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BACKGROUND: The precise diagnosis and medical management of patients with suspected familial adenomatous polyposis should be based on genetic testing, which may not always be available. Therefore, establishing a new model for predicting the likelihood of a germline pathogenic variant (GPV) of APC based on its clinical manifestations could prove to be useful in clinical practice. METHODS: The presence of GPVs of APC gene was investigated in 162 patients with adenomatous polyposis (≥ 10 polyps) using a multigene panel or single-gene testing. To generate a predictive model for GPV of the APC gene, a logistic regression analysis was performed using the clinicopathological variables available at the time of the diagnosis of adenomatous polyposis. RESULTS: Ninety (55.6%) patients had GPV of the APC gene. According to a multivariate logistic regression analysis, age < 40 years, polyps ≥ 100, fundic gland polyposis, and a family history of colorectal polyposis were found to be independent predictors of the GPV of APC and were used to establish a formula for predicting the GPV of APC using the four predictors. The prediction model had an area under the curve of 0.91 (0.86-0.96) according to a receiver operating characteristic analysis. CONCLUSION: The model for predicting the GPV of APC will help patients with adenomatous polyposis and physicians make decisions about genetic testing.
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AIM: Although BRCA1/2 is most frequently associated with hereditary breast and ovarian cancer (HBOC), many other related genes have been implicated. Therefore, we investigated the prevalence of non-BRCA1/2 genes associated with hereditary cancer predisposition in BRCA1/2-negative patients from the Department of Genetic Medicine and Services with breast and ovarian cancer using a multi-gene panel (MGP) analysis. METHODS: We conducted a retrospective MGP analysis (National Cancer Center Onco-Panel for Familial Cancer; NOP_FC) in BRCA1/2-negative patients with breast, ovarian, and overlapping breast/ovarian cancers who visited our genetic counseling between April 2004 and October 2022. RESULTS: NOP_FC was performed in 128 of the 390 BRCA test-negative cases (117 breast cancer, 9 ovarian cancer, and 2 overlapping breast/ovarian cancer cases). Among the BRCA1/2-negative patients, nine (7.7%) with breast cancer and one (11%) with ovarian cancer had pathogenic variants (PVs) in non-BRCA1/2 genes associated with breast and ovarian cancers, respectively. Five patients had PVs in RAD51D, two in PALB2, one in BARD1, one in ATM, and one in RAD51C. CONCLUSIONS: Additional MGP testing of germline genes associated with hereditary cancer predisposition syndrome in BRCA1/2-negative breast and ovarian cancer patients revealed PVs in non-BRCA1/2 breast cancer- and ovarian cancer-related genes in 7.7% of breast cancer and 11% of ovarian cancer. Therefore, additional testing may provide useful information for subsequent risk-reducing surgery and surveillance in BRCA1/2-negative patients.
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PURPOSE: This retrospective study was performed to investigate the recent trend of occurrence of cancer of the remnant colorectal segment(RCRS)after ileal-pouch anal anastomosis(IPAA)/ileorectal anastomosis(IRA)and to consider the optimal surveillance methods in patients with familial adenomatous polyposis(FAP)undergoing(procto)colectomy. PATIENTS AND METHODS: The subject was a total of patients with FAP undergoing IPAA or IRA between 2005 and 2022. Clinicopathological data were extracted from medical charts and analyzed. Cumulative incidence of cancer in the RCRS and overall survival after treatment of such tumors were calculated by the Kaplan-Meier method. RESULTS: There were 45 male and 56 female. IPAA was performed in 49 patients(hand-sewn; n=33, stapled; n=16)and IRA was performed in 52 patients. The median age at initial colorectal surgery was 32 years old(range, 13-66 years old). Median postoperative follow-up was 11 years(range, 1-48 years). Eighty-one patients were confirmed to have pathogenic variant of APC by genetic test. The cumulative incidence of cancer of the RCRS did not differ between patients undergoing IPAA and those undergoing IRA(p= 0.73, 4.1% versus 1.9% at 10 years). The cumulative 5-year overall survival rate after additional surgery for the tumor of RCRS was 82%. CONCLUSION: This study has several limitations due to single institutional retrospective study with small cases and non-standardized postoperative endoscopic surveillance. However, our results seem to show satisfactory oncological outcomes of patients with FAP in terms of the control of cancer of the RCRS under postoperative periodic surveillance, regardless of the type of colorectal resection.
