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1.
Fam Cancer ; 18(2): 211-219, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30627969

RESUMO

Lynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. While the mechanism of mismatch repair deficiency and microsatellite instability and its role in Lynch-associated carcinogenesis has been known for some time, there have been significant advances recently in diagnostic testing and the understanding of the molecular pathogenesis of Lynch tumors. There is also an increased awareness that the clinical phenotype and cancer risk varies by specific mismatch repair mutation, which in turn has implications on surveillance strategies for patients. Even the treatment of Lynch-associated cancers has changed with the addition of immunotherapy for advanced disease. This progress report aims to review some of the many advances in epidemiology, molecular pathogenesis, diagnosis, clinical phenotype, cancer surveillance, treatment, and chemo- and immune-prevention strategies in the Lynch syndrome field over the past 5 years.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Colectomia/tendências , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Testes Genéticos/tendências , Conduta Expectante/tendências , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/tendências , Colectomia/métodos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Instabilidade de Microssatélites , Mutação , Fenótipo , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Conduta Expectante/métodos
2.
Bull Cancer ; 106(7-8): 647-655, 2019.
Artigo em Francês | MEDLINE | ID: mdl-30527816

RESUMO

Lynch syndrome is a genetic condition defined by a germline mutation of an MMR (MisMatch Repair) gene leading to a defective DNA MMR system. Therefore, it is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer (CRC) and endometrial cancer (EC). Lynch syndrome-related CRC accounts for 3% of all CRC. Lynch syndrome also accounts for 2% of all EC. In case of Lynch syndrome, there is usually a familial history of cancer defined by the Amsterdam and Bethesda criteria. Diagnosis is made by tumor testing with (i) MMR immunohistochemistry and (ii) PCR for MSI (microsatellite instability), a genetic phenotype that characterizes these tumors. MSI can also be detected in sporadic tumors, through epigenetic events inactivating the MMR system. Progress in diagnosis and molecular biology has allowed for better identification of Lynch patients but also other rare genetic syndromes. MSI tumors can now benefit from new treatments such as immunotherapy which underlines the importance of their diagnosis. Finally, patients with Lynch syndrome as well as their relatives, undergo specific surveillance in order to prevent development of other cancers. This review will summarize the different aspects of Lynch syndrome and also focus on recent progress on the topic.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Algoritmos , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Risco
3.
Int J Cancer ; 145(1): 87-98, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575961

RESUMO

Colorectal carcinomas that are mismatch repair (MMR)-deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch-like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000-2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer-relevant genes. Among 107 MMR-deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E-negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP-positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population-based study design. Significantly more frequent CIMP-positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1-methylated colorectal carcinomas with CIMP-positive phenotype.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Adulto , Idoso , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Finlândia/epidemiologia , Humanos , Instabilidade de Microssatélites , Epidemiologia Molecular , Proteína 1 Homóloga a MutL/genética , Mutação , Estudos Retrospectivos
4.
Gynecol Oncol ; 150(2): 324-330, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29880284

RESUMO

OBJECTIVE: To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers. METHODS: All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected. RESULTS: A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%. CONCLUSION: Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Prospectivos , Sistema de Registros
5.
Curr Gastroenterol Rep ; 20(4): 15, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29616330

RESUMO

PURPOSE OF REVIEW: Colorectal cancer incidence has been rapidly rising in those under the age of 50 over the last 20 years. This paper will review the epidemiology, clinicopathologic, molecular features, proposed risk factors, and prevention/treatment approach for early onset CRC (EOCRC) patients. RECENT FINDINGS: EOCRC appears to have a different spectrum of clinical, pathologic, and molecular presentation compared to CRC diagnosed in older individuals. EOCRCs are disproportionately located in the distal colon; these patients tend to present with symptoms, and there is a longer interval between symptoms and diagnosis. There may be a distinct molecular signature, including progression through the microsatellite and chromosomal stable (MACS) pathway and LINE-1 hypomethylation for a subset of EOCRCs. The majority of EOCRCs are sporadic without clear risk factors that would have made the patient eligible for earlier screening. There is an acute need for educational efforts aimed at both providers and patients to raise awareness about CRC in the young. Improving adherence to screening in young patients eligible for screening and emphasizing early evaluation of symptoms are important steps to decreasing the burden of CRC in younger patients. Modeling and empiric data are needed to determine whether our current screening approach should be modified and whether causation and treatment options may be different in a molecular subset EOCRCs.


