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1.
J Natl Compr Canc Netw ; 19(3): 329-359, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33724754

RESUMO

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

2.
JAMA Oncol ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33630025

RESUMO

Importance: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. Objective: To determine which patients derived the greatest degree of clinical benefit from NGS profiling. Design, Setting, and Participants: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. Main Outcomes and Measures: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. Results: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. Conclusions and Relevance: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

3.
Am J Gastroenterol ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33577181

RESUMO

INTRODUCTION: The additional diagnostic value of dye-based chromoendosocpy (CE) for surveillance of patients with Lynch syndrome is subject of debate. METHODS: To clarify this debate, we performed an individual patient data meta-analysis of randomized studies that compared CE with WLE for the detection of adenomas in patients with Lynch syndrome. RESULTS: Three randomized studies comprising 533 patients were included. The adenoma detection rate was 74/265 (28%) in patients randomized to WLE compared with 83/266 (31%) in patients randomized to CE (odds ratio 1.17; 95% confidence interval 0.81-1.70). DISCUSSION: Based on low-quality evidence, CE showed no apparent increase in adenoma detection compared to WLE during surveillance of patients with Lynch syndrome.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33359728

RESUMO

BACKGROUND & AIMS: Up to 20% of younger patients (age <50 years) diagnosed with colorectal cancer (CRC) have germline mutations in cancer susceptibility genes. Germline genetic testing may guide clinical management and facilitate earlier intervention in affected relatives. Few studies have characterized differences in genetic testing by race/ethnicity. METHODS: We identified young adults (age 18-49 years) diagnosed with CRC between 2009 and 2017 in 2 health systems in Dallas, TX. We evaluated referral to genetic counseling, attendance at genetic counseling appointments, and receipt of germline genetic testing by race/ethnicity. RESULTS: Of 385 patients with young-onset CRC (median age at diagnosis 44.4 years), 176 (45.7%) were Hispanic, 98 (25.4%) non-Hispanic Black, and 111 (28.8%) non-Hispanic White. Most patients (76.9%) received immunohistochemistry (IHC) for mismatch repair proteins, and there was no difference in receipt of IHC by race/ethnicity. However, a lower proportion of Black patients were referred to genetic counseling (50.0% vs. White patients 54.1% vs. Hispanic patients 65.9%, p = .02) and attended genetic counseling appointments (61.2% vs. 81.7% White patients vs. 86.2% Hispanic patients, p < .01). Of 141 patients receiving genetic testing, 38 (27.0%) had a pathogenic or likely pathogenic variant in a cancer susceptibility gene. An additional 33 patients (23.4%) had variants of uncertain significance, of which 84.8% occurred in racial/ethnic minorities. CONCLUSIONS: In a diverse population of patients diagnosed with young-onset CRC, we observed racial/ethnic differences in referral to and receipt of germline genetic testing. Our findings underscore the importance of universal genetic testing to address racial/ethnic disparities in young-onset CRC.

5.
Gut Pathog ; 12: 46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005238

RESUMO

Fusobacterium nucleatum (Fn) is frequently found in colorectal cancers (CRCs). High loads of Fn DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the CpG island hypermethylation phenotype (CIMP). Fn infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI-L) and/or an elevated level of microsatellite alterations at selected tetra-nucleotide repeats (EMAST). Here we describe two independent CRC cohorts in which heavy or moderate loads of Fn DNA are associated with MSI-H and L/E CRC respectively. We also show evidence that Fn produces factors that induce γ-H2AX, a hallmark of DNA double strand breaks (DSBs), in the infected cells.

