe a comprehensive investigation of monoallelic pathogenic MUTYH germline variants in 10,389 cancer patients across 33 different tumour types and 117,000 healthy individuals. Our results indicate that monoallelic pathogenic MUTYH germline variants can lead to tumorigenesis through a mechanism of somatic loss of heterozygosity of the functional MUTYH allele in the tumour. We confirmed that the frequency of monoallelic pathogenic MUTYH germline variants is higher in individuals with cancer than in the general population, although this frequency is not homogeneous among tumour types. We also demonstrated that the MUTYH mutational signature is present only in tumours with loss of the functional allele and found that the characteristic MUTYH base substitution (C>A) increases stop-codon generation. We identified key genes that are affected during tumorigenesis. In conclusion, we propose that carriers of the monoallelic pathogenic MUTYH germline variant are at a higher risk of developing tumours, especially those with frequent loss of heterozygosity events, such as adrenal adenocarcinoma, although the overall risk is still low. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DNA repair and cell synthesis proteins: immunohistochemical expression and correlation with recurrence-regrowth in meningiomas.

Meningiomas are considered the second most common neoplasm of the central nervous system in adults. Most of them are benign with slow growth, frequent in women and with a high recurrence rate. In tumors, DNA error repair processes lose efficacy, providing mutagenesis and genomic instability. This work evaluated the expression of proteins involved in cell synthesis (cyclin D1) and DNA errors repair (MUTYH, XPF, XPG) in meningiomas, relating them to clinical, tumor and survival variables. The study included 85 patients, with a mean age of 52 ± 13.3 years and most of them women (2:1 ratio). Sixty-seven cases were grade I (79%). Grade II tumors were independent predictors of recurrence-regrowth (HR: 2.8; p = 0.038). The high expression of cyclin D1 was associated with grade II (p = 0.001) and low MUTYH expression with grade I (p = 0.04). Strong expression of XPF and XPG was associated with grade II (p = 0.002; p < 0.001) and with recurrence-regrowth (p = 0.04; p = 0.003). Strong XPF expression was significantly related to large tumors (p = 0.03). An association of cyclin D1, MUTYH and XPF were found. Survival was not associated with the expression of any of the proteins studied. To know the role of DNA repair proteins and cell synthesis is important for understanding the processes of origin and tumor development. Grade II meningiomas and strong expression of XPF and XPG were predictors of recurrence or regrowth and may assist in clinical management, considering the high recurrence of meningiomas and the absence of consensus regarding treatment.

Intussusception reveals MUTYH-associated polyposis syndrome and colorectal cancer: a case report.

BACKGROUND: We are reporting a rare case of MUTYH-associated polyposis, a colorectal cancer hereditary syndrome, diagnosticated after an intussusception. Colorectal cancer is an important cause of cancer related mortality that can be manifested by an intussusception, a rare occurrence in adults and almost always related to tumors. Approximately 5% of colorectal cancers can be attributed to syndromes known to cause hereditary colorectal cancer, such as MUTYH-associated polyposis, autosomal genetic syndrome associated with this disease. CASE PRESENTATION: We present the case of a 44 years old male, that sought medical consultation with a complaint of abdominal discomfort, that after five days changed its characteristics. The patient was sent to the emergency department were a CT-scan revealed intestinal sub-occlusion by ileocolic invagination. Right colectomy was carried out. The anatomic-pathological examination revealed a moderately differentiated mucinous adenocarcinoma and multiples sessile polyps, which led to the suspicion of a genetic syndrome. In the genetics analysis two mutations were observed in the MUTYH gene, and MUTYH-associated polyposis was diagnosticated. CONCLUSION: This case demonstrates the importance of meticulous analysis of the patient examinations results to identify possible discrete alterations that can lead to improved understanding of disease.

Molecular basis of familial adenomatous polyposis in the southeast of Brazil: identification of six novel mutations.

BACKGROUND: The goal of this study was to screen point mutations and deletions in APC and MUTYH genes in patients suspected of familial adenomatous polyposis (FAP) in a Brazilian cohort. METHODS: We used high-resolution melting, Sanger direct sequencing and multiplex ligation-dependent probe association (MLPA) assays to identify point mutations, and large genomic variations within the coding regions of APC and MUTYH genes. RESULTS: We identified 19 causative mutations in 40 Brazilian patients from 20 different families. Four novel mutations were identified in the APC gene and two in the MUTYH gene. We also found a high intra- and inter-familial diversity regarding extracolonic manifestations, and gastric polyps were the most common manifestation found in our cohort. CONCLUSION: We believe that the FAP mutational spectrum can be population-specific and screening FAP patients in different populations can improve pre-clinical diagnosis and improve clinical conduct.

