Hereditary nonpolyposis colorectal cancer (Lynch syndromes I &amp; II)

Lynch, Henry T.; Lanspa, Stephen J.; Smyrk, Thomas C.; Boman, Bruce M.; Watson, Patrice; Lynch, Jane F.

doi:10.1016/0165-4608(91)90093-a

Cited by 155 publications

(73 citation statements)

References 51 publications

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“…Mechanistically, somatic events, such as MLH1 promoter hypermethylation, account for the majority of MSI-H cancers, with a smaller proportion attributable to germline mutations in a DNA MMR gene ( MLH1, MSH2, MSH6, PMS2 ) 13, 14 . Individuals with germline MMR mutations are classified as having Lynch syndrome 15, 16 , which is the most common inherited form of CRC, accounting for 3-6% of cases 17-19 .…”

Section: Introductionmentioning

confidence: 99%

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Ricker

Hanna

Peng

et al. 2017

Cancer

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Background The landscape of hereditary syndromes and clinicopathologic characteristics among U.S. Latinos/Hispanics with colorectal cancer (CRC) remains poorly understood. Methods A total of 265 CRC patients enrolled in the Hispanic Colorectal Cancer Study were included in this study. Information regarding CRC risk factors was elicited through interviews, and treatment and survival data was 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 at diagnosis was 53.7 years (SD=10.3), and 48.3% were female. Overall, 21.2% reported a first- or second-degree relative with CRC; 3.4% met Amsterdam I/II criteria. With respect to Bethesda guidelines, 38.5% met at least one criterion. Of the 161 individuals who had immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing performed, 21 (13.0%) had mismatch repair (MMR) deficient tumors. dMMR tumors were associated with female sex (61.9%), earlier age of diagnosis (50.4 ± 12.4 years), proximal location (61.9%), and first (23.8%) or second (9.5%) degree family history of CRC. Among individuals with dMMR tumors, 13 (61.9%) had a germline MMR mutation (MLH1=6, MSH2=4, MHS6=2, and PMS2=1). We identified two additional MLH1 mutation carriers by genetic testing who had not received IHC/MSI testing. In total, 5.7% of the entire cohort were confirmed cases of Lynch syndrome. Additionally, six individuals (2.3%) had a polyposis phenotype. Conclusions The proportion of dMMR tumors in Latinos (13%) is similar to estimates in non-Hispanic Whites. The majority of individuals with dMMR tumors were confirmed to have Lynch syndrome.

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Section: Introductionmentioning

confidence: 99%

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Ricker

Hanna

Peng

et al. 2017

Cancer

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“…3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in frequent (pseudo)diploidy. [13][14][15][16] The PTEN tumor suppressor gene is located on chromosome 10q23, consists of 9 exons and encodes a protein product of 403 amino acids with phosphatidylinositol, tyrosine and serine/threonine protein phosphatase activity. [17][18][19] Its relation with cancer appears to be centered mainly on its capability to antagonize the phosphatidylinositol 3,4,5-trisphosphate (PIP3) kinase activity, modulating negatively the PIP3-Akt signaling pathway.…”

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confidence: 99%

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

Bilbao

Rodríguez

Ramírez

et al. 2006

Intl Journal of Cancer

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Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p 5 0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p 5 0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p 5 0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p 5 0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p 5 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p 5 0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients. ' 2006 Wiley-Liss, Inc.Key words: microsatellite instability; PTEN mutation; endometrial cancer Microsatellite instability (MSI) is caused by defects in the DNA mismatch repair (MMR) system, either by mutations or by epigenetic events leading to gene silencing. 1,2 Tumors with MSI are characterized by a massive instability in simple repeated sequences and mutations in many cancer-related genes, particularly those with simple repeated sequences in their coding regions. [3][4][5][6][7] Tumors with MSI display a strong microsatellite mutator phenotype (MMP), which underlies a mutational pathway for gastrointestinal cancer that differs in genotype and phenotype from cancers with microsatellite stability (MSS).The MMP pathway for colon cancer possesses several peculiar characteristics in genotype. These tumors show a paradoxically low incidence of mutations affecting the prototypical cancer genes for colon cancer, namely the APC and p53 tumor suppressor genes and the K-ras oncogene. 3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in freque...

