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1.
Medicine (Baltimore) ; 98(51): e18279, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31860975

RESUMEN

RATIONALE: Lynch syndrome (LS) is an autosomal dominant cancer predisposition condition caused by germline heterozygous mutations in mismatch repair (MMR) genes. However, as one of the MMR genes, PMS2 mutation-induced LS-associated endometrial cancer (LSAEC) was rarely reported. PATIENT CONCERNS: A 26-year-old female patient suffered from prolonged menstrual period and increased menstrual flow for 2 months. DIAGNOSES: The patient was diagnosed with cervix CIN III, endometrial cancer (EC), anemia, and LS. INTERVENTIONS: Total hysterectomy, bilateral salpingectomy, pelvic lymphadenectomy were performed for treating EC, while ovariectomy was refused by the patient. The patient underwent postoperative chemotherapy with paclitaxel combined with carboplatin for 6 courses of treatment. Laparoscopic partial enterectomy was applied for treating colon cancer 5 years later after the surgery treatment for EC. Besides, Sanger sequencing and high-throughput genome sequencing were employed to detect the genetic status of the family that included two generations with four members. Immunohistochemistry (IHC) staining was used to identify the function of PMS2 mutation. OUTCOMES: The 26-year-old Chinese patient suffered from LSAEC and recovered well after surgery. A PMS2 germline heterozygous mutation (c.1577delA) was confirmed by gene sequencing 5 years later. In addition, PMS2 mutation was verified by IHC. The patient was followed up for 7 years. LESSONS: Carrying PMS2 germline mutation (c.1577delA) confers an extremely high susceptibility of suffering from LS-associated cancers. Thus, close clinical monitoring and prophylactic surgery are highly recommended to reduce the morbidity and mortality of LS-associated cancers.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Endometriales/genética , Mutación de Línea Germinal/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Neoplasias Endometriales/etiología , Neoplasias Endometriales/patología , Endometrio/patología , Femenino , Humanos
2.
Z Gastroenterol ; 57(11): 1309-1320, 2019 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-31739377

RESUMEN

INTRODUCTION: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. METHODS: The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. RESULTS: A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. CONCLUSION: LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN , Endoscopía del Sistema Digestivo/métodos , Guías de Práctica Clínica como Asunto , Conducta de Reducción del Riesgo , Neoplasias Colorrectales , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Alemania , Humanos , Vigilancia de la Población , Factores de Tiempo
3.
Presse Med ; 48(9): 904-914, 2019 Sep.
Artículo en Francés | MEDLINE | ID: mdl-31561847

RESUMEN

About 5% of colorectal cancer (CRC) cases occurred in the context of an underlying hereditary predisposition syndrome. Lynch syndrome is the main causes of hereditary CRC but is also associated with a higher risk of other cancers (such as endometrial cancer and ovarian cancer). It is the consequence of constitutional mutation in a MisMatch Repair (MMR) gene, involved in DNA repair: MLH1, MSH2, MSH6 or PMS2; or of the EPCAM gene (MSH2 promotor). If a mutation predisposing to Lynch Syndrome is identified in an individual, special monitoring should be initiated, adapted to estimated cancer risk. Clinical criteria (Amsterdam II and Bethesda) have been validated to identify the patients who should be referred for genetic counseling in order to initiate constitutional DNA testing. Furthermore, the French National Cancer Institute (INCa) systematically recommend tumoral testing looking for MMR system failure in case of CRC diagnosed under 60, endometrial cancer diagnosed under 50 or whatever the age in patients diagnosed with CRC or endometrial cancer harbouring personal or familal history of Lunch Syndrome cancers. In this review, we will discuss how to detect Lynch syndrome (identification of the index case and family screening) and how to monitor it in 2019.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Factores de Edad , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Detección Precóz del Cáncer , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Intestino Grueso , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Linaje , Vigilancia de la Población/métodos , Guías de Práctica Clínica como Asunto , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/genética
4.
Semin Oncol ; 46(3): 261-270, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31537299