Assuntos
Neoplasias Colorretais/epidemiologia , Fatores Etários , Idade de Início , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Detecção Precoce de Câncer/métodos , Humanos , Estilo de Vida , Fatores de Risco
6.
PLoS One ; 13(4): e0195572, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29672549

RESUMO

BACKGROUND: Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients. METHODS: This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. RESULTS: The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19-65) and 44 (range, 24-66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9-63.3%] for CRC, 17.4% (95% CI, 5.2-35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4-13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this. CONCLUSION: Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/fisiopatologia , Neoplasias/fisiopatologia , Adulto , Idade de Início , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/genética , Infecções por Helicobacter/patologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori , Humanos , Imuno-Histoquímica , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/patologia , Estudos Retrospectivos , Adulto Jovem
7.
Int J Colorectal Dis ; 33(6): 695-702, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29523990

RESUMO

PURPOSE: Lynch syndrome (LS) is associated with a high risk of colorectal cancer (CRC). The aim of this study was to assess the cumulative risk for the development of colorectal adenomas or carcinomas in a LS CRC surveillance program and to audit the quality of the endoscopic procedures. METHODS: We evaluated 147 asymptomatic LS mutation carriers, without previous CRC, in a surveillance program with colonoscopy every 12-18 months, between 2005 and 2016. Data was obtained by retrospective review of colonoscopy reports and hospital clinical files. The main outcome was assessed using Kaplan-Meier curves. Logistic regression was used to study the risk of developing adenomas. RESULTS: Patients were under surveillance for 1092 observation years (mean, 7.7 years/patient). Most exams presented adequate bowel preparation (83.5%) and 99.2% achieved cecal intubation. The estimated risk for adenomas at age 60 was 75.6% in men (95%CI, 60.5-88.3) and 65.5% in women (95%CI, 50.8-79.7). Male gender (OR 2.4; 95%CI, 1.2-4.9; p = 0.018) and age at start of surveillance > 40 years (OR 3.7; 95%CI, 1.8-7.7; p < 0.001) were independent risk factors for adenoma detection. CRC was diagnosed in 11 patients with an estimated cumulative risk at age 60 of 18.4% (95%CI, 9.2-34.8%); 72.7% of CRC were classified as stage I; no patient died from CRC. CONCLUSION: A colonoscopic surveillance program in LS patients allowed the detection of adenomas in a large group of mutation carriers and diagnosis of early-stage carcinomas. Our findings may help other teams to adopt similar strategies or to refer patients early to specialized centers.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Vigilância da População , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/genética , Adulto , Idoso , Estudos de Coortes , Colonoscopia/normas , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Detecção Precoce de Câncer , Família , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Portugal/epidemiologia , Fatores de Risco , Adulto Jovem
8.
J Obstet Gynaecol Res ; 44(5): 944-950, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29442399

