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BACKGROUND: Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) (OMIM #155,601), which is associated with an increased risk of pancreatic ductal adenocarcinoma and melanoma. FAMMM has been reported globally, but it is quite rare in Japan. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling. CASE PRESENTATION: The first case is a 74-year-old woman with a diagnosis of pancreatic carcinoma with multiple liver metastases. She had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. Whole exon sequencing detected a germline CDKN2A variant evaluated as likely pathogenic. The results were disclosed to her daughters after she died, and the same CDKN2A variant was detected in one of the daughter. The daughter was referred to a nearby hospital for her clinical management. The second case is a 65-year-old man with pancreatic ductal adenocarcinoma. He had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. He underwent a comprehensive genomic profiling test using pancreatic cancer tissue, and detected a presumed germline pathogenic variant of CDKN2A. Germline testing confirmed the same CDKN2A variant. Genetic analysis of his relatives produced negative results. Other blood relatives are scheduled for genetic analysis in the future. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling. CONCLUSIONS: In current Japanese precision medicine, comprehensive genetic analysis can reveal rare genetic syndromes and offer us the opportunity to provide health management for patients and their relatives. However, gene-specific issues are raised in terms of the evaluation of a variant's pathogenicity and the extent of surveillance of the at-risk organs due to a lack of genetic and clinical data concerning CDKN2A variant carriers in Japan.
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Pathological germline variants (PGVs) of RAD51D increase the risk of breast and ovarian cancer. In East Asia, c.270_271dup is the most frequently detected PGV of RAD51D; however, only a few cases have been reported in Japan. We report four cancer cases with a germline RAD51D c.270_271dup PGV. Three of them (lung cancer: 2, oral cancer: 1) were incidentally identified by whole genome sequencing in patients negative for the associated cancer histories, homologous recombination (HR) deficiency, or a second hit of RAD51D in the cancer DNA. For genetic counseling, we provided information on surveillance and cascade testing based on Western guidelines. The PGVs of moderate-risk HR-related genes are difficult to detect based on phenotype, especially in male-predominant pedigrees. The current spread of cancer genomic analysis will increase opportunities for incidental variant identification. The establishment of Japanese guidelines is expected to aid in the management of PGV carriers of moderate-risk genes.
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PURPOSE: Mammography screening has increased the detection of subcentimeter breast cancers. The prognosis for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative T1a/bN0M0 breast cancers is excellent; however, the necessity of adjuvant endocrine therapy (ET) is uncertain. METHODS: We evaluated the effectiveness of adjuvant ET in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer who underwent surgery from 2008 to 2012. Standard ET was administrated after surgery. The primary endpoint was the cumulative incidence of distant metastasis. All statistical tests were 2-sided. RESULTS: Adjuvant ET was administered to 3991 (83%) of the 4758 eligible patients (1202 T1a [25.3%] and 3556 T1b [74.7%], diseases). The median follow-up period was 9.2 years. The 9-year cumulative incidence of distant metastasis was 1.5% with ET and 2.6% without ET (adjusted subdistribution hazard ratio [sHR], 0.54; 95% CI, 0.32-0.93). In multivariate analysis, the independent risk factors for distant metastasis were no history of ET, mastectomy, high-grade, and lymphatic invasion. The 9-year overall survival was 97.0% and 94.4% with and without ET, respectively (adjusted HR, 0.57; 95% CI, 0.39-0.83). In addition, adjuvant ET reduced the incidence of ipsilateral and contralateral breast cancer (9-year rates; 1.1% vs. 6.9%; sHR, 0.17, and 1.9% vs. 5.2%; sHR, 0.33). CONCLUSIONS: The prognosis was favorable in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer. Furthermore, adjuvant ET reduced the incidence of distant metastasis with minimal absolute risk difference. These findings support considering the omission of adjuvant ET, especially for patients with low-grade and no lymphatic invasion disease.