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Polipose Adenomatosa do Colo , Neoplasias , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Íleo/cirurgia , Polipose Adenomatosa do Colo/cirurgia , Anastomose Cirúrgica/efeitos adversosRESUMO
Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.
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BACKGROUND: There has been increasing interest into the role of germline BRCA1/2 pathogenic variants (gBRCA PV) and gATM PV and likely PV (PV and LPV; PV + LPV) in the carcinogenesis and treatment of pancreatic cancer (PC), but the clinical features have not been well described. METHODS: Patients with confirmed gBRCA PV and gATM PV + LPV PC treated at our hospital between April 2016 and December 2021, were retrospectively evaluated for clinical characteristics and outcomes. RESULTS: Twenty-two patients harbored gBRCA PV and three patients harbored gATM PV + LPV. Of the gBRCA PV patients, 81.8 % received platinum-based chemotherapy with favorable treatment outcomes with an objective response rate of 50.0 % (95 % CI: 23.0-77.0), median progression free survival (PFS) of 334 days, and median overall survival (OS) of 926 days from the initiation of first-line chemotherapy. The annual number of patients with gBRCA PV was two patients per year before January 2021 (when BRACAnalysis became available in Japan), and ten patients during the 10 months thereafter. Four patients (20 %) with gBRCA PV developed soft-tissue metastasis with progression. Two patients with gATM PV + LPV received platinum-based chemotherapy and the best response of those patients was partial response and stable disease and their OS from the initiation of first-line chemotherapy was 1192 and 989 days, and PFS was 579 and 140 days, respectively. CONCLUSION: The diagnosis of gBRCA PV-positive PC has increased revealed in recent years. These tumors appear to be sensitive to platinum-based chemotherapy, with long term survival observed in gATM PV + LPV-positive patients.
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Proteína BRCA1 , Neoplasias Pancreáticas , Humanos , Proteína BRCA1/genética , Japão , Estudos Retrospectivos , Proteína BRCA2/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Células Germinativas , Proteínas Mutadas de Ataxia TelangiectasiaRESUMO
Cancer genome profiling (CGP) occasionally identifies pathogenic germline variants (PGV) in cancer susceptibility genes (CSG) as secondary findings. Here, we analyzed the prevalence and clinical characteristics of PGVs based on nationwide real-world data from CGP tests in Japan. We analyzed the genomic information and clinical characteristics of 23,928 patients with solid cancers who underwent either tumor-only (n = 20,189) or paired tumor-normal (n = 3,739) sequencing CGP tests between June 2019 and December 2021 using the comprehensive national database. We assigned clinical significance for all variants and highlighted the prevalence and characteristics of PGVs. Our primary analysis of the tumor-normal sequencing cohort revealed that 152 patients (4.1%) harbored PGVs in 15 CSGs. Among 783 germline variants, 113 were annotated as PGVs, 70 as benign variants, and 600 as variants of uncertain significance. The number of PGVs identified was highest in BRCA1/2, with 56, followed by TP53, with 18. PGVs were the most prevalent in ovarian and peritoneal cancers, including among cancer types common in Asia. In the tumor-only sequencing cohort, of the 5,184 pathogenic somatic variants across 26 CSGs, 784 (15.1%) were extracted according to the European Society for Medical Oncology recommendations for germline-focused tumor analysis. The prevalence of PGVs was similar to that previously reported in Europe and the United States. This is the largest analysis based on real-world tumor-normal sequencing tests in Asia. The more widespread use of the tumor-normal sequencing CGP test could be reasonable for evaluating PGVs. SIGNIFICANCE: We analyzed real-world data from over 23,000 patients in Japan, revealing 4.1% harbored PGVs, particularly in BRCA1/2 and TP53, in CSGs. It highlights the prevalence of PGVs in Asian populations and supports the broader adoption of tumor-normal sequencing CGP tests for PGV evaluation.