RESUMEN

Deficient DNA mismatch repair causes a robust mutator phenotype known as microsatellite instability (MSI). MSI is a feature of Lynch syndrome-related cancers and is also found in approximately 15% of sporadic gastric, colorectal, and endometrial cancers. Epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches for detecting the MSI phenotype of tumors using NGS have been developed. The FDA has recently granted accelerated approval to an anti-PD-1 antibody, pembrolizumab, for use in pediatric and adult patients with MSI+ solid tumors. Genome-wide analyses using NGS have revealed that hypermutation defined as >10 somatic mutations per megabase appears to be more prevalent than previously estimated, affecting approximately 17% of adult cancers. These results potentially expand the use of immunotherapy, which is thought to be effective in cancers with an increased mutational burden. Therefore, evaluation of MSI and MSI-associated molecular changes in tumors has emerged as clinically important. MSI is a valuable diagnostic marker of Lynch syndrome and a potential predictive marker for chemotherapy and immunotherapy efficacy. Here, we provide an update on MSI-associated cancers, focusing on findings obtained by genome-wide analyses using NGS, and the predictive role of MSI in immune checkpoint immunotherapy.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutL/genética , Neoplasias/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Medicina de Precisión , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología
5.
Rev Med Liege ; 74(9): 479-483, 2019 Sep.
Artículo en Francés | MEDLINE | ID: mdl-31486319

RESUMEN

Lynch syndrome is a hereditary predisposition to several cancers. The goals of our study were to know the different mutations in our Lynch population, to evaluate the prevalence of cancers in this population and to determine the mean age of onset of those cancers. This retrospective study includes proven carriers of a MMR mutation diagnosed either by the CHU of Liège or either by the CHC Saint-Joseph in Liège, Belgium. We noted a clear majority of MSH2 mutations (50 %) in the Lynch families recorded in Liège, which is different from the main literature. In our study population (106 subjects), 65 % of subjects were affected by at least one cancer. Prevalences for colorectal and endometrial cancers are, respectively, 50 % and 27.5 %. We found no difference in the mean age of onset of cancers compared to literature. We discuss the follow-up of Lynch patients and the interest of additional exams such as hysteroscopy and cystoscopy.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Neoplasias Endometriales , Predisposición Genética a la Enfermedad , Bélgica , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Endometriales/etiología , Femenino , Humanos , Mutación , Estudios Retrospectivos
6.
World Neurosurg ; 132: 219-222, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31491579

RESUMEN

BACKGROUND: Lynch syndrome (LS) is a cancer-predisposing condition resulting from germline mutations in deoxyribonucleic acid mismatch repair genes. Patients are at high risk for a multitude of tumors, but no reports of undifferentiated sellar carcinomas have previously been described. CASE DESCRIPTION: A 56-year-old female with LS due to MSH2 and MSH6 mutations presented with panhypopituitarism and a sellar mass. She was initially diagnosed with pituitary apoplexy and treated nonoperatively. The mass self-resolved. The mass recurred 2 years later, and she underwent endoscopic endonasal biopsy demonstrating an undifferentiated carcinoma of the sella with MSH2 and MSH6 loss. The tumor was negative for pituitary markers and weakly positive for p63. The patient further developed lung and bone metastases and was treated with radiation and chemotherapy. CONCLUSIONS: This is the first report of an undifferentiated carcinoma of the sella. Our patient harbored a diagnosis of LS and demonstrated local tumor recurrence and aggressive systemic progression. Patients with LS should undergo close follow-up and active surveillance to detect and treat these aggressive lesions in a timely manner.


Asunto(s)
Carcinoma/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Hipofisarias/complicaciones , Neoplasias Óseas/secundario , Carcinoma/patología , Carcinoma/cirugía , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Terapia Combinada , Proteínas de Unión al ADN/genética , Femenino , Humanos , Biopsia Guiada por Imagen , Neoplasias Pulmonares/secundario , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Recurrencia Local de Neoplasia , Procedimientos Neuroquirúrgicos/métodos , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/cirugía , Tomografía Computarizada por Rayos X
7.
Pathologe ; 40(6): 584-591, 2019 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-31372733

RESUMEN

BACKGROUND: Hereditary nonpolyposis colorectal cancer (Lynch/HNPCC syndrome) is based on a germline mutation inducing increased occurrence of colorectal cancer and extracolonic carcinomas in young age. The German HNPCC consortium aims to increase awareness for detection of hereditary colon cancer among patients and physicians. OBJECTIVES: Reliable detection of HNPCC patients is based on a thorough documentation of patients' medical history and on further diagnostics delivered by human genetics and surgical pathology. This manuscript presents a standardized diagnostic concept. METHODS: Relevant literature is reviewed and discussed and diagnostic parameters are outlined. In addition, operating figures of the German HNPCC consortium are presented. RESULTS: The German HNPCC consortium is based on an efficient cooperation between clinical physicians, human geneticists, and surgical pathologists. After a funding period from the Deutsche Krebshilfe, HNPCC diagnostics and preventive medical examinations were transferred into standard care in Germany. In total, 5770 families (8873 patients) were included in HNPCC diagnostics. To date, in 1296 families, mutations of the MLH1-, MSH2-, MSH6-, PMS2-, or EPCAM-gene have been detected. Furthermore, 612 pathogenic variants and 325 variants of unknown significance were found. CONCLUSIONS: Reliable detection of HNPCC patients is based on a standardized diagnostic concept, which has been established within the German HNPCC consortium.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias del Colon/complicaciones , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Alemania , Humanos , Mutación
8.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(7): 684-688, 2019 Jul 25.
Artículo en Chino | MEDLINE | ID: mdl-31302970