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Germline double heterozygosity (GDH) is rarely reported in cases of inherited cancer syndromes, and GDH of a mismatch repair gene and BRCA has never been reported in Japan. Nonetheless, the current report demonstrates a case of ovarian mucinous adenocarcinoma with initiated Lynch syndrome (LS)-related surveillance because of a known germline MSH2 variant. Six and a half years after oophorectomy, multiple tumors developed in the patient's lungs, bones, and lymph nodes, and histology results confirmed mucinous adenocarcinoma. Systemic chemotherapy including an anti-PD-L1 antibody was effective for >1 year, but brain metastases developed. Pathology of the brain tumors showed mucinous adenocarcinoma without expression of MSH2 and MSH6, while multi-gene panel testing demonstrated not only high microsatellite instability and a high tumor mutation burden, but also germline BRCA2 variants. Further, germline testing in relatives confirmed both variants were from the paternal line, from which many LS-related cancers develop, but not BRCA-related cancer.
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Familial malignant melanoma (FMM) is a hereditary tumor that is quite rare in Japan; to date, the germline CDK4 variant has scarcely been reported around the world. Thus, we report on a woman with FMM who developed salivary gland cancer, for which a germline pathogenic variant of CDK4 was incidentally identified through comprehensive genomic profiling. She had a history of multiple atypical nevi and a facial melanoma since her 30 s and multiple family histories of melanoma; however, none of her relatives were aware of its heredity. Genetic counseling and skin surveillance were performed. Precision medicine for cancer can discover this rare genetic syndrome and provides us with the opportunity to manage the health of patients and their relatives.
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Melanoma , Neoplasias Cutâneas , Feminino , Humanos , Quinase 4 Dependente de Ciclina/genética , População do Leste Asiático , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Melanoma Maligno CutâneoRESUMO
In 2021, Japan's national health insurance made germline BRCA (g.BRCA) testing available to unresectable pancreatic cancer (PC) patients as a companion diagnostic (CD) of the PARP inhibitor. This study investigated the incidence of the g.BRCA variant (g.BRCAv.) and the status of the genetic medicine associated with its testing. A total of 110 PC patients underwent the testing, five of whom (4.5%) had a deleterious g.BRCA2v. (all truncations) but no g.BRCA1v. The turnaround time (TAT) to the doctors was 13 days, and to the patients, 17 days. A higher incidence of a BRCA-related family history and a shorter TAT were seen in the g.BRCAv. patients, but they were insignificant (p = 0.085 and p = 0.059, respectively). Genetic counseling was not performed for three g.BRCA2v. patients because two of them had no accessible relatives and one died of the cancer before the genetic report was completed. Two families underwent generic counseling and testing based on the patient's genetic data. g.BRCAv. is recognized in a small fraction of PC cases, and the following genetic counseling is done more for the relatives than for the patients. TAT was constant and did not affect much on the genetic counseling, but the earlier testing is expected for patients with a deadly cancer.
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Neoplasias Ovarianas , Neoplasias Pancreáticas , Humanos , Feminino , Testes Genéticos , População do Leste Asiático , Aconselhamento Genético , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Predisposição Genética para Doença , Proteína BRCA1/genética , Neoplasias PancreáticasRESUMO
Acinic cell carcinoma (ACC) is an exceptionally rare type of breast carcinoma with a low-grade morphology and a favorable prognosis. It is postulated to be a type of invasive carcinoma arising in microglandular adenosis (MGA). We report a case of extensively spreading ACC of the breast with MGA-like features. Macroscopically, yellowish nodules were widely distributed throughout the right breast, up to the axilla, without mass formation. Microscopically, the tumor consisted of two distinct carcinoma components: one was multiple nodular lesions showing invasive carcinoma with fused solid nests, and the other was a widely spreading lesion exhibiting MGA-like features with uniform small single glands. Immunohistochemically, both components were negative for ER, PR, and HER2, and expressed EMA, S100 and lysozyme. The distinct morphology and molecular expression indicated ACC. The single glands in the MGA-like area lacked myoepithelial cells but were linearly surrounded by type IV collagen, a basement membrane component. This case supports the hypothesis that ACC and MGA have the same lineage and indicates that ACC is not necessarily a low-grade malignancy and can be aggressive.