Alterações germinativas em pacientes com câncer de reto em idade jovem / Germline alterations in patients with rectal cancer at a young age

O câncer colorretal (CCR) é o terceiro tipo de câncer mais comum no mundo e a segunda causa de morte por câncer. Dados atuais apontam que o câncer de reto (CaRe) contribui para a maior incidência de CCR observada em pacientes jovens e é responsável por um aumento destes tumores em cerca de 75% nos últimos 40 anos. As variantes germinativas são reportadas em 14 a 16% dos indivíduos jovens com CCR, independente de história familiar de câncer. Ainda assim, a causa do desenvolvimento de CCR na maioria dos casos de indivíduos jovens ou famílias com múltiplos indivíduos afetados permanece desconhecida. Neste estudo, foram investigadas variantes germinativas em 76 pacientes com CaRe incluindo 29 classificados pelos critérios de Amsterdam I/II para a Síndrome de Lynch (Grupo 1) e 47 pacientes com idade igual ou inferior 40 anos (Grupo 2). O objetivo principal foi identificar variantes em 93 genes relacionados ao câncer que possam contribuir para o risco de desenvolvimento da doença usando sequenciamento de alto desempenho. Quinze variantes foram selecionadas e avaliadas em membros de oito famílias. Foram identificadas 153 variantes envolvendo 65 genes. Pacientes com câncer de reto apresentaram alta frequência de variantes germinativas em ATM (19%), APC (10%) e BRCA2 (9%). Variantes patogênicas ou likely-patogênicas foram identificadas em genes de alta (MSH2, MSH6, MLH1, MUTYH e BRCA2), moderada (ATM) e baixa (MTHFR e NOTCH1) penetrância, em 18% (14/76) dos pacientes, concordante com dados da literatura. Variantes características da Síndrome de Lynch foram identificadas em seis pacientes (6/76) e variantes associadas à polipose no gene MUTYH, em dois pacientes (2/76). Variantes patogênicas ou likely-patogênicas foram identificadas em 17% (8/47) dos pacientes jovens, especialmente em MUTYH (3/47), MTHFR (2/47), ATM, MSH6 e MLH1 (1/47 cada). Dentre estes, dois de 14 pacientes não reportaram câncer na família e seis tiveram pelo menos um caso de câncer na família, mas não preencheram os critérios clínicos para síndrome de predisposição hereditária ao câncer. Este estudo revelou 25 variantes novas (não identificadas em bancos de dados públicos ou reportadas em literatura). Em adição, foram observadas variantes germinativas em diferentes genes das vias MMR e de recombinação homóloga, incluindo ATM, BRCA2 e POLD1. Foram identificadas 15 variantes candidatas e ou associadas ao fenótipo nos genes ATM, APC, MSH2, MTHFR, CDKN2A, MUTYH e POLD1. Essas variantes foram avaliadas em 20 indivíduos de 8 famílias, sendo confirmadas nos probandos e identificadas em mais de um membro das famílias investigadas. A identificação de genes associados à predisposição ao CaRe tem potencial importância para o delineamento de estratégias mais eficientes de diagnóstico e aconselhamento genético em famílias com um alto risco de desenvolver este tumor (AU)

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. Recent studies suggest that rectal cancer (ReCa) contributes to the higher CRC incidence observed in young patients, and it is responsible for 75% of the increased incidence in colorectal tumors over the last 40 years. Germline variants have been reported in 14-16% of patients with early-onset CRC, regardless of family history of cancer. Nonetheless, the causes of CRC onset in most young patients or families with multiple affected cases remain unknown. We investigated germline variants in 76 ReCa patients, including 29 cases classified by the Amsterdam I/II criteria for Lynch Syndrome (Group 1) and 47 early-onset ReCa patients (≤40 years old, Group 2). The main objective was to identify variants in 93 cancer-related genes that can contribute to increased risk of the disease development using next-generation sequencing. Fifteen candidate variants were evaluated in eight selected families. Next-generation sequencing revealed 153 variants involving 65 genes. ReCa patients showed high frequency of germline variants in ATM (19%), APC (10%) and BRCA2 (9%). Pathogenic or likely-pathogenic variants were observed in high (MSH2, MSH6, MLH1, MUTYH, and BRCA2), moderate (ATM) and low (MTHFR and NOTCH1) penetrance genes, in 18% (14/76) of the patients, consistent with the literature data. Variants associated with Lynch Syndrome were identified in six patients (6/76), and variants involved in MUTYH-associated polyposis in two patients (2/76). Pathogenic or likely-pathogenic variants were identified in 17% (8/47) of early-onset patients, especially in the MUTYH (3/47), MTHFR (2/47), ATM, MSH6, and MLH1 (1/47 each) genes. Among these, two of fourteen patients had no family history of cancer and six reported at least one case of cancer in the family, but none of them met clinical criteria for the hereditary cancer syndrome. This study revealed 25 new variants (not reported in public databases or previous studies). In addition, germline variants were observed in several genes involved in MMR and homologous recombination (HR) pathways, including ATM, BRCA2 and POLD1. Fifteen candidates and associated to the phenotype variants were identified in the ATM, APC, MSH2, MTHFR, CDKN2A, MUTYH, and POLD1 genes. These variants were evaluated in 20 individuals (8 families), being confirmed in the index cases and identified in more than one relative of the evaluated families. The identification of genes associated with ReCa predisposition is crucial for outlining more efficient diagnostic strategies and for improving genetic counseling for families with high risk to develop this tumor type (AU)