RESUMO
BACKGROUND: Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR. METHODS: This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance. RESULTS: We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS. CONCLUSION: Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Reparo de Erro de Pareamento de DNA , Humanos , Reino Unido/epidemiologia , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Consenso , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Instabilidade de Microssatélites , Testes Genéticos , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia , Predisposição Genética para Doença , Neoplasias EncefálicasRESUMO
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
Assuntos
Proteínas de Ligação a DNA , Síndromes Neoplásicas Hereditárias , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Estudos Transversais , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/epidemiologia , Reparo de Erro de Pareamento de DNA , Estudos Longitudinais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Incidência , Proteína 2 Homóloga a MutS/genética , Proteína 1 Homóloga a MutL/genética , Adulto , Adulto Jovem , MutaçãoRESUMO
BACKGROUND: Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. METHODS: A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). RESULTS: One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. CONCLUSION: These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.
Assuntos
Adenocarcinoma , Polipose Adenomatosa do Colo , DNA Glicosilases , Neoplasias Gástricas , Humanos , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/terapia , Polipose Adenomatosa do Colo/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adenocarcinoma/diagnóstico , DNA Glicosilases/genética , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndromes Neoplásicas Hereditárias/diagnóstico , Europa (Continente) , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/terapia , PóliposRESUMO
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
Assuntos
Neoplasias Colorretais , Síndrome do Hamartoma Múltiplo , Hamartoma , Polipose Intestinal , Síndromes Neoplásicas Hereditárias , Síndrome de Peutz-Jeghers , Telangiectasia Hemorrágica Hereditária , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Hemorragia Gastrointestinal , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/congênito , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Pólipos Intestinais , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndrome de Peutz-Jeghers/complicações , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/genéticaRESUMO
BACKGROUND: Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival. METHODS: In order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus. RESULTS: The working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia. CONCLUSIONS: This position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.
Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Consenso , Reparo de Erro de Pareamento de DNA/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapiaRESUMO
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
Assuntos
Neoplasias Colorretais , Síndrome do Hamartoma Múltiplo , Hamartoma , Polipose Intestinal , Síndromes Neoplásicas Hereditárias , Síndrome de Peutz-Jeghers , Telangiectasia Hemorrágica Hereditária , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Hemorragia Gastrointestinal/complicações , Hamartoma/complicações , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/congênito , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Pólipos Intestinais/complicações , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndrome de Peutz-Jeghers/complicações , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/genética , Telangiectasia Hemorrágica Hereditária/complicaçõesRESUMO
PURPOSE OF REVIEW: To provide an overview of diagnosis, genetic abnormalities, clinical signs and treatment options for the major heritable renal cell carcinoma (RCC) syndromes. RECENT FINDINGS: RCC in major hereditary syndromes are disorders which are typically autosomal dominant. They predispose patients to early onset of RCC and may exhibit other extrarenal manifestations. Early recognition of these diseases allows correct screening at appropriate ages as well as early detection of RCC. Moreover, expedient identification may optimize the management of extra renal manifestations as well as allow for genetic testing and screening of at-risk relatives. SUMMARY: The risk of RCC in these major heritable syndromes is higher than sporadic disease. They occur at earlier age groups and can be multifocal or bilateral. Tumours are observed until at least 3âcm before any intervention, while nephron sparing surgery is widely considered as the treatment of choice except for hereditary leiomyomatosis with renal cell cancer, of which radical nephrectomy is treatment of choice. Intervention should be timeous as there is a highly reported incidence of early metastasis. Molecular therapies have been used in the setting of patients with metastasis, some of which show favourable outcomes.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Leiomiomatose , Síndromes Neoplásicas Hereditárias , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/terapia , Leiomiomatose/genética , Leiomiomatose/patologia , Leiomiomatose/terapia , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Nefrectomia , SíndromeRESUMO
The potential for preventive medicine to lead to more equitable health outcomes exists with the inclusion of genetic testing in medicine. Because of the medical implications of genetic testing for hereditary cancer syndromes and the financial cost attached to recommended management, ensuring equitable access to cancer screening and prevention must be made a priority. For patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome, the benefits of early detection and prevention are clear, significant, and create the opportunity to provide more equitable, personalized, preventive healthcare. Thus, for genetics providers who offer testing access for their patients, it is important to reflect on the ethical responsibility of advocating for access to appropriate management. Cancer genetic counselors can advocate for health equity by providing thorough pre-test genetic counseling, collaborating with other disciplines to coordinate care, lobbying state, and national representatives to pass legislation promoting health equity, and developing a management clinic that helps to ensure follow-up. Equitable access to and benefit from hereditary cancer risk management must be achieved in the pursuit of personalized preventive medicine.