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Proteína BRCA1 , Neoplasias , Humanos , Estados Unidos , Proteína BRCA1/genética , Proteína Supressora de Tumor p53/genética , Proteína BRCA2/genética , Neoplasias/diagnóstico , Células GerminativasRESUMO
A 47-year-old woman diagnosed with transverse colon cancer with liver, peritoneal, and lymph node metastases was admitted. Modified FOLFOX6(mFOLFOX6)regimen was given as a first line chemotherapy and was followed by pembrolizumab after 1 cycle of the mFOLFOX6, because microsatellite instability(MSI)test of the tumor showed high-frequency MSI. Because of the transverse colon obstruction after 2 cycles of pembrolizumab, she underwent right hemicolectomy. Histological examination of the resected specimen revealed no residual tumor cells in the primary tumor and reginal lymph nodes. Immunohistochemistry for mismatch repair proteins(IHC-MMR)showed loss of MSH2 and MSH6 expression. Genetic test identified a MSH2 pathogenic variant leading to the diagnosis of Lynch syndrome. The present case shows the importance of MSI test or IHC-MMR before the treatment of metastatic colorectal cancer.
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Colo Transverso , Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/cirurgia , Colo Transverso/cirurgia , Colo Transverso/patologia , Proteína 2 Homóloga a MutS/genética , Reparo de Erro de Pareamento de DNA , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Neoplasias do Colo/complicações , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismoRESUMO
INTRODUCTION: Since May 2019, comprehensive genomic profiling (CGP) has been covered by Japan's health insurance system for patients with solid tumours that have progressed on standard chemotherapy, rare tumours or tumours of unknown primary origin. Although CGP has the potential to identify actionable mutations that can guide the selection of genomically matched therapies for patients with advanced cancer and limited treatment options, less than 10% of patients benefit from CGP testing, which may have a negative impact on patients' mental status. The aim of this study is to investigate the prevalence of psychological distress and associated factors among patients with advanced cancer who are undergoing CGP testing across Japan. METHODS AND ANALYSIS: This multicentre, prospective cohort study will enrol a total of 700 patients with advanced cancer undergoing CGP testing. Participants will be asked to complete questionnaires at three timepoints: at the time of consenting to CGP testing (T1), at the time of receiving the CGP results (T2; 2-3 months after T1) and 4-5 months after T2 (T3). Primary outcome is the prevalence of depression as measured by the Patient Health Questionnaire-9 at the three timepoints. Secondary outcomes are the prevalence of anxiety and Quality of Life Score. Associated factors with psychological distress will also be examined, including knowledge about CGP, attitudes, values and preferences towards CGP, satisfaction with oncologists' communication and patient characteristics as well as medical information including CGP test results and genomically matched therapies if provided. The prevalence of depression and anxiety will be estimated using the unadjusted raw rates observed in the total sample. Longitudinal changes in measures will be explored by calculating differences between the timepoints. Multivariate associations between variables will be examined using multiple or logistic regression analysis depending on the outcomes to adjust for confounders and to identify outcome predictors. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of the National Cancer Center Japan on 5 January 2023 (ID: 2022-228). Study findings will be disseminated through peer-reviewed journals and conference presentations. TRIAL STATUS: The study is currently recruiting participants and the enrolment period will end on 31 March 2025, with an expected follow-up date of 31 March 2026. TRIAL REGISTRATION NUMBER: UMIN000049964.