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Neoplasias da Mama , Carcinoma de Células Acinares , Carcinoma , Doença da Mama Fibrocística , Feminino , Humanos , Carcinoma de Células Acinares/patologia , Mama/patologia , Neoplasias da Mama/patologia , Doença da Mama Fibrocística/química , Doença da Mama Fibrocística/metabolismo , Doença da Mama Fibrocística/patologia , Carcinoma/patologiaRESUMO
BACKGROUND: Microsatellite instability (MSI) is a key marker for predicting the response of immune checkpoint inhibitors (ICIs) and for screening Lynch syndrome (LS). AIM: This study aimed to see the characteristics of cancers with high level of MSI (MSI-H) in genetic medicine and precision medicine. METHODS: This study analyzed the incidence of MSI-H in 1000 cancers and compared according to several clinical and demographic factors. RESULTS: The incidence of MSI-H was highest in endometrial cancers (26.7%, 20/75), followed by small intestine (20%, 3/15) and colorectal cancers (CRCs)(13.7%, 64/466); the sum of these three cancers (15.6%) was significantly higher than that of other types (2.5%)(P < 0.0001). MSI-H was associated with LS-related cancers (P < 0.0001), younger age (P = 0.009), and family history, but not with smoking, drinking, or serum hepatitis virus markers. In CRC cases, MSI-H was significantly associated with a family history of LS-related cancer (P < 0.0001), Amsterdam II criteria [odds ratio (OR): 5.96], right side CRCs (OR: 4.89), and multiplicity (OR: 3.31). However, MSI-H was very rare in pancreatic (0.6%, 1/162) and biliary cancers (1.6%, 1/64) and was null in 25 familial pancreatic cancers. MSI-H was more recognized in cancers analyzed for genetic counseling (33.3%) than in those for ICI companion diagnostics (3.1%)(P < 0.0001). Even in CRCs, MSI-H was limited to 3.3% when analyzed for drug use. CONCLUSIONS: MSI-H was predominantly recognized in LS-related cancer cases with specific family histories and younger age. MSI-H was limited to a small proportion in precision medicine especially for non-LS-related cancer cases.
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Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Anamnese/estatística & dados numéricos , Instabilidade de Microssatélites , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Medicina de PrecisãoRESUMO
OBJECTIVE: Since 2019, precision cancer medicine has been covered by national insurance in Japan; however, to date, germline findings have not been fully reported. The aim of this study was to evaluate the current status and raise a problem of germline finding analysis and disclosure in Japanese precision cancer medicine. METHODS: Germline findings of 52 genes were examined in 296 cases with advanced cancer by a case series study. RESULTS: Six (2.0%) cases were examined by the Oncoguide™ NCC Oncopanel with germline testing, but no germline findings were reported. The remaining 290 (98.0%) cases were analyzed by FoundationOne® CDx (tumor-only testing), which recognized 404 pathogenic variants; those of BRCA1/2 were recognized in 16 (5.5%) tumors. Our institutional algorithm suggested 39 candidate germline findings in 34 cases, while the public algorithm listed at least 91 candidate germline findings. Four germline findings had been previously identified (BRCA1: 3 and ATM: 1). Nine of 30 cases with candidate germline findings excluding these known germline findings refused or deferred germline testing. Only 4 of 16 cases that received counseling underwent germline testing, and those 4 revealed 3 germline findings (BRCA2, CDK4 and RAD51C); in total, 8 (2.7%) germline findings were revealed. Reasons for refusing genetic counseling and/or germline testing included extra hospital visits, added expense for germline testing due to limited national insurance coverage, poor patient physical condition and no known family members associated with the possible germline finding. CONCLUSIONS: In current Japanese precision cancer medicine, only a small fraction of the patients undergoes germline testing and demonstrated germline finding. The current results suggested a need for earlier indications for precision cancer medicine, broader insurance coverage and more efficient germline finding prediction algorithms, to increase the number of germline testings and to improve the following managements.