RESUMEN

Lynch syndrome (LS), which is the most common hereditary colorectal cancer, accounts for about 3% of all colorectal cancers. However, due to its various clinical manifestations, it is difficult to be diagnosed. The diagnosis of LS requires comprehensive application of various screening criteria (such as the Amsterdam criteria, Bethesda criteria), predictive models, risk factors, immunohistochemistry test of mismatch repair (MMR) protein, microsatellite instability (MSI) detection, MLH1 methylation detection, BRAF gene mutation detection, germline gene mutation detection, and so on. LS can be diagnosed only after the identification of pathogenic germline mutation of MMR gene. The first-degree and second-degree relatives of LS patients are recommended to be tested for the identified mutant gene. For LS patients and gene mutation carriers, LS associated cancer can be detected early or even prevented by monitoring and preventive surgery. Reproductive techniques can be used to prevent this disease from being passed down to the next generation.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Tamizaje Masivo/métodos , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Inestabilidad de Microsatélites , Pronóstico , Medición de Riesgo
9.
J Med Case Rep ; 13(1): 216, 2019 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-31307558

RESUMEN

BACKGROUND: Lynch syndrome, or hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic syndrome that predisposes individuals to multiple cancer types. The known cancers associated with Lynch syndrome include colorectal and endometrial cancers as well as cancers of the stomach, ovary, urinary tract, hepatobiliary tract, pancreas, small bowel, and brain. There are no searchable cases of malignant phyllodes of the breast associated with Lynch syndrome. CASE PRESENTATION: Our patient was a 43-year-old Caucasian woman who felt a lump in her left breast and was found to have a spindle cell neoplasm. Definitive surgery revealed a malignant phyllodes tumor. On the basis of her cancer diagnosis and family history of multiple cancers, a Myriad myRisk Hereditary Cancer® test panel of 25 genes was performed. This testing revealed that she had a heterozygous MSH6 mutation as part of the Lynch syndrome panel. Due to positive margins, the patient received adjuvant chemotherapy with doxorubicin and ifosfamide. She also had a subsequent total abdominal hysterectomy and a bilateral salpingo-oophorectomy for risk reduction. She remains in a high-risk surveillance program. Her family members have been tested, which revealed that her two brothers and daughter also carry the genetic mutation. CONCLUSIONS: This case highlights the importance of genetic testing with rare malignancies because the full scope of phenotypic sequelae for known hereditary syndromes has not been mapped.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Predisposición Genética a la Enfermedad , Tumor Filoide/genética , Adulto , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Proteínas de Unión al ADN , Femenino , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Mastectomía , Tumor Filoide/diagnóstico por imagen , Tumor Filoide/patología , Tumor Filoide/terapia , Procedimientos Quirúrgicos Profilácticos , Ultrasonografía
10.
Int J Clin Oncol ; 24(9): 999-1011, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31273487

RESUMEN

Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSß, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/fisiología , Neoplasias Encefálicas/genética , Niño , Reparación de la Incompatibilidad de ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Neoplasias Endometriales/genética , Molécula de Adhesión Celular Epitelial/genética , Femenino , Asesoramiento Genético , Pruebas Genéticas , Humanos , Inestabilidad de Microsatélites , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutación
11.
Urology ; 134: 24-31, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31302137