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Neoplasias , Angústia Psicológica , Humanos , Estudos Prospectivos , Qualidade de Vida , Prevalência , Neoplasias/genética , Neoplasias/terapia , Genômica/métodos , Estudos Multicêntricos como Assunto , Estudos Observacionais como AssuntoRESUMO
Genetic testing of the APC gene by sequencing analysis and MLPA is available across commercial laboratories for the definitive genetic diagnosis of familial adenomatous polyposis (FAP). However, some genetic alterations are difficult to detect using conventional analyses. Here, we report a case of a complex genomic APC-TP63 rearrangement, which was identified in a patient with FAP by a series of genomic analyses, including multigene panel testing, chromosomal analyses, and long-read sequencing. A woman in her thirties was diagnosed with FAP due to multiple polyps in her colon and underwent total colectomy. Subsequent examination revealed fundic gland polyposis. No family history suggesting FAP was noted except for a first-degree relative with desmoid fibromatosis. The conventional APC gene testing was performed by her former doctor, but no pathogenic variant was detected, except for 2 variants of unknown significance. The patient was referred to our hospital for further genetic analysis. After obtaining informed consent in genetic counseling, we conducted a multigene panel analysis. As insertion of a part of the TP63 sequence was detected within exon16 of APC, further analyses, including chromosomal analysis and long-read sequencing, were performed and a complex translocation between chromosomes 3 and 5 containing several breakpoints in TP63 and APC was identified. No phenotype associated with TP63 pathogenic variants, such as split-hand/foot malformation (SHFM) or ectrodactyly, ectodermal dysplasia, or cleft lip/palate syndrome (EEC) was identified in the patient or her relatives. Multimodal genomic analyses should be considered in cases where no pathogenic germline variants are detected by conventional genetic testing despite an evident medical or family history of hereditary cancer syndromes.
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PURPOSE: This single-center, prospective molecular profiling study characterizes genomic alterations and identifies therapeutic targets in advanced pediatric solid tumors. METHODS: As part of the TOP-GEAR (Trial of Onco-Panel for Gene profiling to Estimate both Adverse events and Response by cancer treatment) project at the National Cancer Center (NCC), Japan, we enrolled pediatric patients with a refractory or recurrent disease during August 2016-December 2021 and performed genomic analysis of matched tumors and blood using originally developed cancer gene panels, NCC Oncopanel (ver. 4.0) and NCC Oncopanel Ped (ver. 1.0). RESULTS: Of 142 patients (age, 1-28 years) enrolled, 128 (90%) were evaluable for genomic analysis; 76 (59%) patients harbored at least one reportable somatic or germline alteration. The tumor samples were collected during the initial diagnosis in 65 (51%) patients, after treatment initiation in 11 (9%) patients, and upon either disease progression or relapse in 52 (41%) patients. The leading altered gene was TP53, followed by MYCN, MYC, CDKN2A, and CDK4. The commonly affected molecular processes were transcription, cell-cycle regulation, epigenetic modifiers, and RAS/mitogen-activated protein kinase signaling. Twelve (9%) patients carried pathogenic germline variants in cancer-predisposing genes. Potentially actionable findings were identified in 40 (31%) patients; to date, 13 (10%) patients have received the recommended therapy on the basis of their genomic profiles. Although four patients had access to targeted therapy through clinical trials, the agents were used in nine patients in an off-label setting. CONCLUSION: The implementation of genomic medicine has furthered our understanding of tumor biology and provided new therapeutic strategies. However, the paucity of proposed agents limits the full potential of actionability, emphasizing the significance of facilitating access to targeted cancer therapies.
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Neoplasias , Medicina de Precisão , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Japão , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Genômica , Mutação em Linhagem GerminativaRESUMO
Precision medicine is rapidly changing the diagnostic and treatment spectrum of oncology. In May 2019, comprehensive genomic profiling (CGP) (somatic and/or germline) was approved for reimbursement in Japan. While the promise of novel and targeted therapies has elevated hopes for the benefits of CGP, the lack of relevant genomic findings and/or limited access to relevant therapies remain important themes in this field. These challenges may also negatively influence the psychology of both cancer patients and their family members. However, few studies have reported longitudinal data on quality of life (QOL) with CGP. Here, we report the protocol of a prospective study, Q-CAT (QOL for Cancer genomics and Advanced Therapeutics among patients and their family members), which aims to explore the mental burden on patients and families arising from the implementation of CGP testing by collecting real-world longitudinal data using outcomes obtained with an electronic patient report, known as ePRO. This study has been registered with the Japan Registry of Clinical Trials (jRCT1030200039).
