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1.
Am J Epidemiol ; 190(2): 230-238, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524116

RESUMO

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.


Assuntos
Estatura , Neoplasias Colorretais/epidemiologia , Neoplasias do Endométrio/epidemiologia , Adulto , Fatores Etários , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais
2.
Am J Hum Genet ; 108(1): 163-175, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33357406

RESUMO

The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed "variants of uncertain significance" (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians' interpretations. The large majority (89%) of missense variants were functionally neutral, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the ∼1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.


Assuntos
Predisposição Genética para Doença/genética , Proteína 2 Homóloga a MutS/genética , Mutação de Sentido Incorreto/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Células HEK293 , Humanos
4.
Acta Gastroenterol Belg ; 83(3): 399-405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33094586

RESUMO

BACKGROUND AND STUDY AIMS: The most important causes of hereditary colorectal cancer are Lynch syndrome (LS) and the adenomatous polyposis syndromes (familial adenomatous poly- posis syndrome or FAP, attenuated FAP or AFAP and MUTYH associated polyposis syndrome or MAP). The aim of this study was to investigate whether all patients with a hereditary syndrome within one center receive uniform advice regarding surveillance and treatment. PATIENTS AND METHODS: A retrospective analysis was performed of all electronic patient health records of patients with LS, FAP, AFAP and MAP who received genetic counselling or were followed by a health care specialist at the University Hospital in Ghent. RESULTS: Data from 122 patients were collected. For all patients, recommendations from the medical genetics department were highly consistent. Adherence to their recommendations was good within the center for the management of colon polyps. There was a lack of consistency in the screening and surveillance advice for other tumors in departments other than gastroenterology. Only 33 patients had systematic follow-up consultations to check results and organize surveillance. CONCLUSION: Previously, small studies have suggested that patients with hereditary gastrointestinal cancer syndromes infrequently have surveillance as specified in the guidelines. This study shows almost uniform recommendations and good adherence for surveillance of the colon, but incomplete or contradictory advice for surveillance of other organs. The need for an integrated approach from a multidisciplinary team will only increase in the future, because more families with hereditary cancer are likely to be found due to the increased use of next generation sequencing in cancer diagnostics.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , 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 , Humanos , Estudos Retrospectivos
5.
Acta Gastroenterol Belg ; 83(3): 479-481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33094597

RESUMO

PURPOSE: To present a case series of two fraternal twin girls who passed away from brain and colorectal cancers attributed to Constitutional Mismatch Repair Deficiency syndrome (CMMRD). A review of literature for CMMRD-related pediatric malignancies is also presented. METHODS: The two girls were diagnosed with cancer at the age of 11 and 13 respectively. The early onset of multiple malignancies in the family raised clinical suspicion for a potential genetic mutation. The presence of café-au-lait spots at clinical examination led to further investigations for neurofibromatosis. RESULTS: Neurofibromatosis type 1 testing was negative in both children. Genetic analysis turned out positive for biallelic MSH6 mutations in the two girls, leading to CMMRD syndrome diagnosis. Both parents and two out of three alive siblings were diagnosed with Lynch syndrome. CONCLUSIONS: Colorectal cancer is a very rare finding in childhood and should raise suspicion for CMMRD syndrome and should be followed by regular screening.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias Encefálicas , Criança , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA , Feminino , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Mutação , Síndromes Neoplásicas Hereditárias
6.
PLoS Med ; 17(9): e1003263, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941469

RESUMO

BACKGROUND: Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. METHODS AND FINDINGS: This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1-hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1-hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1-methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity (p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1-hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, which means that the sensitivity and specificity of tumour triage strategies for LS detection may be overestimated, although the risk of LS in women with no clinical or tumour predictors is expected to be extremely low. CONCLUSIONS: In this study, we observed that age, family history, and histology are imprecise clinical correlates of LS-EC. IHC outperformed MSI for tumour triage and reliably identified both germline and somatic MMR mutations. The 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/genética , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Estudos Transversais , Metilação de DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/diagnóstico , Feminino , Testes Genéticos/métodos , Humanos , Imuno-Histoquímica , Programas de Rastreamento/métodos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Reino Unido
7.
Vnitr Lek ; 66(5): 80-84, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32942876