6.
PLoS One ; 15(10): e0239676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33027290

RESUMO

Black Americans (BA) have higher incidence and higher mortality rates for colorectal cancers (CRC) as compared to White Americans (WA). While there are several identified risk factors associated with the development of CRC and evidence that high levels of adequate screening can reduce differences in incidence for CRC between BA and WA, there remains little data regarding patient co-morbid contributions towards survival once an individual has CRC. Here we set out to identify patient risk factors that influenced overall survival in a cohort of 293 BA and 348 WA with colon cancer. Amid our cohort, we found that patients' age, tobacco usage, and pre-diagnosed medical conditions such as hypertension and diabetes were associated with shorter overall survival (OS) from colon cancer. We identified pre-diagnosed hypertension and diabetes among BA were responsible for one-third of the colon cancer mortality disparity compared with WA. We also identified long-term regular use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, was associated with shorter OS from colon cancer among WA >65 years of age, but not younger WA patients or any aged BA patients. Our results raise the importance of not only treating the colon cancer itself, but also taking into consideration co-morbid medical conditions and NSAID usage to enhance patient OS. Further evaluation regarding adequate treatment of co-morbidities and timing of NSAID continuance after cancer therapy will need to be studied.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Neoplasias Colorretais/mortalidade , Comorbidade/tendências , Adulto , Afro-Americanos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/metabolismo , Aspirina/uso terapêutico , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Complicações do Diabetes , Diabetes Mellitus , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
N Engl J Med ; 383(11): 1028-1039, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32905675

RESUMO

BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Progressão da Doença , Eflornitina/uso terapêutico , Sulindaco/uso terapêutico , Adulto , Quimioterapia Combinada , Eflornitina/efeitos adversos , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Sulindaco/efeitos adversos , Resultado do Tratamento
9.
J Natl Compr Canc Netw ; 18(7): 806-815, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32634771

RESUMO

The NCCN Guidelines for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy approach for localized rectal cancer; and biomarker-targeted therapy for metastatic colorectal cancer, with a focus on new treatment options for patients with BRAF V600E- or HER2 amplification-positive disease.

10.
Sci Adv ; 6(26): eaba3231, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32637605

RESUMO

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

11.
Gut ; 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641470

RESUMO

OBJECTIVE: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. DESIGN: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). RESULTS: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. CONCLUSIONS: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. TRIAL REGISTRATION NUMBER: gov Identifier: NCT02052908.

12.
Clin Transl Gastroenterol ; 11(4): e00151, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251017

RESUMO

INTRODUCTION: We aimed to estimate the effects of a family history of colorectal cancer (CRC) or esophageal cancer on the risk of Barrett's esophagus (BE) and identify variants in cancer genes that may explain the association. METHODS: Men scheduled for screening colonoscopy were recruited to undergo upper endoscopy. Cases and noncases were screenees with and without BE, respectively. The effects of family histories on BE were estimated with logistic regression, adjusting for the potential confounders. We additionally recruited men recently diagnosed with BE by clinically indicated endoscopies. Banked germline DNA from cases of BE with ≥2 first-degree relatives (FDRs) with CRC and/or an FDR with esophageal cancer underwent next-generation sequencing using a panel of 275 cancer genes. RESULTS: Of the 822 men screened for CRC who underwent upper endoscopy, 70 were newly diagnosed with BE (8.5%). BE was associated with family histories of esophageal cancer (odds ratio = 2.63; 95% confidence interval = 1.07-6.47) and CRC in ≥2 vs 0 FDRs (odds ratio = 3.73; 95% confidence interval = 0.898-15.4). DNA analysis of subjects with both BE and a family history of cancer identified one or more germline variants of interest in genes associated with cancer predisposition in 10 of 14 subjects, including the same novel variant in EPHA5 in 2 unrelated individuals. DISCUSSION: We found an increased risk for BE associated with a family history of esophageal cancer or CRC. Although analysis of germline DNA yielded no clinically actionable findings, discovery of the same EPHA5 variant of uncertain significance in 2 of 14 cases merits additional investigation.