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Neoplasias , Angústia Psicológica , Humanos , Qualidade de Vida , Prevalência , Estudos Prospectivos , Satisfação do Paciente , Neoplasias/genética , Neoplasias/terapia , Neoplasias/epidemiologia , Genômica/métodos , Satisfação PessoalRESUMO
Gastric foveolar-type adenoma (FA) is a rare benign neoplasm occurring either sporadically or in patients with familial adenomatous polyposis (FAP). However, the molecular features of FA and the relationship between sporadic and syndromic lesions remain unclear. In this study, we performed clinicopathological, immunohistochemical, and genetic analyses of 18 sporadic and 30 FAP-associated FAs. Most sporadic and FAP-associated FAs were located in the upper or middle third of the stomach, on a background of fundic gland mucosa. Most lesions were low-grade, but 3 lesions had a high-grade component. Sporadic FAs included 2 morphologically distinct subtypes, that is, flat and raspberry-like FAs, which we distinguished based on the endoscopic features. Seven lesions were regarded as flat FAs, appearing as large, slightly elevated lesions and measuring 11 to 87 mm in size. Conversely, 10 raspberry-like FAs were small bright-red polyps, measuring 2 to 8 mm in size. FAP-associated FAs, particularly larger lesions, exhibited morphologic features resembling flat FAs but varied significantly in size (2 to 103 mm). Mutation analysis identified APC and KRAS mutations in all flat FAs but never in raspberry-like FAs. Remarkably, somatic APC and KRAS mutations were also detected in 19 (63%) and 27 (90%) of FAP-associated FAs, respectively. This indicates that they are genetically equivalent to sporadic, flat FAs. This study showed that sporadic FA includes at least 2 morphologically and genetically distinct subtypes: flat and raspberry-like FA. Furthermore, flat FA represents a sporadic counterpart of FAP-associated FA.
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Polipose Adenomatosa do Colo , Neoplasias Gástricas , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise Mutacional de DNA , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Mucosa Gástrica/patologiaRESUMO
BACKGROUND AND AIMS: In familial adenomatous polyposis (FAP), neoplastic lesions outside the colon have become increasingly important. The genotype-phenotype correlation has been established for duodenal polyps, and regular screening is recommended. However, this correlation remains unclear for small-intestinal lesions, except for reports on the relationship between their occurrence and Spigelman stage. Here, we used small-bowel capsule endoscopy (SBCE) to investigate the genotype-phenotype correlation of small-intestinal polyps in FAP. METHODS: The genotype-phenotype correlation of small-intestinal polyps was investigated in patients with FAP who underwent SBCE, Esophagogastroduodenoscopy (EGD), and adenomatous polyposis coli (APC) gene analysis. Of 64 patients with FAP who underwent SBCE, 41 were included in the final analysis, 4 did not undergo a complete small intestine examination, and 19 did not undergo genetic analysis. RESULTS: The prevalence (median number) of small-intestinal polyps by Spigelman stage was 26% (1.5), 0% (0), 44% (5), 60% (4), and 73% (25.5) for stages 0 to IV, respectively. Significantly more small-intestinal polyps were found in Spigelman stage III and IV groups than in the stage 0 group (P < .05). The APC variant was negative for 6 patients (15%), and the sites associated with more than 5 small-intestinal polyps were codons 278, 1062, 1114, 1281, 1307, 1314, and 1504. CONCLUSIONS: In FAP patients, SBCE surveillance is potentially recommended for patients with pathogenic variants in the APC gene at codons 278 and 1062 to 1504 or with Spigelman stage III or higher.