RESUMO

AIM: To investigate the clinicopathologic and genetic correlations between double primary endometrial and colorectal cancer related to Lynch syndrome and to analyze germline mutations in mismatch repair genes in endometrial cancer patients in Korea. METHODS: Thirteen patients diagnosed with pathologically endometrial and colorectal cancer between January 2005 and November 2016 in a single institution were enrolled in the study. The medical records were retrospectively analyzed. The genetic mutational information of endometrial cancer in Korea was retrieved from the literature review. RESULTS: Endometrial cancer was diagnosed first in eight (62%) patients, and one patient was diagnosed with colorectal cancer first. Endometrioid adenocarcinoma was reported in 10 of 13 (77%) endometrial cancer patients. Endometrial cancer was found at the low uterine segment in three patients. Three of four patients had high microsatellite instability. The loss of mismatch repair proteins was confirmed in 7 of 11 cases using immunohistochemistry. Four patients fulfilled clinical criteria based on a family history of cancer. Overall, the incidence of suspected Lynch syndrome was 77% (10/13). Four of them underwent genetic testing and three were found to have a pathogenic germline mutation. A possible founder mutation, c.1757_1758insC in MLH1, was observed in 21 germline mutation information from literature review. CONCLUSION: The present study describes the clinicopathologic data of double primary endometrial and colorectal cancer patients and supports that these patients should undergo closed approach for Lynch syndrome. Moreover, a possible founder mutation in Korean endometrial cancer patients was identified.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias do Endométrio , Adulto , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , República da Coreia/epidemiologia
9.
Future Oncol ; 14(3): 277-290, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29345160

RESUMO

Environmental factors that play a role in the urothelial carcinogenesis have been well characterized. Current research is continuously exploring potential heritable forms of bladder cancer. Lynch syndrome is a well-known inheritable disease that increases the risk for a variety of cancers, including urothelial carcinomas. Screening of patients with known Lynch syndrome is important to evaluate for development of new primary tumors. Further study may provide more information on what level of follow-up each patient needs. Recent data suggest that mismatch repair mutations confer a greater risk for urothelial cancer. Additional large patient series as well as advancement of molecular testing may provide triage for Lynch syndrome patients in regards to the frequency and type of screening best suited for individual patient.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias da Bexiga Urinária/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Detecção Precoce de Câncer , Humanos , Programas de Rastreamento , Instabilidade de Microssatélites , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Vigilância da População , Prognóstico , Fatores de Risco , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/epidemiologia
10.
BMC Cancer ; 17(1): 843, 2017 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-29237405

RESUMO

BACKGROUND: The prevalence of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is 2 to 5% in the Caucasian population. HNPCC is caused by genomic mutations in DNA mismatch repair genes (MMR), namely MLH1, MSH2, MSH6, PMS2, and EPCAM. A non-hereditary, acquired process of hypermethylation of the MLH1 promoter can also lead to silencing of MLH1 protein expression. Diagnosis of HNPCC in patients with colorectal and other related cancers is important in the clinical treatment and surveillance of related cancers. The prevalence and clinical characteristics of HNPCC in Asian colorectal cancer patients has been reported in small studies and unique features have been suggested. METHODS: We retrospectively reviewed the clinical characteristics of Asian patients who were diagnosed of colon cancer between 1/2002 and 6/2015, and performed IHC for four MMR protein expressions on tumor specimens as a screening test for HNPCC, followed by confirmatory tests of genomic sequencing and hypermethylation analysis. RESULTS: One hundred forty-three patients were identified. Thirty-one patients were diagnosed younger than 50 years old, while 112 patients were diagnosed older than 50 years old. Six cases of HNPCC were found with a prevalence of 4.19%. The prevalence in the group of patients diagnosed younger than 50 years old is 16.1%, and that in patients diagnosed older than 50 years old is 0.89%. All patients with HNPCC had family histories of colon or gastric cancer. Tumor locations in the HNPCC patients were predominantly in the descending or sigmoid colon (67%). Half of the HNPCC patients had MSH6 mutations. Hypermethylation of the MLH1 gene was only present in 2.80% of the patients. CONCLUSION: The prevalence of HNPCC is high in patients younger than 50 years old and extremely low in those older than 50 years old. These results may be useful in the future development of guidelines for HNPCC laboratory screening among Asian patients. The pathological and clinical features of HNPCC in this group of Asian immigrant patients are more similar to those reported on Asian patients in their home countries than to Caucasian patients in Western countries, and will warrant further large-scale evaluation.