RESUMEN

Lynch Syndrome (LS) entails a defective DNA mismatch repair system, which is the postreplicative proofreading and editing system, ensuring our genome's integrity. LS predisposes to several cancers, most commonly colorectal and endometrial cancers. LS occurs in approximately 1 in 250-1000 people. LS is associated with urological malignancies with upper tract urothelial carcinoma the most common, although still clinically underestimated. Other urologic malignancies possibly associated with LS include bladder, prostate, testis, and renal cell carcinoma. Ascertaining their true prevalence in LS is mandatory for their and their relatives' diagnosis and treatment. Awareness regarding identifying patients at risk for LS through assessment of personal and familial oncologic history is critical among urologists.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Urogenitales , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/terapia , Reparación de la Incompatibilidad de ADN/genética , Humanos , Manejo de Atención al Paciente , Medición de Riesgo , Neoplasias Urogenitales/genética , Neoplasias Urogenitales/patología , Neoplasias Urogenitales/terapia
12.
Anticancer Res ; 39(6): 3131-3136, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31177158

RESUMEN

BACKGROUND/AIM: Although genoproteomic and clinicopathological knowledge on Lynch syndrome (LS) and familial adenomatous polyposis (FAP) has notably increased during the past two decades and even though surgery represents the mainstay of treatment for both conditions, as of 2019, the surgical choice in terms of timing and procedure still appears controversial in the absence of definitive guidelines. MATERIALS AND METHODS: Data were retrospectively analyzed of patients with colorectal cancer (CRC) surgically treated at our Institution between 1st January 2003 and 31st December 2018. Particular attention was given to patients with LS and FAP ≤45 years of age (young-onset CRC); for this category of patients, the surgical procedures performed were compared in terms of benefits and disadvantages. RESULTS: A total of 1,878 primary CRCs were submitted to major surgery; young-onset malignancies accounted for 3.8% of all CRCs. Thirteen young-onset inherited CRCs were surgically removed from 11 patients with LS and two with FAP. Segmental colectomy and restorative proctocolectomy were the procedures most frequently performed in young patients with LS and FAP, respectively. CONCLUSION: In the light of our retrospective results, we highlight the need for randomized controlled trials comparing the surgical options for LS- and FAP-related CRC developing in young patients. Defining the advantages and risks of each surgical option is of the utmost importance in order to improve prognosis of such patients and establish unanimous recommendations.


Asunto(s)
Poliposis Adenomatosa del Colon/cirugía , Colectomía , Neoplasias Colorrectales Hereditarias sin Poliposis/cirugía , Proctocolectomía Restauradora , Procedimientos Quirúrgicos Profilácticos , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/mortalidad , Poliposis Adenomatosa del Colon/patología , Adolescente , Adulto , Edad de Inicio , Colectomía/efectos adversos , Colectomía/mortalidad , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/mortalidad , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Proctocolectomía Restauradora/efectos adversos , Proctocolectomía Restauradora/mortalidad , Procedimientos Quirúrgicos Profilácticos/efectos adversos , Procedimientos Quirúrgicos Profilácticos/mortalidad , Estudios Retrospectivos , Factores de Riesgo , Roma , Factores de Tiempo , Resultado del Tratamiento
13.
Trials ; 20(1): 373, 2019 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-31221211

RESUMEN

BACKGROUND: Lynch syndrome (LS) is an inherited, cancer predisposition syndrome associated with an increased risk of colorectal, endometrial and other cancer types. Identifying individuals with LS allows access to cancer risk management strategies proven to reduce cancer incidence and improve survival. However, LS is underdiagnosed and genetic referral rates are poor. Improving LS referral is complex, and requires multisystem behaviour change. Although barriers have been identified, evidence-based strategies to facilitate behaviour change are lacking. The aim of this study is to compare the effectiveness of a theory-based implementation approach against a non-theory based approach for improving detection of LS amongst Australian patients with colorectal cancer (CRC). METHODS: A two-arm parallel cluster randomised trial design will be used to compare two identical, structured implementation approaches, distinguished only by the use of theory to identify barriers and design targeted intervention strategies, to improve LS referral practices in eight large Australian hospital networks. Each hospital network will be randomly allocated to a trial arm, with stratification by state. A trained healthcare professional will lead the following phases at each site: (1) undertake baseline clinical practice audits, (2) form multidisciplinary Implementation Teams, (3) identify target behaviours for practice change, (4) identify barriers to change, (5) generate intervention strategies, (6) support staff to implement interventions and (7) evaluate the effectiveness of the intervention using post-implementation clinical data. The theoretical and non-theoretical components of each trial arm will be distinguished in phases 4-5. Study outcomes include a LS referral process map for each hospital network, with evaluation of the proportion of patients with risk-appropriate completion of the LS referral pathway within 2 months of CRC resection pre and post implementation. DISCUSSION: This trial will determine the more effective approach for improving the detection of LS amongst patients with CRC, whilst also advancing understanding of the impact of theory-based implementation approaches in complex health systems and the feasibility of training healthcare professionals to use them. Insights gained will guide the development of future interventions to improve LS identification on a larger scale and across different contexts, as well as efforts to address the gap between evidence and practice in the rapidly evolving field of genomic research. TRIAL REGISTRATION: ANZCTR, ACTRN12618001072202 . Registered on 27 June 2018.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Derivación y Consulta , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Humanos
14.
BMC Med Genet ; 20(1): 67, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-31046708