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Polipose Adenomatosa do Colo , Endoscopia por Cápsula , Hamartoma , Humanos , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Pólipos Intestinais/diagnóstico , Pólipos Intestinais/genética , Pólipos Intestinais/patologia , Intestino Delgado/patologia , Códon , Hamartoma/patologia , Estudos de Associação GenéticaRESUMO
BACKGROUND/PURPOSE: Pancreatic and biliary tract cancers are one of the Lynch syndrome-associated malignancies. There are few reports describing the patients' backgrounds and clinical characteristics. METHODS: We retrospectively reviewed the medical records of patients with Lynch syndrome-associated pancreatic or biliary tract malignant tumors at National Cancer Center Hospital between March 1992 and October 2019. RESULTS: Fourteen patients were included. They had a history of multiple cancers and a family history of cancer. For the six patients with pancreatic malignant tumor, the median age was 63 years. The primary tumor site of 5/6 patients with pancreatic cancer was the body or tail. Only one patient had pancreatic head cancer. The median overall survival (OS) was 68 (range, 17-198) months. For the eight patients with biliary tract malignant tumor, the median age was 65.5 years. The primary tumor site of 5/8 patients was the intrahepatic bile duct, whereas the primary site of 2/8 was the hilar bile duct. The median OS was 62 (range, 3-183) months. CONCLUSIONS: This study brought out several observations on tumor location, late development, and favorable long-term outcomes. Additional studies are needed to identify the characteristics.
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Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Pancreáticas , Idoso , Neoplasias dos Ductos Biliares/etiologia , Ductos Biliares Intra-Hepáticos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Muir-Torre syndrome (MTS), which accounts for a small subset (1-3 %) of Lynch syndrome (LS), is an autosomal dominant genetic disorder characterized by sebaceous gland or keratoacanthoma associated with visceral malignancies. Most families with MTS have pathogenic germline variants (PGV) in MSH2. Sarcomas are not common on the LS tumor spectrum, and sarcomas associated with MTS are extremely rare. CASE PRESENTATION: Here we report a myxofibrosarcoma of the abdominal wall in a 73-year-old man with a sebaceoma that occurred synchronically, leading to a diagnosis of MTS. The loss of MLH1 and PMS2 protein expression was detected in immunohistochemistry, and high-frequency microsatellite instability (MSI-H) was also confirmed. A germline genetic analysis revealed that he harbored the MLH1 PGV. CONCLUSIONS: This is the first case of MSI-H myxofibrosarcoma with MTS in an MLH1 PGV carrier. Although rare, we should recognize that sarcomas can be part of the spectrum of LS and MTS.
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BACKGROUND: Although gastric cancer is one of the Lynch syndrome (LS)-related tumors, the clinicopathological features of gastric cancer in patients with LS remain uncertain. To investigate the incidence risk and clinicopathological features of gastric neoplasms in LS, we conducted a retrospective cohort study in Japanese LS patients. METHODS: LS patients with pathogenic mismatch repair (MMR) gene variants were extracted from the LS registry of the National Cancer Center Hospital, Japan. Cumulative risks of gastric neoplasm, including dysplasia and cancer, were estimated using the Kaplan-Meier method. Gastric atrophy was evaluated endoscopically and/or histologically. Immunohistochemical staining for MMR proteins was performed for all available specimens. RESULTS: Of 118 eligible patients, 26 patients were diagnosed with 58 gastric neoplasms. The cumulative incidence of gastric neoplasm was 41.0% (95% confidence interval, 26.9-55.0) at the age of 70. Of these, 13 (50%) patients developed synchronous and/or metachronous multiple gastric neoplasms. Among the 49 gastric neoplasms available for detailed pathological evaluation, all were associated with intestinal metaplasia. Immunohistochemically, 42 (86%) were MMR-deficient. The individuals with gastric atrophy had a significantly higher risk of developing gastric neoplasms compared with those without gastric atrophy (26 cases/54 individuals vs. 0 cases/53 individuals) (P = 0.026). CONCLUSION: LS patients, particularly those with atrophic gastritis, are at high risk of gastric neoplasm and often develop multiple tumors. Endoscopic surveillance for gastric cancer is recommended for LS patients, especially those with atrophic gastritis.