Assuntos
Síndrome Hereditária de Câncer de Mama e Ovário , Síndromes Neoplásicas Hereditárias , Feminino , Aconselhamento Genético , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Medicina de PrecisãoRESUMO
Gynecologic cancers are more often caused by genetic factors than other cancers. Genetic testing has become a promising avenue for the prevention, prognosis, and treatment of cancers. This review describes molecular features of gynecologic tumors linked to hereditary syndromes, gives an overview of the current state of clinical management, and clarifies the role of gynecology in the treatment of hereditary tumors. Typical hereditary gynecologic tumors include hereditary breast and ovarian cancer, Lynch syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. Multigene panel testing, which analyzes a preselected subset of genes for genetic variants, has recently become the first-choice test because it can provide more accurate risk assessment than a single test. Furthermore, comprehensive genomic cancer profiling enables personalized cancer treatment and aids in germline findings.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias dos Genitais Femininos , Ginecologia , Síndromes Neoplásicas Hereditárias , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Feminino , Predisposição Genética para Doença , Testes Genéticos , Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/terapia , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapiaRESUMO
Hereditary pancreatic cancers are caused by several inherited genes. Familial pancreatic cancer is defined as pancreatic cancer arising in a patient with at least two first-degree relatives with pancreatic cancer in the absence of an identified genetic cause. Hereditary pancreatic cancer syndromes and familial pancreatic cancers account for about 10% of pancreatic cancer cases. Germline mutations in BRCA1, BRCA2, ATM, PALB2, CDKN2A, STK11, and TP53 and mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) are among the well-known inherited susceptibility genes. Currently available targeted medications include poly (ADP-ribose) polymerase inhibitors (PARP) for cases with mutant BRCA and immune checkpoint inhibitors for cases with mismatch repair deficiency. Loss of heterozygosity of hereditary pancreatic cancer susceptibility genes such as BRCA1/2 plays a key role in carcinogenesis and sensitivity to PARP inhibitors. Signature 3 identified by whole genome sequencing is also associated with homologous recombination deficiency and sensitivity to targeted therapies. In this review, we summarize molecular features and treatments of hereditary pancreatic cancer syndromes and surveillance procedures for unaffected high-risk cases. We also review transgenic murine models to gain a better understanding of carcinogenesis in hereditary pancreatic cancer.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma/terapia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/terapia , Neoplasias Pancreáticas/terapia , Carcinoma/genética , Carcinoma/patologia , Gerenciamento Clínico , Humanos , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologiaRESUMO
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline amorphic allele of the FH gene, which encodes the TCA cycle enzyme, fumarate hydratase (FH). HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss-of-heterozygocity at the FH locus that cause a complete loss of FH enzymatic function is always detected in these tumor tissues. Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells. These treatment strategies include ferroptosis induction, oxidative stress promotion, and metabolic alteration. As the fundamental biology of HLRCC continues to be uncovered, these treatment strategies continue to be refined and may one day lead to a strategy to prevent disease onset among HLRCC patients. With a more complete picture of HLRCC biology, the safe translation of experimental treatment strategies into clinical practice is achievable in the foreseeable future.