RESUMEN

BACKGROUND: Lynch syndrome, is an autosomal dominantly inherited disease that predisposes individuals to a high risk of colorectal cancers, and some mismatch-repair genes have been identified as causative genes. The purpose of this study was to investigate the genomic rearrangement of the gene in a family with Lynch syndrome followed for more than 45 years. CASE PRESENTATION: The family with Lynch syndrome is family N, who received colorectal cancer treatment for 45 years. The proband of family N had multiple colorectal and uterine cancers. Because the proband met the diagnostic Amsterdam criteria and was Microsatellite instability (MSI) - positive, we performed genetic testing several times. However, germline mutations in MLH1 and MSH2 genes were not found by long-distance PCR or RT-PCR/direct sequencing analysis within the 45-year follow-up. MLPA analysis showed that the genomes of the proband and proband's daughter contained a deletion from exon 4 through exon 19 in the MLH1 gene. Her son's son and her daughter's son were found to be carriers of the mutation. CONCLUSIONS: For carriers of mismatch-repair gene mutation among families with Lynch syndrome, the onset risk of associated cancers such as uterine cancer is particularly high, including colorectal cancer. The diagnosis of carriers among non-onset relatives is important for disease surveillance.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Homólogo 1 de la Proteína MutL/genética , Femenino , Humanos , Masculino , Linaje
15.
Cas Lek Cesk ; 158(1): 15-21, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31046387

RESUMEN

About 5-10 % of cancer diseases may be caused by genetic predisposition, in ovarian cancer it could be almost 20 % of cases. The cause is mostly a pathogenic germline mutation in tumor suppressor genes, DNA repair genes, less frequently in oncogenes. So far, we know more than 200 hereditary cancer syndromes. The most frequently tested are hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer (Lynch syndrome), quite frequent are also hereditary gastrointestinal polyposes. Genetic counseling and testing are routinely available for patients or their relatives. Testing methods are changing; nowadays we use next generation sequencing methods (massive parallel sequencing) with testing of panels of high-risk genes. If the mutation is discovered, we may offer the testing to relatives. Genetic testing is indicated by medical geneticist after the genetic counseling session. High-risk individuals should be followed oncology clinics or by other specialists.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Síndromes Neoplásicos Hereditarios , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/prevención & control , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/prevención & control
16.
Minerva Med ; 110(4): 301-319, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31081309

RESUMEN

The identification of a mutation in ovarian cancer (OC) predisposition genes plays a crucial role in the management of cancer prevention, diagnosis, and treatment. In healthy carriers, the detection of a specific mutation might justify more intensive and personalised surveillance programmes, chemopreventive measures, and prophylactic surgeries. Moreover, the identification of a mutation in affected OC patients might provide fundamental knowledge of the tumour pathogenesis, thus guiding treatment choices. This is a comprehensive review of the molecular pathways involved in the pathogenesis of hereditary ovarian cancers, the clinical-pathological features of these tumours, and the potential implications for their prevention and clinical management.


Asunto(s)
Neoplasias Ováricas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Vigilancia de la Población , Procedimientos Quirúrgicos Profilácticos
17.
PLoS One ; 14(5): e0216472, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31095598