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Neoplasias , Medicina de Precisão , Predisposição Genética para Doença , Testes Genéticos/métodos , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Japão , Neoplasias/genética , Neoplasias/terapiaRESUMO
High-throughput sequencing has greatly contributed to precision medicine. However, challenges remain in reporting secondary findings (SFs) of germline pathogenic variants and managing the affected patients. The aim of this study was to examine the incidence of SFs in Japanese cancer patients using whole exome sequencing (WES) and to understand patient preferences regarding SF disclosure. WES was conducted for 2480 cancer patients. Genomic data were screened and classified for variants of 59 genes listed by the American College of Medical Genetics and Genomics SF v2.0 and for an additional 13 hereditary cancer-related genes. Majority of the participants (68.9%; 1709/2480) opted for disclosure of their SFs. Thirty-two pathogenic or likely pathogenic variants, including BRCA1 (7 patients), BRCA2 (4), CHEK2 (4), PTEN (3), MLH1 (3), SDHB (2), MSH6 (1), NF1 (1), EXT2 (1), NF1 (1), NTRK1 (1), MYH7 (3), MYL2 (1), TNNT2 (1), LDLR (2), FBN1 (1), and KCNH2 (1) were recognized in 36 patients (1.5%). Twenty-eight (77.8%) patients underwent genetic counseling and received their SF results. Eighteen (64.3%) patients underwent clinical management for SFs. Genetic validation tests were administered significantly more frequently to patients with than without a SF-related personal history (P = 0.025). This was a first attempt at a large-scale systematic exome analysis in Japan; nevertheless, many cancer patients opted for disclosure of SFs and accepted or considered clinical management.
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Povo Asiático/genética , Exoma/genética , Predisposição Genética para Doença/genética , Neoplasias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Revelação , Feminino , Aconselhamento Genético/métodos , Testes Genéticos/métodos , Genômica/métodos , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Sequenciamento do Exoma/métodos , Adulto JovemRESUMO
OBJECTIVE: This study aimed to determine whether Japanese cancer patients share test results of germline pathogenic variants of hereditary cancer with their relatives. METHODS: This single-center cross-sectional study enrolled 21 Japanese patients who received results of germline pathogenic variants of hereditary cancer at least 6 months prior. RESULTS: All patients shared their test results with at least one relative, with the following sharing rates: 85.7% for first-degree relatives, 10% for second-degree relatives and 8.3% for third-degree relatives. Patients most commonly shared the information with their children aged >18 years (86.7%), followed by their siblings (73.6%), spouses (64.7%) and parents (54.5%). Three categories were extracted from qualitative analysis: 'characteristics of my cancer', 'knowledge and caution about inheritability' and 'utilization of medical care.' CONCLUSIONS: The rate of test result sharing with first-degree relatives was comparable with those in Europe and the USA. Patients with germline pathogenic variants also tended to share their test results more with their children and siblings than with their parents. Informing their relatives of the results was suggestive of the motivation to influence their relatives' health outcome and contribute to the well-being of their children and siblings.
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Predisposição Genética para Doença , Neoplasias , Criança , Estudos Transversais , Testes Genéticos , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Neoplasias/genéticaRESUMO
This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single-center study called "High-tech Omics-based Patient Evaluation" or "Project HOPE" conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole-exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed "Shizuoka Multi-omics Analysis Protocol" developed in-house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non-cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.
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Biomarcadores Tumorais/genética , Bases de Dados Factuais , Mutação , Neoplasias/genética , Feminino , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Japão , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Medicina de Precisão , Sequenciamento do ExomaRESUMO
OBJECTIVES: The purpose of our study was to assess whether there is a potential additional value of real-time virtual sonography (RVS) to second-look ultrasound (US) examination and biopsy for breast lesions identified on MRI alone. METHODS: A retrospective review of the records of 70 consecutive patients (78 lesions) with breast abnormalities identified on MRI alone was performed. All suspicious enhancing lesions were subsequently evaluated with second-look US. Lesions not observed on second-look US underwent RVS. Pathological findings were confirmed by subsequent percutaneous biopsy or excision. RESULTS: Of the 78 MRI-detected lesions, second-look US correlation was made in 50 (64 %), including 22 malignant and 28 benign lesions. The remaining 28 lesions (36 %) were scheduled to undergo RVS. Four lesions were not visible on the second breast MRI. The remaining 24 lesions were RVS correlated and underwent RVS-guided biopsy; these included seven malignant and 17 benign lesions. Overall, 74 of 74 (100 %) true MRI-detected lesions were confirmed by histological results without using MRI-guided breast biopsy. The cancer rate was 29 %. CONCLUSIONS: RVS can increase the sonographic detection and biopsy rate of lesions identified on breast MRI alone. KEY POINTS: ⢠All 74 MRI-detected lesions were confirmed without using MRI-guided biopsy. ⢠Four lesions were not visible on second breast MRI. ⢠RVS can increase sonographic detection of lesions identified on breast MRI alone. ⢠RVS-guided breast biopsy can be an alternative to MRI-guided biopsy.