Assuntos
Americanos Asiáticos/estatística & dados numéricos , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Emigrantes e Imigrantes , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Adulto Jovem
11.
Bull Cancer ; 104(10): 831-839, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28988047

RESUMO

BACKGROUND: We aimed to investigate the prevalence of Lynch syndrome as one of hereditary causes of colorectal cancer (CRC) among young Congolese individuals affected by the CRC, and to define methods for diagnosis in Congo Brazzaville. METHODS: We conducted a transversal cohort study of 34 patients having a CRC with a family history for a period of eight years. They were selected among 89 CRCs of any type from the Bethesda guidelines criteria combined with pedigrees. Mismatch repair (MMR) genes alterations were researched by immunohistochemistry (IHC). RESULTS: We identified with the Bethesda criteria a total of 38.2% (34/89) patients having familial CRC with a confidence interval (CI) of 95%=[0.34-0.41]. Only 14.7% (5/34) 95% CI=[0.34-2.32] patients showed MMR immunodeficiency involving firstly MLH1 protein then MSH2 protein. These data account for 5.6% (5/89) 95% CI=[0.15-0.33] of patients affected by Lynch syndrome with an earlier median age of 35 years (range 20 to 47 years). CONCLUSION: The prevalence of Lynch syndrome found in Brazzaville is comparable to that is found in northern countries. The combined Bethesda guidelines, pedigree and IHC is an accessible and good alternative method for the positive diagnosis of Lynch syndrome in current practice in Congo.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Adulto , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Intervalos de Confiança , Congo/epidemiologia , Estudos Transversais , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Molécula de Adesão da Célula Epitelial/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Linhagem , Prevalência , Fatores de Risco , Fatores de Tempo
12.
BMC Cancer ; 17(1): 623, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874130

RESUMO

BACKGROUND: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. METHODS: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. RESULTS: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. CONCLUSION: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Biologia Computacional/métodos , Reparo de Erro de Pareamento de DNA , Feminino , Efeito Fundador , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Mutação em Linhagem Germinativa , Humanos , América Latina/epidemiologia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Processamento de RNA , Sistema de Registros , Fatores de Risco
13.
Gynecol Oncol ; 147(2): 381-387, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28822557

RESUMO

OBJECTIVE: To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. METHODS: Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression. RESULTS: Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC (P=3.8×10-7), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives (PTrend=4.43×10-6), and with increasing numbers of Lynch cancers in relatives (PTrend≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24-3.37, P=0.004). CONCLUSION: The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/genética , Aconselhamento Genético/métodos , Austrália/epidemiologia , Estudos de Casos e Controles , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/prevenção & controle , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Anamnese , Pessoa de Meia-Idade
14.
Can J Gastroenterol Hepatol ; 2017: 9625638, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28752083

RESUMO

BACKGROUND: Lynch Syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). In British Columbia, most centres still use clinical criteria (Amsterdam II, Revised Bethesda, or the BC Cancer Agency's criteria) to determine who should undergo further first-line testing in the form of microsatellite instability or immunohistochemistry staining. Given the limitations with this strategy, LS is thought to be underrecognized. OBJECTIVE: To investigate whether LS is truly underrecognized when compared to the reported prevalence. METHODS: A retrospective chart review of all CRC cases diagnosed at St. Paul's Hospital from 2010 to 2013 was conducted. RESULTS: 246 patients met inclusion criteria. 76% (83/109) with a family history of malignancy were unable to recall the specific malignancy or age of diagnosis. 18% (43/235) were only asked about a history of gastrointestinal related malignancy and 26% (65/246) met at least one of the three criteria but only 21% (13/63) received further investigation. Only 1.6% (4/246) had LS compared to the reported prevalence of 2-5% of all CRC cases. CONCLUSION: This data supports our hypothesis that LS is underrecognized. Issues at the patient, physician, and systems level need to be evaluated to determine where the limitations preventing appropriate testing are occurring.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Instabilidade de Microssatélites , Adulto , Idoso , Colúmbia Britânica/epidemiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos
15.
Dis Colon Rectum ; 60(8): 792-799, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28682964