RESUMO

Pheochromocytoma is a catecholamine-producing neuroendocrine tumor arising from chromaffin cells of the adrenal medulla. The detection of these tumors is extremely important because they are associated with high cardiovascular morbidity and mortality. Progress in molecular genetics has revealed that up to 35% of pheochromocytomas are inhereted. Lynch syndrome (hereditary nonpolypous colorectal cancer - HNPCC) is an autosomal dominant genetic condition that is associated with a high risk of colorectal cancer or other extracolonic tumors (adenocarcinoma of endometrium, stomach, ovarian carcinoma, carcinoma of urinary tract, small intestine, brain tumors and skin cancer). Foreign medical journals are reporting an increasing number of cases on coexistence of HNPCC and neuroendocrine tumors, including pheochromocytoma. It increases the likelihood that this type of tumor could represent an additional extracolonic manifestation of Lynch syndrome.


Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/complicações , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Humanos , Achados Incidentais
8.
Nat Med ; 26(8): 1235-1239, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32719484

RESUMO

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Testes Genéticos , Genética Populacional , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Hiperlipoproteinemia Tipo II/genética , Adolescente , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Triagem de Portadores Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/patologia , Pessoa de Meia-Idade
9.
PLoS One ; 15(7): e0235613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634176

RESUMO

Germline variants inactivating the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome that implies an increased cancer risk, where colon and endometrial cancer are the most frequent. Identification of these pathogenic variants is important to identify endometrial cancer patients with inherited increased risk of new cancers, in order to offer them lifesaving surveillance. However, several other genes are also part of the MMR pathway. It is therefore relevant to search for variants in additional genes that may be associated with cancer risk by including all known genes involved in the MMR pathway. Next-generation sequencing was used to screen 22 genes involved in the MMR pathway in constitutional DNA extracted from full blood from 199 unselected endometrial cancer patients. Bioinformatic pipelines were developed for identification and functional annotation of variants, using several different software tools and custom programs. This facilitated identification of 22 exonic, 4 UTR and 9 intronic variants that could be classified according to pathogenicity. This study has identified several germline variants in genes of the MMR pathway that potentially may be associated with an increased risk for cancer, in particular endometrial cancer, and therefore are relevant for further investigation. We have also developed bioinformatics strategies to analyse targeted sequencing data, including low quality data and genomic regions outside of the protein coding exons of the relevant genes.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/patologia , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Variações do Número de Cópias de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Neoplasias do Endométrio/genética , Éxons , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Fatores de Risco , Regiões não Traduzidas/genética
10.
PLoS One ; 15(7): e0235038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609729

