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  • 1
    Online Resource
    Online Resource
    Novel and Significant Impact of Germline Variants Predisposed to Pathogenic Somatic Mutations and Loss of Heterozygosity (LOH) in Myelodysplastic Syndromes (MDS) and Clonal Hematopoiesis of Indeterminate Potential (CHIP)
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 108-108
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 108-108
    Abstract: While germline predisposition to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) has long been recognized mainly through rare familial and pediatric cases, it has been drawing an increasing attention, on the basis of the recent discovery of novel risk alleles for MDS/AML through studies relying on revolutionized sequencing technologies; according to these studies, it suggest that more numbers of MDS/AML cases than expected might have germline predisposition. Moreover, it is suggested that germline variations may also confer predisposition to age-related clonal hematopoiesis or "CHIP", which has been implicated in the development of MDS/AML. In this study, we explored germline predisposition to MDS and CHIP through intensive sequencing of blood samples from large cohorts of AML/MDS patients and 'hematologically' healthy individuals (HHIs), in which germline variants in 21 genes implicated in sporadic or familial MDS/AML or CHIP were interrogated among patients with MDS/AML from the Japan Marrow Donor Program (n=797) and HHIs aged 〉 60 years from Biobank Japan (n=10,852). Germline variants were referred to NCBI dbSNP Build 151 database, excluding the entries in COSMIC ver.7 and in-house database, followed by manual curations. Somatic mutations and CHIP in the 21 genes were also analyzed for MDS/AML and HHIs, respectively. In total, 30,286 germline variants, including both synonymous and non-synonymous changes, were detected in 21 genes in the entire cohort. By comparing their frequencies between in MDS/AML and HHIs, we identified 6 germline variants in showing a significant enrichment in MDS/AML. Among these most frequently observed was variants in DDX41, for which a total of 3,721 variants were detected in 3,688 HHIs. Among these, 3 variants were significantly enriched in MDS/AML, including p.A500fs (OR=13.1 [6.6-25.9] (95%CI) (n=15), p.S363del (OR=41.0, [4.3-349.5] ) (n=3), and p.Y259C (OR=34.2, [6.6-176.8]) (n=5). Of interest, 14 of 23 MDS patients with one of these alleles carried somatic DDX41 mutations, typically p.R525H, which were not found in any of HHIs, further supporting the relevance of these DDX41 risk alleles. Also including an additional 2 nonsense/splicing variants, 5 DDX41 alleles found in 25 MDS/AML patients were thought to represent germline predisposition to MDS/AML. Similarly, RUNX1 p.H85N (OR=9.10, [1.52-54.52] ) (n=2), CBL p.P782L (OR=4.27, [1.56-11.70]) (n=5), and GNAS p.H69N (OR = 2.90, [1.28-6.59] ) (n=7) showed a significant enrichment in MDS/AML. Combined, these putative risk alleles accounted for 4.6% (37/797) of sporadic MDS and sAML. None of these alleles were observed in the Caucasian population of Exome Aggregation Consortium dataset, suggesting Asian origins of these variants. We next evaluated the effects of germline variants on CHIP. CHIP mutations were detected in 929 HHIs, where DNMT3A mutations (n=290) were most prevalent, followed by TET2 (n=124) and ASXL1 (n=68) mutations. By comparing allele frequency of each of 1,276 germline variants between healthy donors with and without CHIP, we identified two haplotypes at the JAK2 and TET2 loci, defined by T/A at c.C489T/c.G2490A (JAK2) and G/G/T at c.G652A/c.G3117A/c.T4140C (TET2), which were significantly enriched in the cases carrying CHIP with the JAK2 (p.V617F) and TET2 mutations, respectively (T/A vs. C/G; OR=3.36, [1.41-8.01] for JAK2 and G/G/T vs. A/A/C; OR=1.85, [1.19-2.86] for TET2). Intriguingly, the JAK2 risk haplotype (C/G) were also enriched in MDS cases with JAK2 p.V617F mutations (T/A vs. C/G; OR=3.06, [1.26-7.60]). Similarly, the TET2 risk haplotype (G/G/T) tended to be enriched in MDS cases with TET2 mutations, although not statistically significant. Finally, variant allele frequency of JAK2 p.V617F mutations in CHIP exceeded 0.5 in 4 out of 26 JAK2 CHIP-positive patients (15%), suggesting the presence of loss of heterozygosity (LOH) in chromosome 9p. In conclusion, through a large-scale detection of germline variants in 21 common drivers of MDS/AML as well as CHIP, we identified multiple novel germline variants or haplotypes that showed a significant predisposition to the development of adult-onset MDS or CHIP, respectively. Our findings provide novel insights into the genetic basis of myeloid leukemogenesis and the development of CHIP. Disclosures Nakagawa: Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Kanda:Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-118833