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Neoplasias Colorretais Hereditárias sem Polipose/genética , Gastrite Atrófica/genética , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Reparo de Erro de Pareamento de DNA/genética , Bases de Dados Factuais , Feminino , Mutação em Linhagem Germinativa , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-IdadeRESUMO
Colorectal carcinogenesis in familial adenomatous polyposis (FAP) follows a conventional adenoma-carcinoma sequence. However, previous studies have also reported the occurrence of traditional serrated adenomas (TSAs) in patients with FAP. In the present study, we analyzed the clinicopathologic and molecular features of 37 TSAs from 21 FAP patients. Histologically, the majority of FAP-associated TSAs showed typical cytology and slit-like serration; however, ectopic crypt formation was infrequent. Next-generation sequencing and Sanger sequencing identified KRAS and BRAF V600E mutations in 18 (49%) and 14 (38%) TSAs, respectively. Somatic APC mutations were detected in 26 lesions (84% of analyzed cases). Three lesions had BRAF non-V600E mutations, and 2 of them had a concurrent KRAS mutation. Seven TSAs (19%) were associated with a precursor polyp, 6 with a hyperplastic polyp, and 1 with a sessile serrated lesion, and all of them showed the BRAF V600E mutation. Additional sequencing analysis of 4 TSAs with a precursor polyp showed that the BRAF V600E mutation was shared between the TSA and precursor components, but APC mutations were exclusive to the TSA component in all the analyzed lesions. None of the lesions showed the high CpG island methylation phenotype. These results indicate that FAP-associated TSAs frequently have KRAS or BRAF mutations, similar to sporadic cases, and second-hit somatic APC mutations are commonly involved in their tumorigenesis as in other FAP-associated tumors. Although progression to adenocarcinoma is likely rare, tumorigenesis via the serrated pathway occurs in patients with FAP.
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Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , Pólipos do Colo/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Polipose Adenomatosa do Colo/patologia , Polipose Adenomatosa do Colo/cirurgia , Adolescente , Adulto , Idoso , Pólipos do Colo/patologia , Pólipos do Colo/cirurgia , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
Next-generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital-based prospective study (TOP-GEAR project, 2nd stage) to investigate the feasibility and utility of NGS-based analysis of 114 cancer-associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer-related societies. Twenty-five (13.3%) cases have since received molecular-targeted therapy according to their gene aberrations. These results indicate the utility of tumor-profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141).
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Biomarcadores Tumorais , Perfilação da Expressão Gênica , Genes Neoplásicos , Neoplasias/genética , Adulto , Idoso , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Prognóstico , Resultado do TratamentoRESUMO
Mesenchymal stem cells (MSCs) have various functions, making a significant contribution to tissue repair. On the other hand, the viability and function of MSCs are not lasting after an in vivo transplant, and the therapeutic effects of MSCs are limited. Although various chemical modification methods have been applied to MSCs to improve their viability and function, most of conventional drug modification methods are short-term and unstable and cause cytotoxicity. In this study, we developed a method for long-term drug modification to C3H10T1/2 cells, murine mesenchymal stem cells, without any damage, using the avidin-biotin complex method (ABC method). The modification of NanoLuc luciferase (Nluc), a reporter protein, to C3H10T1/2 cells by the ABC method lasted for at least 14 days in vitro without major effects on the cellular characteristics (cell viability, cell proliferation, migration ability, and differentiation ability). Moreover, in vivo, the surface Nluc modification to C3H10T1/2 cells by the ABC method lasted for at least 7 days. Therefore, these results indicate that the ABC method may be useful for long-term surface modification of drugs and for effective MSC-based therapy.