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Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Imageamento por Ressonância Magnética/métodos , Ultrassonografia de Intervenção/métodos , Ultrassonografia Mamária/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Doenças Mamárias/patologia , Feminino , Humanos , Biópsia Guiada por Imagem/métodos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
We classified ipsilateral breast tumor recurrences (IBTRs) based on strict pathological rules. Ninety-six women who were surgically treated for IBTR were included. IBTRs were classified according to their origins and were distinguished based on strict pathological rules: relationship between the IBTR and the primary lumpectomy scar, surgical margin status of the primary cancer, and the presence of in situ lesions of IBTR. The prognosis of these subgroups were compared to that of new primary tumors (NP) in the narrow sense (NPn) that occurred far from the scar. Distant-disease free survival of IBTR that occurred close to the scar with in situ lesions and a negative surgical margin of the primary cancer (NP occurred close to the scar, NPcs) was similar to that of NPn. In contrast, IBTR that occurred close to the scar without in situ lesions (true recurrence (TR) that arose from residual invasive carcinoma foci, TRinv) had significantly poorer prognosis than NPn. IBTR that occurred close to the scar with in situ lesions and a positive surgical margin of the primary cancer (TR arising from a residual in situ lesion, TRis) had more late recurrences than NPcs. Precise pathological examinations indicated four distinct IBTR subtypes with different characteristics.
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Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/patologia , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Mastectomia Segmentar , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/patologiaRESUMO
Lateral chest wall perforator flaps, such as the lateral intercostal artery perforator flap, lateral thoracic artery perforator flap, and thoracodorsal artery perforator flap, have been used for volume replacement oncoplastic breast-conserving surgery (VR-OPBCS) in the lateral and central breast. However, there are cases in which these perforators are missing or too thin, making it difficult to raise a flap for partial breast reconstruction. A 58-year-old woman underwent VR-OPBCS for breast cancer in the lower quadrant of the right breast. Preoperative imaging studies did not identify lateral thoracic artery perforator or thoracodorsal artery perforator but identified a well-developed superficial thoracic artery perforator (STAP). A flap based on the STAP was dissected, and partial breast reconstruction was performed. The flap survived with no complications. No deformity of the lower breast or displacement of the nipple-areola complex was observed 8 months after the completion of postoperative radiotherapy. The STAP flap can be used as an alternative to VR-OPBCS when other lateral chest wall perforator flaps are unavailable.
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Multiple gastroenteric, pancreatic, and pituitary neuroendocrine neoplasms (NENs) were diagnosed in a 74-year-old man with a history of primary hyperparathyroidism (PHPT). Germline testing demonstrated a variant of MEN1 (c.1694T>A, p.L565Q), whose pathogenicity was classified as a variant of uncertain significance (VUS) according to the ACMG/AMP guidelines. The same germline variant was detected in the patient's son and daughter, who also showed PHPT or hypercalcemia and met the clinical diagnostic criteria for multiple endocrine neoplasia type 1 (MEN1). During surveillance of the son, multiple pancreatic tumors suggestive of NENs were detected. The pathogenicity of the current MEN1 variant was re-evaluated as likely pathogenic, based on additional family data.
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Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Masculino , Humanos , Idoso , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/patologia , Japão , Tumores Neuroendócrinos/patologia , Mutação em Linhagem GerminativaRESUMO
BACKGROUND/AIM: Brain metastasis, a leading cause of cancer death, is a clinical challenge. Recently, genetic characterization of brain metastatic lesions based on next generation sequencing-based advanced technologies, such as single-cell RNA sequencing, has been performed to develop novel efficient therapies. The present study aimed to investigate brain-metastasis-specific biomarkers as well as relevant prognostic factors. PATIENTS AND METHODS: The genetic profiles and expression levels of immune response-associated genes and 820 cancer-associated genes were compared between primary cancer lesions and metastatic cancer lesions obtained from nine cancer patients at the Shizuoka Cancer Center. Cytokine and chemokine marker genes were analyzed via quantitative PCR. T-cell receptor (TCR) repertoire profiling was performed for the same patients. For survival analysis, survival data of 52 cancer patients with brain metastases were utilized. RESULTS: Comparison of driver mutation profiling between primary and metastatic lesions revealed shared core mutations in both lesions and a few new mutations in metastatic lesions. A high tumor mutation burden (TMB) was detected in metastatic lesions. Volcano plot analysis revealed specific features of the metastatic tumor microenvironment, such as cancer signaling promotion and immune suppression due to decreased immune cell infiltration. Survival analysis revealed that three genes, the TREML2 gene, the BTLA gene on activated microglia and the CERS2 gene on metastatic tumor, were potent prognostic factors. CONCLUSION: High TMB in metastatic lesions indicates potential benefit from immune checkpoint inhibitor usage for brain metastasis and TREML2 and BTLA are factors associated with poor prognosis. Activated microglia may be novel targets for the treatment of brain metastasis.