RESUMO

Lynch syndrome (LS) is an autosomal dominant condition caused by pathogenic variants in mismatch repair (MMR) genes that predispose individuals to different malignancies, such as colorectal cancer (CRC) and endometrial cancer. Current guidelines recommended testing for LS in individuals with newly diagnosed CRC to reduce cancer morbidity and mortality in relatives. Economic evaluations in support of such approach, however, are not available in Italy. We developed a decision-analytic model to analyze the cost-effectiveness of LS screening from the perspective of the Italian National Health System. Three testing strategies: the sequencing of all MMR genes without prior tumor analysis (Strategy 1), a sequential IHC and MS-MLPA analysis (Strategy 2), and an age-targeted strategy with a revised Bethesda criteria assessment before IHC and methylation-specific MLPA for patients ≥ than 70 years old (Strategy 3) were analyzed and compared to the "no testing" strategy. Quality Adjusted Life Years (QALYs) in relatives after colonoscopy, aspirin prophylaxis and an intensive gynecological surveillance were estimated through a Markov model. Assuming a CRC incidence rate of 0.09% and a share of patients affected by LS equal to 2.81%, the number of detected pathogenic variants among CRC cases ranges, in a given year, between 910 and 1167 depending on the testing strategy employed. The testing strategies investigated, provided one-time to the entire eligible population (CRC patients), were associated with an overall cost ranging between €1,753,059.93-€10,388,000.00. The incremental cost-effectiveness ratios of the Markov model ranged from €941.24 /QALY to €1,681.93 /QALY, thus supporting that "universal testing" versus "no testing" is cost-effective, but not necessarily in comparison with age-targeted strategies. This is the first economic evaluation on different testing strategies for LS in Italy. The results might support the introduction of cost-effective recommendations for LS screening in Italy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Testes Genéticos/economia , Neoplasias Colorretais/economia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/economia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Custo-Benefício , Reparo de Erro de Pareamento de DNA , Testes Genéticos/métodos , Humanos , Itália/epidemiologia , Proteína 1 Homóloga a MutL/genética , Linhagem , Probabilidade , Anos de Vida Ajustados por Qualidade de Vida
11.
Lancet ; 395(10240): 1855-1863, 2020 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-32534647

RESUMO

BACKGROUND: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. METHODS: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. FINDINGS: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43-0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39-0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34-0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31-0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43-0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. INTERPRETATION: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. FUNDING: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Método Duplo-Cego , Seguimentos , Heterozigoto , Humanos , Análise de Intenção de Tratamento , Tábuas de Vida , Adesão à Medicação , Modelos de Riscos Proporcionais
12.
Surg Clin North Am ; 100(3): 483-498, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32402295

RESUMO

For most individuals, cancer development is multifactorial; however, up to 10% of all cancers are related to an inherited genetic mutation. As health care shifts to having a greater emphasis on prevention, care providers, including general surgeons, will need to play a role in identifying patients at high risk for cancer development. Genetic testing provides a tool to determine those patients with a genetic mutation and to whom appropriate preventive care and treatment may be offered. It is imperative for general surgeons to understand the role genetics plays in the care of individual patients and their relatives.


Assuntos
Neoplasias/genética , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Mutacional de DNA , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Neoplasias/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Linhagem , Cuidado Pré-Concepcional , Medição de Risco , Neoplasias Gástricas/genética
13.
Medicine (Baltimore) ; 99(19): e20124, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384491

