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Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double MSH3 somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with POLD1 potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating MSH3 and POLD1 double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.
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BACKGROUND: Chagas disease (CD) is endemic in Latin America and particularly common in Bolivia, but there is little information on the characteristics of chronic digestive involvement. OBJECTIVES: To determine the prevalence and characterize digestive manifestations in chronic CD patients in Cochabamba, Bolivia. METHODS: Eighty-five T. cruzi-seropositive individuals with or without digestive symptoms (G1 group), and fifteen T. cruzi-seronegative patients with similar digestive symptoms to those seen in CD (G2 group) were included in the study. All patients underwent a detailed history including past medical history, epidemiological information, hygiene and dietary habits, a complete physical examination, two serological tests for T. cruzi, video endoscopy, barium swallow, and barium enema. FINDINGS: We observed digestive manifestations in T. cruzi seropositive and seronegative patients. Colonic manifestations were detected in both groups, highlighting the relevance of other confounder factors in the region. Constipation was present in 52.9% of G1 patients, 62.4% presented two or more upper digestive tract symptoms, and 5.9% of them presented esophageal manifestations. Helicobacter pylori infection was detected in 58.8% of G1 patients, and all patients presented gastritis on endoscopy. CONCLUSIONS: Prevalence of digestive involvement in CD patients is higher than expected. However, digestive symptoms are not always caused by T. cruzi infection and require differential diagnoses.
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Early-onset (<50 years-old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed "Lynch-like syndrome" (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003-2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Adolescente , Adulto , Criança , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Feminino , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously. DESIGN: We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤ 50 years old (n=188), a group of sporadic CRC >50 years (MSS n=89; MSI n=46), and a group of Lynch syndrome CRCs (n=20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated. RESULTS: Mean LINE-1 methylation levels (± SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥ 65% LINE-1 methylation had significantly better overall survival (p=0.026, log rank test). CONCLUSIONS: LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.
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Adenoma/epidemiologia , Adenoma/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/metabolismo , Elementos Nucleotídeos Longos e Dispersos , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenoma/genética , Adenoma/mortalidade , Adulto , Idade de Início , Argentina/epidemiologia , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , DNA Glicosilases/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 3 Homóloga a MutS , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas B-raf/genética , Espanha/epidemiologia , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
Uterine malignant peripheral nerve sheath tumors (MPNST) are rare and have been reported in the cervix. We describe a case of MPNST of the uterine corpus, and discuss its differential diagnosis.