RESUMO

BACKGROUND: The risk of metachronous colorectal cancer is high after surgical resection for first colon cancer in Lynch syndrome. OBJECTIVE: This study aimed to examine whether extended surgery decreases the risk of subsequent colorectal cancer and improves long-term survival. DESIGN: This was a retrospective study. SETTING: Data were collected from a nationwide registry. PATIENTS: Two hundred forty-two Lynch syndrome pathogenic variant carriers who underwent surgery for a first colon cancer from 1984 to 2009 were included. INTERVENTIONS: Patients underwent standard segmental colectomy (n = 144) or extended colectomy (n = 98) for colon cancer. Patients were followed a median of 14.6 up to 25 years. MAIN OUTCOME MEASURES: Risk of subsequent colorectal cancer in either group, overall and disease-specific survival, and operative mortality were the primary outcomes measured. RESULTS: Subtotal colectomy decreased the risk of subsequent colorectal cancer (HR, 0.20; 95% CI, 0.08-0.52; p = 0.001), compared with segmental resection. Subsequent colorectal cancer decreased in MLH1 carriers. The MSH2 carriers showed no statistical difference, possibly because of their small number. Disease-specific and overall survival within 25 years did not differ between the standard and extended surgeries (82.7% vs 87.2%, p = 0.76 and 47.2% vs 41.4%, p = 0.83). The cumulative risk of subsequent colorectal cancer was 20% in 10 years and 47% within 25 years after standard resection and 4% and 9% after extended surgery. The cumulative risk of metachronous colorectal cancer was 7% within 25 years after subtotal colectomy with ileosigmoidal anastomosis. One patient died of postoperative septicemia within 30 days after segmental colectomy. LIMITATIONS: Data on surgical procedures were primarily collected retrospectively. CONCLUSIONS: Lynch syndrome pathogenic variant carriers may undergo subtotal colectomy to manage first colon cancer and avoid repetitive abdominal surgery and to reduce the remaining bowel to facilitate easier endoscopic surveillance. It provides no survival benefit, compared with segmental colon resection. See Video Abstract at http://links.lww.com/DCR/A319.


Assuntos
Carcinoma/cirurgia , Colectomia/métodos , Neoplasias do Colo/cirurgia , Neoplasias Colorretais Hereditárias sem Polipose/cirurgia , Segunda Neoplasia Primária/epidemiologia , Adulto , Anastomose Cirúrgica , Colo Sigmoide/cirurgia , Neoplasias do Colo/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Íleo/cirurgia , Masculino , Pessoa de Meia-Idade , Proctocolectomia Restauradora , Estudos Retrospectivos , Risco
16.
Cancer ; 123(19): 3732-3743, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28640387