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“…Em 1991 foram estabelecidos critérios para o diagnóstico clínico e epidemiológico desta síndrome -conhecidos como critérios de Amsterdam -, que incluem o diagnóstico de três familiares, duas gerações consecutivas e pelo menos um paciente com idade inferior a 50 anos 12,21 . Estes pacientes freqüentemente apresentavam tumores de localização proximal, com componente mucinoso, estadiamento pTNM avançado, maior risco de lesões sincrônicas e metacrônicas 13 .…”

Section: Discussionunclassified

A expressão de genes reparadores do DNA nos tumores sincrônicos de câncer colorretal esporádico

Proscurshim

Perez

Santos

et al. 2007

ABCD, arq. bras. cir. dig.

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InTRODUÇÃOO câncer colorretal (CCR) persiste como uma das neoplasias mais freqüentes no mundo ocidental, estimando-se aproximadamente 150 mil casos novos nos Estados Unidos e cerca de 20 mil no Brasil 7,15 .A descoberta de mecanismos genéticos e moleculares envolvidos no processo da carcinogênese colorretal permitiu a identificação de uma síndrome hereditária com grande suscetibilidade para algumas neoplasias (além do CCR) conhecida como síndrome hereditária não-polipóide do câncer colorretal (HNPCC -Hereditary Non-Polyposis Colorectal Cancer). Atualmente, acredita-se que estes pacientes possam corresponder a cerca de 10% dos casos de neoplasia colorretal.Nesta síndrome hereditária, acredita-se que o mecanismo genético envolvido no processo de carcinogênese inclui defeitos no mecanismo de reparo do DNA, levando à ocorrência de erros freqüentes de replicação -fenômeno conhecido como instabilidade de microssatélites -. Com isso, foram identificadas alterações nos genes de proteí-nas envolvidas no processo de reparo do DNA, sendo os genes mais frequentemente afetados o MSH2, MLH1 e MSH6 0 .Ao contrário, tumores ditos esporádicos, estariam associados a mutação e ativação de proto-oncogenes (mais frequentemente o K-ras) assim como a deleção de áreas cromossômicas de genes supressores de tumor (como p53, DCC e APC) 5 . ABCDDV/518Além de estar associada a mecanismos genéticos e moleculares distintos das neoplasias colorretais usuais, pacientes com HNPCC apresentam características clinicas, patológicas e prognóstico que também os diferenciam dos pacientes com neoplasia esporádica. Entre estas características, a presença de tumores sincrônicos nestes pacientes com HNPCC é achado muito mais freqüente quando comparado aos pacientes com tumor esporádico 8,11,14 .Apesar disso, uma parcela significativa (até 15%) dos pacientes com tumor esporádico pode apresentar alterações genéticas compatíveis com defeito no mecanismo de reparo do DNA e instabilidade de microssatélites 8 .A ocorrência deste fenômeno poderia justificar a presença nestes pacientes com tumor esporádico de características clinicas e patológicas semelhantes aos tumores de pacientes com HNPCC.Por esta razão decidiu-se, por objetivo deste trabalho, investigar as alterações dos genes responsáveis pelo mecanismo de reparo do DNA em pacientes com tumor esporádico e manifestação clínica muito característica dos tumores HNPCC, a presença de tumores sincrônicos. MÉTODOSPacientes com adenocarcinoma do cólon ou do reto tratados pela Disciplina de Coloproctologia da Faculdade

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Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II)

Cited by 155 publications

References 51 publications

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

A expressão de genes reparadores do DNA nos tumores sincrônicos de câncer colorretal esporádico

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