13.
Annu Rev Med ; 71: 85-102, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31756137

RESUMO

The prevalence of genetic predisposition to cancer is greater than initially appreciated, yet most affected individuals remain undiagnosed. Deleterious germline variants in cancer predisposition genes are implicated in 1 in 10 cases of advanced cancer. Next-generation sequencing technologies have made germline and tumor DNA sequencing more accessible and less expensive. Expanded access to clinical genetic testing will improve identification of individuals with genetic predisposition to cancer and provide opportunities to effectively reduce morbidity through precision cancer therapies and surveillance. Cross-disciplinary clinical education in genomic medicine is needed to translate advances in genomic medicine into improved health outcomes.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/epidemiologia , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Incidência , Masculino , National Institutes of Health (U.S.) , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Prognóstico , Medição de Risco , Análise de Sobrevida , Estados Unidos
14.
Gastroenterology ; 158(2): 341-353, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31394082

RESUMO

In contrast to the decreasing incidence of colorectal cancer (CRC) in older populations, the incidence has nearly doubled in younger adults since the early 1990s. Approximately 1 in 10 new diagnoses of CRC are now made in individuals 50 years or younger. Patients' risk of CRC has been calculated largely by age and family history, yet 3 of 4 patients with early-onset CRC have no family history of the disease. Rapidly increasing incidence rates in younger people could result from generational differences in diet, environmental exposures, and lifestyle factors. We review epidemiologic trends in CRC, data on genetic and nongenetic risk factors, and new approaches for determining CRC risk. These may identify individuals likely to benefit from early screening and specialized surveillance.


Assuntos
Neoplasias do Colo/epidemiologia , Detecção Precoce de Câncer/normas , Estilo de Vida , Programas de Rastreamento/normas , Neoplasias Retais/epidemiologia , Fatores Etários , Idade de Início , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/prevenção & controle , Humanos , Incidência , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Neoplasias Retais/diagnóstico , Neoplasias Retais/prevenção & controle , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto Jovem
15.
J Natl Compr Canc Netw ; 17(9): 1109-1133, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31487687

RESUMO

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/terapia , Intestino Delgado/patologia , Guias de Prática Clínica como Assunto , Adenocarcinoma/etiologia , Adenocarcinoma/mortalidade , Terapia Combinada , Diagnóstico Diferencial , Humanos , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/mortalidade , Estadiamento de Neoplasias , Fatores de Risco , Sobrevivência , Resultado do Tratamento , Conduta Expectante
16.
J Low Genit Tract Dis ; 23(3): 214-219, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31232912

RESUMO

OBJECTIVE: Vulvar lichen sclerosus (LS) is known to occur in families, suggesting a genetic link. Genomic profiling of patients with vulvar LS was investigated to find underlying pathogenetic mechanisms, with the hope that targeted therapies and future clinical research will arise. METHODS: Two unrelated families with vulvar LS were investigated using whole-exome sequencing. Five affected sisters from 1 family were compared with their unaffected paternal aunt (unaffected control). A mother-daughter pair from a second affected family was compared with the first family. The results of the sequencing were compared with population-specific allele frequency databases to prioritize potential variants contributing to vulvar LS development. RESULTS: Recurrent germ-line variants in 4 genes were identified as likely to be deleterious to proper protein function in all of the 7 affected patients, but not in the unaffected control. The genes with variants included CD177 (neutrophil activation), CD200 (inhibitory signal to macrophages), ANKRD18A (ankyrin repeat protein, epigenetic regulation), and LATS2 (co-repressor of androgen signaling). CONCLUSIONS: Although many providers may see a mother and daughter with vulvar LS, this condition is rarely seen in multiple family members who are available for genetic testing. This is the first report to detail genomic profiling related to a familial association of vulvar LS.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Líquen Escleroso Vulvar/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade
17.
Gastroenterology ; 157(1): 87-96, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30935944