RESUMO

Recent studies have suggested an increased risk of prostate cancer in men with Lynch syndrome driven by germline mutations in mismatch repair (MMR) genes. However, the incidence and clinical implication of MMR deficiency in sporadic prostate cancers remain poorly understood. We immunohistochemically stained for MLH1, MSH2, MSH6, and PMS2 in a set of tissue microarray consisting of 220 radical prostatectomy specimens and evaluated the relationship between loss of their expression and available clinicopathological features. MLH1, MSH2, MSH6, and PMS2 were lost in 2 (0.9%), 6 (2.7%), 37 (16.8%), and 27 (12.3%) prostate cancers, respectively. Loss of at least 1 MMR protein was identified in 50 (22.7%) cases. There were no statistically significant associations between MMR deficiency and patient age, family history of prostate cancer, Gleason score, or pT/pN stage. Nonetheless, the levels of preoperative prostate-specific antigen (PSA) were significantly (P = .015) higher in patients with MMR deficiency (mean ±â€ŠSD: 9.12 ±â€Š9.01 ng/mL) than in those without abnormal MMR (5.76 ±â€Š3.17 ng/mL). There were 15 (6.8%) cases showing loss of at least 2 MMR proteins, which was not significantly associated with PSA level or tumor grade/stage. Additionally, 5 and 2 cases showed losses of at least 3 MMR proteins and all 4 proteins, respectively. Kaplan-Meier analysis revealed no significant associations between loss of MLH1 (P = .373), MSH2 (P = .348), MSH6 (P = .946), or PMS2 (P = .681), or at least 1 (P = .477), 2 (P = .486), or 3 (P = .352) MMR proteins and biochemical recurrence. Further analyses of the data on programmed death-ligand 1 (PD-L1) expression previously stained in the same set of tissue microarray demonstrated associations between loss of ≥2 MMR proteins and a higher rate of PD-L1 expression in cancer cells (17.2% vs 5.2%; P = .033) as well as between cases showing both loss of ≥1 MMR protein(s) and PD-L1 expression in tumor-infiltrating immune cells vs a higher risk of biochemical recurrence (P = .045). MMR protein loss was seen in a subset of prostate cancers. Interestingly, it was associated with significantly higher levels of PSA. Moreover, immunohistochemical detection of MMR proteins together with other proteins, such as PD-L1, might be helpful in predicting tumor recurrence following radical prostatectomy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/fisiologia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Fatores Etários , Idoso , Antígeno B7-H1/biossíntese , Biomarcadores Tumorais , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Proteínas de Ligação a DNA/biossíntese , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/biossíntese , Proteína 1 Homóloga a MutL/biossíntese , Proteína 2 Homóloga a MutS/biossíntese , Gradação de Tumores , Recidiva Local de Neoplasia , Antígeno Prostático Específico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Análise Serial de Proteínas
14.
Jpn J Clin Oncol ; 50(6): 635-642, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32372090

RESUMO

BACKGROUND: Regular endoscopic surveillance for Lynch syndrome is reported to reduce colorectal cancer (CRC)-related mortality. However, the appropriate surveillance intervals are still unclear. We evaluated the adequacy of annual colonoscopy and investigated the differences in tumor occurrence rates between individual patients. METHODS: In total, 25 patients with Lynch syndrome who underwent colonoscopic surveillance between 2007 and 2016 at the Iwakuni Clinical Center were included. We retrospectively investigated the surveillance frequency and the clinical features associated with tumor development. RESULTS: Colonoscopic surveillance was performed every 397 days on average. A total of 101 tumors, including 8 intramucosal carcinomas and 15 carcinomas, were observed within the study period. Annual colonoscopy detected six malignancies, including a carcinoma requiring surgery. Tumor incidence was associated with tumor existence in the initial colonoscopies (P = 0.018). Patients with a tumor occurrence rate of 0.4 tumors per year during our observation period were significantly more likely to have malignancies detected during regular surveillance than patients who had a lower occurrence rate (P < 0.001). Malignancy occurrence rate was strongly associated with tumor occurrence rate (P < 0.001, R2 = 0.44). CONCLUSIONS: Annual colonoscopic surveillance for Lynch syndrome patients was effective in reducing the risk of CRC progression, but was insufficient to completely avoid surgery. Because the tumor occurrence rate differed substantially between individuals, more intensive surveillance was required for high-risk patients.


Assuntos
Variação Biológica da População , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/diagnóstico , Adulto , Idoso , Colonoscopia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Estudos Retrospectivos
15.
Pediatr Blood Cancer ; 67(8): e28309, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32472748

RESUMO

Germline biallelic mutations in one of the mismatch repair genes, mutS homolog 2, mutS homolog 6, mutL homolog 1, or postmeiotic segregation increased 2, result in one of the most aggressive cancer syndromes in humans termed as constitutional mismatch repair deficiency (CMMRD). Individuals with CMMRD are affected with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood without specific interventions. The most common tumors observed are central nervous system, hematological, and gastrointestinal malignancies. The incidence of CMMRD is expected to be high in low-resource settings due to a high rate of consanguinity in these regions, and it is thought to be underrecognized and consequently underdiagnosed. This position paper is therefore important to provide a summary of the current situation, and to highlight the necessity of increasing awareness, diagnostic criteria, and surveillance to improve survival for patients and family members.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Reparo de Erro de Pareamento de DNA , Genes Neoplásicos , Mutação em Linhagem Germinativa , Proteínas de Neoplasias/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , Humanos , Incidência
16.
Int J Clin Oncol ; 25(9): 1644-1652, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32430733