Assuntos
Leiomiomatose/etiologia , Síndromes Neoplásicas Hereditárias/etiologia , Neoplasias Cutâneas/etiologia , Neoplasias Uterinas/etiologia , Biomarcadores Tumorais , Gerenciamento Clínico , Suscetibilidade a Doenças , Fumarato Hidratase/genética , Genes Supressores de Tumor , Predisposição Genética para Doença , Testes Genéticos , Genômica/métodos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leiomiomatose/diagnóstico , Leiomiomatose/metabolismo , Leiomiomatose/terapia , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/terapia , Proteoma , Transdução de Sinais , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/terapia , Pesquisa Translacional Biomédica , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/terapiaRESUMO
PURPOSE OF REVIEW: Polyposis syndromes are rare but significant entities that often present during childhood and adolescence. Polyposis syndromes should remain high on the differential diagnoses for any child presenting with rectal bleeding, protein-losing enteropathy or intussusception in the setting of multiple polyps in the gastrointestinal tract. There are three primary paediatric polyposis syndromes: Juvenile polyposis syndrome (JPS), Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS). This review will cover recent guidelines for these conditions and advances in genetic testing. RECENT FINDINGS: The first set of paediatric guidelines were released in 2019 by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for FAP, JPS and PJS. Even with advances in genetic testing, a significant proportion of patients with polyposis syndromes have no identifiable genetic mutations. Recent research has shown that polyps behave differently in patients with and without disease-causing variants, emphasizing the role of genetic testing in the diagnosis and management of polyposis syndromes. SUMMARY: Polyposis syndromes in the paediatric population are growing due to increased recognition and advances in genetic testing. A timely diagnosis and surveillance of a paediatric polyposis syndrome are pivotal for the management of disease burden and early identification of cancers within the gastrointestinal tract and beyond. Paediatricians, paediatric gastroenterologists, paediatric oncologists and paediatric surgeons should be familiar with the presentation and comorbidities of polyposis syndromes in children and adolescents. Further research into genotype-phenotype correlations is needed to tailor the care for paediatric patients with polyposis syndromes.
Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Síndrome de Peutz-Jeghers , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , Adolescente , Criança , Efeitos Psicossociais da Doença , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapiaRESUMO
OPINION STATEMENT: Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Terapia de Alvo Molecular , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia , Medicina de Precisão , Biomarcadores Tumorais , Neoplasias Encefálicas/etiologia , Tomada de Decisão Clínica , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Humanos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Síndromes Neoplásicas Hereditárias/etiologia , Síndromes Neoplásicas Hereditárias/metabolismo , Medicina de Precisão/métodos , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
Hereditary tumor syndromes are characterized by a familial occurrence of tumors/cancer. A hereditary tumor syndrome should be suspected if a familial occurrence of cancer is seen and/or persons at younger age are affected. Some of the currently known tumor syndromes are associated with specific skin symptoms that can aid the physician in establishing the correct diagnosis. Examples are fibrofolliculoma in Birt-Hogg-Dubé syndrome, epidermal cysts, sebaceous cysts, neurofibroma in Gardner syndrome and sebaceous neoplasms or keratoacanthoma in Muir-Torre syndrome. If a genetic tumor syndrome is suspected, genetic testing and counselling should be performed in the index patient and is also recommended for family members. Affected patients should be offered regular clinical surveillance by the appropriate medical disciplines. Since curative therapy does not exist so far, preventive screening is of great importance.
Assuntos
Síndrome de Birt-Hogg-Dubé , Síndromes Neoplásicas Hereditárias , Neoplasias das Glândulas Sebáceas , Dermatopatias , Neoplasias Cutâneas , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapiaRESUMO
Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Vigilância da População , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/prevenção & controle , Polipose Adenomatosa do Colo/terapia , Colonoscopia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/terapia , DNA Glicosilases/genética , Saúde da Família , Humanos , Polipose Intestinal/congênito , Polipose Intestinal/genética , Polipose Intestinal/terapia , Irlanda , Estilo de Vida , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Encaminhamento e Consulta/normas , Fatores de Risco , Reino UnidoRESUMO
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.