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    The Prognostic Value of TP53 Mutations Depends on Clinical Backgrounds in Pediatric Patients with Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4077-4077
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4077-4077
    Abstract: Introduction TP53 mutations in relapsed cases with pediatric acute lymphoblastic leukemia have been implicated in poor clinical outcomes. However, the prevalence and clinical significance of TP53 mutations at diagnosis have not been fully investigated. Such knowledge is essential for the care of patients, because treatment intensity is tailored to predictive prognosis, where increased attention has been directed toward de-escalation of treatment for the problem of long term effects and second malignancies in childhood cancer survivors. Methods Mutation status of TP53 was detected by targeted-capture sequencing of TP53 coding regions in 1,003 children with B-precursor ALL who had been treated in either of the two prospective clinical trials, JACLS (Japan Association of Childhood Leukemia Study) ALL-02 and TCCSG (Tokyo Children's Cancer Study Group) L04-16. Detection of common fusion genes, including BCR-ABL, ETV6-RUNX1, MLL-AF4, MLL-ENL, MLL-AF9, and TCF3-PBX1, were performed using qPCR assays. We designed SNP baits to analyze copy number status of chromosome 17, and also captured 662 probes tiling the entire IgH enhancer locus to identify IGH-DUX4 rearrangement. Result In total, 36 different non-silent coding TP53 mutations were identified in 30 (3%) patients, including 22 missense, 7 frameshift indel, 5 in-frame indel, and 2 nonsense mutations. All missense mutations were found in the core DNA-binding domain (n=21), except for one mutation, which affected the tetramerization motif. Variant allele frequencies (VAF) of TP53 mutations varied from 3% to 97% with 14 mutations showing 〈 10% VAFs. Showing a significant correlation with mutated TP53 (Odds ratio 20: 95%CI 6.4-61, P 〈 0.001), loss of heterozygosity affecting the TP53 locus was observed in 11 (37%) cases and caused by del(17p) in most cases (n=10). We next evaluated clinical features of TP53-mutated cases. TP53 was most frequently mutated in Hypodiploid ALL (33% n=3), followed by MLL rearrangement (12% n=4), IGH-DUX4 (9% n=5), Others (3% n=8), TCF3-PBX1 (2% n=2), Hyperdiploid (2% n=6), and ETV6-RUNX1 (n=2 0.9%). TP53 mutations were not associated with age or white blood cell count at diagnosis. However, significantly more patients were categorized into National Cancer Institute (NCI) high risk (HR) category (Odds ratio 2.4: 95%CI 1.1-5.3, P = 0.03) and TP53 mutation was associated with a significantly shorter overall survival (OS) among NCI-HR patients (n = 16; HR for death, 6.3; 95% CI, 3.1-13; P 〈 0.001). Five-year OS of NCI-HR patients with TP53 mutations was 44%, suggesting that early treatment intensification or alternative treatment strategies are warranted for these patients. TP53 mutations were also associated with a shorter OS in MLL rearrangement and IGH-DUX4 ALL. Particularly, 67% (n=4/6) of cases with any cause of death harbored TP53 mutation in IGH-DUX4 ALL. In contrast, TP53 mutation was not associated with shorter overall survival in NCI-SR cases. In Hyperdiploid ALL, 5 out of 6 cases with TP53 mutations were categorized into the NCI-SR category and were all alive. Prognostic impact of TP53 mutation was also investigated using recursive partitioning to generate a hierarchical prognostic model for OS by incorporating genetic subgroups and the NCI risk criteria. This model also demonstrated that the NCI risk criteria was the most important prognostic variable and TP53 mutation was used for stratification of patients only in the NCI-HR category. Conclusion TP53 mutations at diagnosis are common in Hypodiploid ALL and also found in a substantial fraction of MLL rearrangement and IGH-DUX4 ALL, where the mutations predict a poor prognosis. TP53 mutation is also found in NCI-SR cases but may not be associated with poor prognosis. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-115617