RESUMEN

Comparative studies of colorectal cancer (CRC) according to the age of onset have found differences between early-onset CRC (EOCRC) and late-onset CRC (LOCRC). Using this as a starting point, we wished to determine whether intermediate-onset CRC (IOCRC) might also be considered as an independent group within CRC. We performed a retrospective comparative study of the clinicopathological and familial features, as well as of the symptoms and their duration, of a total of 272 subjects diagnosed with CRC classified into three groups according to the age-of-onset (98 EOCRC, 83 IOCRC and 91 LOCRC). The results show that from a clinicopathological point of view, IOCRC shared certain features with EOCRC (gender, prognosis), and with LOCRC (multiple primary CRCs), whereas it also had characteristics that were specific for IOCRC (mean number of associated polyps). A gradual progression was observed from EOCRC to LOCRC from a greater family aggregation to sporadic cases, in parallel with a change of Lynch Syndrome cases to the sporadic microsatellite instability pathway, with the IOCRC being a boundary group that is more related to EOCRC. With respect to symptoms, duration and correlation with stages, IOCRC appeared more similar to EOCRC. Clinically, IOCRC behaves as a transitional group between EOCRC and LOCRC, with features in common with both groups, but also with IOCRC-specific features. Excluding cases with familial cancer history, the awareness for EOCRC diagnosis should be extended to IOCRC.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales Hereditarias sin Poliposis , Inestabilidad de Microsatélites , Adulto , Edad de Inicio , Anciano , Neoplasias del Colon/genética , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/mortalidad , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia
18.
J Hum Genet ; 64(8): 729-740, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31089268

RESUMEN

Polymerase proofreading-associated polyposis (PPAP) is a disease caused by germline variations in the POLE and POLD1 genes that encode catalytic subunits of DNA polymerases. Studies of cancer genomes have identified somatic mutations in these genes, suggesting the importance of polymerase proofreading of DNA replication in suppressing tumorigenesis. Here, we identified a germline frameshift variation in the POLE gene (c.4191_4192delCT, p.Tyr1398*) in a case with multiple adenomatous polyps and three synchronous colon cancers. Interestingly, one of the colon cancers showed microsatellite instability-high (MSI-H) and another microsatellite stable. Immunohistochemical staining revealed that the MSI-H tumor cells lost the expression of MLH1 protein. Whole genome sequencing of the MSI-H tumor did not find pathogenic somatic mutations in mismatch repair genes but found frameshift mutations in the TET genes that catalyze 5-methylcytosine hydroxylation. Bisulfite sequencing of the tumor corroborated an increase in the number of hypermethylated regions including the MLH1 promoter. These data indicate that PPAP patients might develop MSI-positive tumors through epigenetic silencing of MLH1. These findings will contribute to comprehensive understanding of the molecular basis of tumors that involve deficiency of proofreading activity of DNA polymerases.


Asunto(s)
Neoplasias del Colon/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Metilación de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Inestabilidad de Microsatélites , Anciano , Alelos , Neoplasias del Colon/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Análisis Mutacional de ADN , ADN Polimerasa II/genética , ADN Polimerasa II/metabolismo , Femenino , Mutación del Sistema de Lectura , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genotipo , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Masculino , Estadificación de Neoplasias , Linaje , Fenotipo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas Represoras/genética , Secuenciación Completa del Genoma
19.
Fam Cancer ; 18(3): 343-348, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31114938

RESUMEN

A high colorectal cancer (CRC) incidence is observed in Tunisia, with a relatively high proportion of patients developing CRC before the age of 40. While this suggests a genetic susceptibility, only a few Tunisian Lynch Syndrome families have been described. In this study we aimed to identify the underlying genetic cause in 32 patients with early onset CRC and/or a positive family history. Of twenty-four patients' tumor or biopsies could be analyzed with immunohistochemical staining to detect loss of expression of one of the MMR proteins. Ten tumors showed loss of expression, of which one tumor was from a patient where a germline pathogenic MSH2 variant was detected previously with Sanger sequencing. Next generation sequencing of the MMR, POLE and POLD1 genes was performed in leukocyte and tumor DNA of the remaining nine patients, as well as in two patients with MMR-proficient tumors, but with severe family history. In six of 11 patients a germline variant was detected in MLH1 (n = 5) or MSH2 (n = 1). Two of six patients were from the same family and both were found to carry a novel in-frame MLH1 deletion, predicted to affect MLH1 function. All MLH1 variant carriers had loss of heterozygosity with retention of the variant in the tumors, while a somatic pathogenic variant was detected in the patient with the germline MSH2 variant.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , Anciano , Neoplasias Colorrectales/genética , ADN Polimerasa II/genética , ADN Polimerasa III/genética , Salud de la Familia , Femenino , Eliminación de Gen , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Linaje , Proteínas de Unión a Poli-ADP-Ribosa/genética , Túnez , Adulto Joven
20.
Fam Cancer ; 18(3): 331-342, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30989425

RESUMEN

Many colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MSI and absence of MLH1 methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified five cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Mutación de Línea Germinal , Adulto , Anciano , Anciano de 80 o más Años , Metilación de ADN , Proteínas de Unión al ADN/genética , Femenino , Heterocigoto , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Análisis de Secuencia de ADN
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