Assuntos
Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais , Feminino , Estudos de Associação Genética , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Síndromes Neoplásicas Hereditárias/terapia , Penetrância , Neoplasias PancreáticasRESUMO
LAG-3 is an immunosuppressive checkpoint molecule expressed on T cells. One of its ligands, GAL-3, can promote the progression of malignancy and has been identified on tumor cells. Both LAG-3 and GAL-3 are the targets of emerging immunotherapies, but have not been well-studied in endometrial carcinomas. LAG-3, CD3, and GAL-3 immunohistochemistry was performed on 75 endometrial cancers (25 nonmethylated mismatch repair-deficient, 25 MLH1-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact). LAG-3 and CD3 lymphocytes were averaged per high-power field. Tumoral GAL-3 expression was semiquantitatively scored. Tumor-infiltrating lymphocyte expression of LAG-3 and CD3 were positively correlated (Spearman ρ=0.521, P<0.001) and greater in mismatch repair-deficient compared with mismatch repair-intact tumors (LAG-3: P<0.001; CD3: P<0.001). The majority (64%) of endometrial carcinomas demonstrated ≥1% tumoral GAL-3 expression, with higher rates in mismatch repair-deficient versus intact tumors at the ≥1% (80% vs. 32%, P<0.001) and the ≥5% thresholds (52% vs. 16%, P=0.003). At the ≥5% threshold, nonmethylated mismatch repair-deficient cancers were more likely than intact tumors carcinomas to express GAL-3 (60% vs. 4/25 16%, P=0.003). LAG-3 lymphocytes were positively correlated with GAL-3 expression in nonmethylated mismatch repair-deficient endometrial carcinomas only (Spearman ρ=0.461, P=0.020). LAG-3 tumor-associated lymphocytes and GAL-3 neoplastic cells are common in endometrial carcinomas, particularly in nonmethylated mismatch repair-deficient cancers. This supports a role for immunotherapies targeting LAG-3 and/or GAL-3 in a subset of endometrial carcinomas, potentially in concert with other checkpoint inhibitors.
Assuntos
Antígenos CD/metabolismo , Proteínas Sanguíneas/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias Colorretais/terapia , Neoplasias do Endométrio/terapia , Galectinas/metabolismo , Imunoterapia , Síndromes Neoplásicas Hereditárias/terapia , Antígenos CD/genética , Proteínas Sanguíneas/genética , Neoplasias Encefálicas/patologia , Complexo CD3/genética , Complexo CD3/metabolismo , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/patologia , Feminino , Galectinas/genética , Humanos , Ligantes , Linfócitos do Interstício Tumoral/patologia , Síndromes Neoplásicas Hereditárias/patologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Multiple primary tumors are defined by the presence of two or more independent primary tumors in the same or different organs of an individual patient. However, the underlying genetic cause for the development of multiple primary tumors is largely unknown. In the study, we report a rare case with four synchronous distinct histological cancer types in a 26 years old Chinese female. In the patient, whole-exome sequencing identified a homozygous germline insertion mutation in WWOX which encodes the DNA repair-related enzyme, WW domain containing oxidoreductase. The mutation was found in a heterozygous state in her parents and brother without any cancer phenotype thus far. Surprisingly, we found multiple novel aberrant WWOX transcripts in the patient's normal colon tissue. The patient's colon metastasis from clear cell adenocarcinoma of the ovary showed a nonhypermutated profile enriched for C-T transition, and harbored somatic pathogenic mutations of HRAS, BRCA2, SMAD4, CHEK2, and AKT1 genes. To our knowledge, this is the first study reporting WWOX gene aberrations in a young patient with the early occurrence of multiple primary tumors. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Mutação em Linhagem Germinativa , Neoplasias Primárias Múltiplas/genética , Síndromes Neoplásicas Hereditárias/genética , RNA Mensageiro/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Metástase Neoplásica , Neoplasias Primárias Múltiplas/enzimologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/terapia , FenótipoRESUMO
OPINION STATEMENT: Oncologists should be able to discern the salient clinical features of the most common germline mutations that give rise to neuroendocrine tumors. Astute recognition of an index patient affected by a hereditary syndrome can lead to a "tip-of-the-iceberg" phenomenon whereby their entire kindred can then be proactively monitored and managed potentially with substantial reduction of morbidity and mortality. Through careful history-taking, as well as thoughtful assimilation of findings from the physical exam, biochemical laboratories, scans, and pathology reports, the clinician can spot phenotypic clues that distinguish these familial patterns from sporadic cases of tumorigenesis.
Assuntos
Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/etiologia , Síndromes Neoplásicas Hereditárias/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/etiologia , Tumores Neuroendócrinos/terapia , Fatores Etários , Biomarcadores Tumorais , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Diagnóstico Diferencial , Gerenciamento Clínico , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Fenótipo , Resultado do TratamentoRESUMO
Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas (CLM), uterine leiomyomas, and the increased risk of renal cell carcinoma. Piloleiomyomas develop from the arrectorpili muscle and are usually painful. For 22% of the affected patients, the pain is reported to impair their life quality. Since there are few case reports about cryotherapy for cutaneous leiomyomas in the literature, we have decided to present three patients who had painful cutaneous leiomyomas treated with cryotherapy.