RESUMO

BACKGROUND: The landscape of hereditary syndromes and clinicopathologic characteristics among US Latino/Hispanic individuals with colorectal cancer (CRC) remains poorly understood. METHODS: A total of 265 patients with CRC who were enrolled in the Hispanic Colorectal Cancer Study were included in the current study. Information regarding CRC risk factors was elicited through interviews, and treatment and survival data were abstracted from clinical charts. Tumor studies and germline genetic testing results were collected from medical records or performed using standard molecular methods. RESULTS: The mean age of the patients at the time of diagnosis was 53.7 years (standard deviation, 10.3 years), and 48.3% were female. Overall, 21.2% of patients reported a first-degree or second-degree relative with CRC; 3.4% met Amsterdam I/II criteria. With respect to Bethesda guidelines, 38.5% of patients met at least 1 criterion. Of the 161 individuals who had immunohistochemistry and/or microsatellite instability testing performed, 21 (13.0%) had mismatch repair (MMR)-deficient (dMMR) tumors. dMMR tumors were associated with female sex (61.9%), earlier age at the time of diagnosis (50.4 ± 12.4 years), proximal location (61.9%), and first-degree (23.8%) or second-degree (9.5%) family history of CRC. Among individuals with dMMR tumors, 13 (61.9%) had a germline MMR mutation (MutL homolog 1 [MLH1] in 6 patients; MutS homolog 2 [MSH2] in 4 patients; MutS homolog 6 [MHS6] in 2 patients; and PMS1 homolog 2, mismatch repair system component [PMS2] in 1 patient). The authors identified 2 additional MLH1 mutation carriers by genetic testing who had not received immunohistochemistry/microsatellite instability testing. In total, 5.7% of the entire cohort were confirmed to have Lynch syndrome. In addition, 6 individuals (2.3%) had a polyposis phenotype. CONCLUSIONS: The percentage of dMMR tumors noted among Latino individuals (13%) is similar to estimates in non-Hispanic white individuals. In the current study, the majority of individuals with dMMR tumors were confirmed to have Lynch syndrome. Cancer 2017. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Cancer 2017;123:3732-3743. © 2017 American Cancer Society.


Assuntos
Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Família , Hispano-Americanos/genética , Fatores Etários , California/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etnologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Prevalência , Fatores de Risco , Fatores Sexuais
17.
Int J Gynecol Cancer ; 27(5): 931-937, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28498244

RESUMO

BACKGROUND: Lynch syndrome (LS) is an inherited disorder associated with genetic predisposition to endometrial, colorectal, ovarian, and other cancers. There is consensus for the necessity of assessment for LS in view of the established survival benefits for identified patients and affected family members. The debate regarding the best screening policy is far from being concluded. OBJECTIVES: The aim of this study was to evaluate a realistic protocol for identifying LS families by assessing young women with a diagnosis of endometrial cancer (EC). METHODS: Consecutive cases of women with a diagnosis of endometrioid EC younger than 50 years were recruited. A complete 3-generation pedigree was drawn and assessed against the Amsterdam II criteria. Tumor DNA microsatellite instability and immunohistochemistry testing for the expression of mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2 was offered to all patients. MLH1 gene promoter methylation and EPCAM gene deletion testing were also offered where appropriate. Genetic counseling and MMR germline mutation tests were offered in women with abnormal results. RESULTS: Fifty-eight women were invited, and 38 (65.5%), consented for LS assessment (95% confidence interval CI 53%-78%). A complete data set was obtained in 35 women (60.3%). Lynch syndrome according to clinical and/or molecular characteristics was diagnosed in 8 cases or 22.8% (95% CI 15%-48%). There was no significant difference at the age of women with a diagnosis of LS (median, 45 years; range, 37-48 years) compared with that of the non-LS ones (median, 45 years; range, 31-49 years). Three pathogenic MMR mutations were identified in the 8 cases with a diagnosis of LS, 37.5% (95% CI 5%-72%), estimating an 8.5% (95% CI 1%-19%) mutation prevalence in the study population. CONCLUSIONS: All women with newly diagnosed EC should be assessed for inherited predisposition. Regional policies for assessment should be developed in accordance with available resources. Gynecologists are required to upgrade their skills in order to identify, assess, and counsel patients with suspected or established LS and appropriately refer to clinical genetics.


Assuntos
Carcinoma Endometrioide/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias do Endométrio/diagnóstico , Adulto , Índice de Massa Corporal , Carcinoma Endometrioide/epidemiologia , Carcinoma Endometrioide/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/genética , Feminino , Humanos , Corpo Clínico Hospitalar , Pessoa de Meia-Idade , Reino Unido/epidemiologia
18.
Curr Treat Options Oncol ; 18(4): 23, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28391421

RESUMO

OPINION STATEMENT: Colorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.