RESUMO

BACKGROUND: Risk factors for metachronous colorectal cancer (mCRC) in Lynch Syndrome (LS) patients are essential for colorectal cancer (CRC) treatment strategy to perform not only a curative but also preventive surgery. The aim of this study was to evaluate the risk factors for mCRC development in LS patients to define the patient subset that may benefit an extended curative and preventive surgical resection. METHODS: Patient's clinical history, oncological, molecular and follow-up were collected retrospectively from the Hereditary Digestive Tumors Registry at the National Cancer Institute of Milan. The age-related cumulative risk of mCRC was calculated using the Kaplan-Meier method. Factors significantly associated with mCRC were analyzed with a Cox regression model. Overall and specific competitive risks were also calculated. RESULTS: In a total of 1346 CRC patients, 159 (11.8%) developed a mCRC after a mean follow-up of 138 months from the primary tumor. The independent risk factors reported by a multivariate analysis were: pathogenetic variants in MLH1 and MSH2 (HR 2.96 and 1.91, respectively) and history of colorectal adenomas (HR 1.54); whereas female sex and extended surgery were protective (HR 0.59 and 0.79, respectively). CONCLUSIONS: Among a high-risk population for CRC, in particular LS, an extended surgery may be considered in CRC patients with specific risk factors (MLH1 or MSH2 germline pathogenic variants, history of colorectal adenomas) to reduce the risk of mCRC development.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Segunda Neoplasia Primária/patologia , Adulto , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco
17.
JAMA Netw Open ; 3(4): e203959, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32347951

RESUMO

Importance: Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening. Objectives: To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care. Design, Setting, and Participants: This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019. Exposures: Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist. Main Outcomes and Measures: Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome. Results: Among 49 738 participants (mean [SD] age, 57 [8] years; 27 144 female [55%]), 441 (0.9%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3%) for familial hypercholesterolemia, 235 (0.5%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4%) vs 4663 of 49 607 noncarriers (9.4%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6%) vs 2080 of 27 028 female noncarriers (7.7%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4%) vs 929 of 49 662 noncarriers (1.9%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3% for carriers of familial hypercholesterolemia, 41.1% for hereditary breast and ovarian cancer syndrome, and 38.3% for Lynch syndrome. Across the 3 conditions, 39.7% (175 of 441) of the carriers reported a family history of disease vs 23.2% (34 517 of 148 772) of noncarriers. Conclusions and Relevance: The findings suggest that approximately 1% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Hiperlipoproteinemia Tipo II/genética , Idoso , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Modelos de Riscos Proporcionais , Reino Unido/epidemiologia , Sequenciamento Completo do Exoma
18.
Best Pract Res Clin Obstet Gynaecol ; 65: 139-153, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32245629