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Biomarcadores Tumorais , Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Feminino , Masculino , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Prognóstico , Idoso , Mutação , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND/AIM: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. PATIENTS AND METHODS: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. RESULTS: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers. CONCLUSION: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.
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Neoplasias , Microambiente Tumoral , Animais , Humanos , Microambiente Tumoral/genética , Mutação , Neoplasias/genética , Mamíferos , DNA Helicases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genéticaRESUMO
INTRODUCTION: Daily burden of patients with chronic kidney disease (CKD) who have not received maintenance dialysis or renal transplantation has not been well reported compared with patients receiving dialysis. We conducted a patient survey and an advisory board in Japan to investigate the experience and perception of CKD and its treatments from the patient's perspective. METHODS: An anonymous web survey (n = 342) was conducted in October and November 2020. Participants, who were recruited through multiple panels, aged 20 years or older, diagnosed with any stage of CKD, and who had neither received nor planned maintenance dialysis or renal transplantation were included. A questionnaire prepared under the medical advisor's guidance was used to collect the background information, burden of disease and treatments, and needs and expectations for future treatments. An advisory board with five patients nominated from a patient group was conducted in December 2020. Additional insights to interpret the results of the preceding survey were collected using pre-identified discussion topics. RESULTS: Establishing a diagnosis of CKD generally took a long time; approximately 20% of the patients waited more than 5 years before diagnosis. In daily life, patients were burdened with CKD-related symptoms (e.g., tinnitus, leg cramps) and behavioral restrictions, including diet. They also felt psychological burdens, such as concerns about possible future dialysis and/or renal transplantation, lack of awareness and understanding of disease among the other people in their lives, and financial burdens related to medical expenses. Furthermore, they felt a lack of communication in daily interactions with health care professionals and others around them, and they desired interaction with patients with CKD. CONCLUSION: Understanding the burdens and the thoughts of patients with CKD could inform discussions about the ways to improve communication with patients in daily practice, the role of the patient community, and new therapeutic options to address patients' expectations. TRIAL REGISTRATION: UMIN000042300.
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Transplante de Rim , Insuficiência Renal Crônica , Humanos , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , ComunicaçãoRESUMO
BACKGROUND: Research on whole genome/exome sequencing is increasing worldwide. However, challenges are emerging in relation to receiving germline pathogenic variant results and sharing them with relatives. OBJECTIVE: The aim of this study was to investigate the occurrence of and reasoning related to regret among patients with cancer who shared single-gene testing results and whole exome sequencing with family members. METHODS: This was a single-center, cross-sectional study. The Decision Regret Scale was administered, and descriptive questionnaires were used with 21 patients with cancer. RESULTS: Eight patients were classified as having no regret, 9 patients were classified as having mild regret, and 4 patients were classified as having moderate to strong regret. Reasons patients felt that sharing was the right decision included the following: to allow relatives and children to take preventive measures, the need for both parties to be aware of and ready for the hereditary transmission of cancer, and the need to be able to discuss the situation with others. On the other hand, some patients did not think it was a good decision to share the information because of the associated anxiety. CONCLUSIONS: Regret over sharing test results for pathogenic germline variants of hereditary cancers with relatives tended to be low. The main reason was that patients believed that they were able to benefit others by sharing. IMPLICATIONS FOR PRACTICE: Healthcare professionals need to understand the postsharing perceptions and experiences of patients and support them throughout the sharing process.