Assuntos
Neoplasias Colorretais/epidemiologia , Adulto , Fatores Etários , Idade de Início , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Gerenciamento Clínico , Detecção Precoce de Câncer/métodos , Predisposição Genética para Doença , Humanos , Incidência , Vigilância da População , Fatores de Risco , Adulto Jovem
19.
J Gene Med ; 19(4)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28306219

RESUMO

BACKGROUND: We identified a new and a recurrent POLD1 mutation associated with predisposition to colorectal cancer (CRC). We characterized the molecular and clinical nature of the potential POLD1 founder mutation in families from Valencia (Spain). METHODS: Clinical and molecular data were collected from four independent families known to have a POLD1 Leu474Pro mutation. To establish its founder effect, haplotype construction was performed using 14 flanking POLD1 polymorphic markers. We calculated penetrance estimates and clinical expressivity, globally and stratified by age and sex. RESULTS: We included 32 individuals from the four families: 20 carriers and 12 noncarriers. A common haplotype was identified in these families in a region comprising 2,995 Mb, confirming L474P as the first founder POLD1 mutation identified. Thirteen tumors diagnosed in 10 POLD1 carriers: eight CRC, three endometrial and two other tumors were considered. The median age of cancer onset for POLD1 mutation carriers was 48 years. The observed penetrance was 50% and the cumulative risk at age of 50 years was 30%. CONCLUSIONS: The findings of the present study contribute to a better understanding of CRC genetics in the Spanish population. The clinical phenotype for this mutation is similar to that in Lynch syndrome. Future studies using next generation sequencing with large gene panels for any hereditary cancer condition will offer the possibility of detecting POLE/POLD1 mutations in unsuspected clinical situations, demonstrating a more real and unbiased picture of the associated phenotype.


Assuntos
DNA Polimerase III/genética , Grupo com Ancestrais do Continente Europeu/genética , Efeito Fundador , Genética Populacional , Mutação de Sentido Incorreto , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Heterozigoto , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Penetrância , Fenótipo , Polimorfismo de Nucleotídeo Único , Vigilância da População , Espanha , Adulto Jovem
20.
Clin Colorectal Cancer ; 16(3): 173-177, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28242162

RESUMO

BACKGROUND: The frequency of mismatch repair (MMR) deficiency (dMMR) in patients < 50 years with adenomas without a known germline mutation is unknown. Our aim was to define the frequency of dMMRs in adenomas from patients aged < 50 years. PATIENTS AND METHODS: We identified all patients aged 18 to 49 years who had undergone colonoscopy at Memorial Sloan Kettering Cancer Center from 2008 to 2013 and were identified as having tubular, villous, or tubulovillous adenomas on pathology. Patients with a personal history of colorectal cancer, polyposis syndrome, or inflammatory bowel disease before colonoscopy were excluded. Age, demographic data, family history of cancer, personal history of cancer, use of radiation, reason for colonoscopy, and colonoscopy findings were recorded. Polyps were stained using immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins. RESULTS: A total of 208 patients with 266 polyps were identified. Of the 266 polyps, 259 could be stained. Of the 208 patients, 82 (40%) were men; their mean age was 44 years. The indication for colonoscopy was screening for 120, diagnostic for 75, and therapeutic for 15. Of the 259 examined polyps, 246 (95%) were tubular adenomas and 13 were tubulovillous adenomas (5%). One patient (0.4%) was found to have dMMRs in 1 polyp. This patient was a 42-year-old woman with a history of endometrial cancer who had undergone colonoscopy for hematochezia. A 15-mm transverse tubular adenoma was found that was deficient in MLH1 and PMS2. CONCLUSION: Our results indicate that routine screening of polyps in patients aged < 50 years old is not an effective tool for identifying Lynch syndrome carriers.


Assuntos
Adenoma/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
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