RESUMO

Germline mutations in cancer-susceptibility-genes (CSG) can dramatically increase womens' lifetime risk of ovarian, endometrial, breast and bowel cancers. Identification of unaffected carriers is important to enable proactive engagement with highly effective screening and preventive options to minimise cancer risk. Currently, a family-history model is used to identify individuals with CSGs. Complex regional referral guidelines specify the family-history criteria required before an individual is eligible for genetic-testing. This model is ineffective, resource intense, misses >50% CSG carriers, is associated with underutilisation of genetic-testing services and delays detection of mutation carriers. Although awareness and detection of CSG-carriers has improved, over 97% carriers remain unidentified. This reflects significant missed opportunities for precision-prevention. Population-based genetic-testing (PBGT) represents a novel healthcare strategy with the potential to dramatically improve detection of unaffected CSG-carriers along with enabling population risk-stratification for cancer precision-prevention. Several research studies have assessed the impact, feasibility, acceptability, long-term psychological outcomes and cost-effectiveness of population-based BRCA-testing in the Ashkenazi-Jewish population. Initial data on PBGT in the general-population is beginning to emerge and large implementation studies investigating PBGT in the general-population are needed. This review will summarise the current research into the clinical, psycho-social, health-economic, societal and ethical consequences of a PBGT model for women's cancer precision-prevention.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença/etnologia , Testes Genéticos/métodos , Genética Populacional , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Neoplasias Ovarianas/genética , Neoplasias da Mama/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Detecção Precoce de Câncer , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Síndrome Hereditária de Câncer de Mama e Ovário/etnologia , Humanos , Mutação , Neoplasias , Neoplasias Ovarianas/diagnóstico
19.
Am J Surg Pathol ; 44(5): 649-656, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32294063

RESUMO

Mismatch repair deficiency (MMRD) is involved in the initiation of both hereditary and sporadic tumors. MMRD has been extensively studied in colorectal cancer and endometrial cancer, but not so in other tumors, such as ovarian carcinoma. We have determined the expression of mismatch repair proteins in a large cohort of 502 early-stage epithelial ovarian carcinoma entailing all the 5 main subtypes: high-grade serous carcinoma, endometrioid ovarian carcinoma (EOC), clear cell carcinoma (CCC), mucinous carcinoma, and low-grade serous carcinoma. We studied the association of MMRD with clinicopathologic and immunohistochemical features, including tumor-infiltrating lymphocytes in EOC, the histologic type in which MMRD is most frequent. In addition, MLH1 promoter methylation status and massive parallel sequencing were used to evaluate the proportion of sporadic and Lynch syndrome-associated tumors, and the most frequently mutated genes in MMRD EOCs. MMRD occurred only in endometriosis-associated histologic types, and it was much more frequent in EOC (18%) than in CCC (2%). The most frequent immunohistochemical pattern was loss of MLH1/PMS2, and in this group, 80% of the cases were sporadic and secondary to MLH1 promoter hypermethylation. The presence of somatic mutations in mismatch repair genes was the other mechanism of MMRD in sporadic tumors. In this series, the minimum estimated frequency of Lynch syndrome was 35% and it was due to germline mutations in MLH1, MSH2, and MSH6. ARID1A, PTEN, KTM2B, and PIK3CA were the most common mutated genes in this series. Interestingly, possible actionable mutations in ERRB2 were found in 5 tumors, but no TP53 mutations were detected. MMRD was associated with younger age and increased tumor-infiltrating lymphocytes. Universal screening in EOC and mixed EOC/CCC is recommended for the high frequency of MMRD detected; however, for CCC, additional clinical and pathologic criteria should be evaluated to help select cases for analysis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Neoplasias Ovarianas/genética , Fatores Etários , Biomarcadores Tumorais/deficiência , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma/terapia , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Metilação de DNA , Análise Mutacional de DNA , Enzimas Reparadoras do DNA/deficiência , Progressão da Doença , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Fenótipo , Intervalo Livre de Progressão , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Espanha , Fatores de Tempo
20.
Nat Commun ; 11(1): 1802, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286276

RESUMO

Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.


Assuntos
Colite/complicações , Colite/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Dano ao DNA , Helicobacter pylori/fisiologia , Estresse Oxidativo , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Colite/induzido quimicamente , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/efeitos dos fármacos , Sulfato de Dextrana , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/patologia , Escherichia coli/metabolismo , Feminino , Guanosina/análogos & derivados , Guanosina/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/efeitos dos fármacos , Humanos , Inflamação/complicações , Inflamação/patologia , Interleucina-10/deficiência , Interleucina-10/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação/genética , Estresse Oxidativo/efeitos dos fármacos
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