RESUMO

BACKGROUND & AIMS: Pathogenic germline variants in CDH1 are associated with risk for diffuse gastric cancer (DGC) and lobular breast cancer. The reported high incidence of DGC and limited sensitivity of endoscopy in detection have prompted recommendation for total prophylactic gastrectomy for carriers of pathogenic or likely pathogenic (PLP) germline variants of CDH1. Multigene panel tests have identified increasing numbers of carriers of PLP variants in CDH1 who lack a family history of DGC. We evaluated outcomes of endoscopic surveillance for carriers of PLP variants of CDH1 with and without family history of DGC. METHODS: Individuals from 13 families with germline PLP variants of CDH1 were evaluated at the Michigan Medicine Cancer Genetics Clinic from January 1998 through May 2018. Outcomes of esophagogastroduodenoscopy examinations, histopathology analyses, and surgery were compared between individuals with and without a family history of DGC. RESULTS: We identified 20 carriers of germline CDH1 PLP variants; they underwent endoscopic examinations and/or gastrectomy. None had abnormal findings visible during endoscopy. Signet ring cell carcinoma (SRCC) was detected in 12 of 20 subjects. All but 1 of the carcinomas were tiny and confined to the lamina propria, and 1 was transmural. Seven of 12 subjects who had SRCC reported no diagnoses of DGC in first-degree relatives and did not meet established criteria for CDH1 analysis based on a 3-generation family pedigree. CONCLUSIONS: More than half of individuals with germlines variants of CDH1 that are PLP had histopathologic evidence for DGC on endoscopy and/or gastrectomy. Family history of DGC and endoscopic findings therefore do not appear to be reliable determinants of risk of SRCC in individuals with genetic predisposition to DGC.


Assuntos
Carcinoma de Células em Anel de Sinete/diagnóstico , Detecção Precoce de Câncer/métodos , Endoscopia do Sistema Digestório , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Antígenos CD/genética , Caderinas/genética , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/prevenção & controle , Estudos de Casos e Controles , Feminino , Gastrectomia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Procedimentos Cirúrgicos Profiláticos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Adulto Jovem
18.
Curr Treat Options Gastroenterol ; 17(1): 89-98, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30712157

RESUMO

PURPOSE OF REVIEW: Routine screening for colorectal cancer (CRC) in adults > 50 years of age has led to overall reductions in CRC incidence and CRC-related mortality. Yet CRC incidence among young adults age < 50 continues to increase without a clear explanation. This review examines the changing epidemiology of CRC and emerging evidence regarding the influence of genetic and lifestyle factors on risk for colorectal neoplasia. RECENT FINDINGS: Young-onset CRC (yCRC), defined as CRC diagnosed in individuals younger than age 50, is a heterogeneous disease. Approximately, one in every five individuals affected with yCRC carries a pathogenic germline variant in genes associated with predisposition to cancer. However, most have no clinically identifiable risk factors. Analyses of birth cohorts estimate CRC risk among millennials to be 2-4 times higher than their grandparents', suggesting that changes in health behaviors and environmental factors are having an impact on CRC risk. Young individuals with CRC tend to be diagnosed at later stages and often present with metastatic disease. yCRC tumors arise predominantly in the distal colon and are more likely than older-onset tumors to exhibit microsatellite and chromosome stable (MACS) phenotypes. Although yCRC patients are more likely than their older counterparts to be treated with multimodality chemotherapy regimens, more aggressive treatments have not yielded measurable survival gains. Since one in ten new CRC diagnoses involve individuals age < 50, recent guidelines have proposed lowering the age for average risk CRC screening from 50 to 45; however, further studies are needed to evaluate testing strategies based on individuals' age and risk. Significant shifts in CRC epidemiology and diversity of tumor phenotypes support genetic and environmental factors as modifiers of cancer risk. Emerging data correlating tumor molecular features with outcomes justify further investigation into mechanisms of carcinogenesis to elucidate how specific factors (inherited and/or acquired) might stimulate young-onset colorectal neoplasia.

20.
J Pathol ; 247(5): 574-588, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30584801

RESUMO

This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Neoplasias Colorretais/genética , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/terapia , Genes Neoplásicos/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Mutação/genética , Penetrância , Medicina de Precisão/métodos
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