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Online Resource
    Distinct Pathogenesis of Clonal Hematopoiesis Revealed By Single Cell RNA Sequencing Integrated with Highly Sensitive Genotyping Method
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 34-34
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 34-34
    Abstract: Background Recent evidence suggests that age-related clonal hematopoiesis (CH) might represent the earliest precursor of myeloid neoplasms. Although the exact mechanism of clonal selection that shapes CH is still to be elucidated, both cell intrinsic and non-cell intrinsic effects of mutations, including the interplay between mutated cells and the bone marrow environment, are thought to play important roles, which are best studied using single-cell sequencing analysis of both mutations and gene expression. Methods We performed single-cell sequencing of hematopoietic stem and progenitors (HSPCs) from BM of the 16 patients with CH along with 16 control patients without CH identified by screening otherwise healthy individuals who received hip joint replacement, using a novel platform that enables simultaneous detection of gene mutations and expression based on the Fluidigm C1-HT system. Sequence data were analyzed with Seurat (Stuart et al Cell 2019) with integration of genotyping information. Cells were clustered and each cluster was assigned by marker-gene expressions for major cell-types in HSPCs, including hematopoietic stem cell (HSC)-like and erythroid progenitors. Cells were grouped by their genotypes and pathway analysis were performed. Results In total, we identified 35 subjects who had CH-related mutations, including those affecting DNMT3A, TET2, ASXL1, SF3B1, PPM1D, IDH1, GNB1 and TP53, of which 11 had more than one CH-related mutation. Most of these mutations showed a low variant allele frequency (VAF) ≤ 0.05. However, clones having double mutations of DNMT3A/TET2 or those having biallelic TET2 mutations tended to show a higher VAF as high as 0.4, suggesting an enhanced clonal advantage for clones having multiple mutations. Using our novel single-cell platform, we analyzed 3,767 cells from control patients without CH and 1,474 mutated cells and 7,234 wild-type (WT) cells from patients with CH. By targeting both genomic DNA and RNA, we successfully obtained a sufficient number of single-cell reads for genes whose expression was too low to evaluate by only targeting RNA, such as TET2 and DNMT3A. Although some clones having a high-VAF mutation caused a skewed clustering to be detected as a CH clone, many clones with low-VAF mutations did not make distinct clusters, indicating the importance of genotyping at a single cell level to identify and characterize mutated cells. Simultaneous detection of genotype and expression allowed us to see the effect of CH-mutations on cell phenotype and differentiation. For example, cells having compound TET2/DNMT3A mutations were significantly enriched in the erythroid cluster, while another clone with double TET2 mutations were more enriched in the HSC-like cluster, compared to cells from individuals without CH (WTcont). These are in line with the previous findings of TET2/DNMT3A double knockout mice or TET2 knockout mice, respectively. In another case with an IDH1 mutation, IDH1-mutated (MUTIDH1) cells less contributed to the HSC-like fraction, showing an enhancement of cell proliferation-signature, compared to WT (WTIDH1) cells in the same patient. Strikingly, compared to WTcont cells, WTIDH1 cells were significantly enriched in the HSC-like fraction and showed an enhanced expression of cytokine-related pathway genes, which was in line with a finding seen in mouse cells treated with 2-hydroxy-glutalate, an mutant IDH-related oncometabolite. Similarly, when compared to WTcont cells, WT cells from patients with DNMT3A- (WTDNMT3A) or TET2- (WTTET2) mutated CH significantly showed an enhanced cell proliferation. HSC-like WTTET2 cells also showed aberrant IFN-response signatures compared to corresponding WTcont cells, which was confirmed in competitive transplantation of Tet2 heterozygous knockout (hKO) and WT cells in a mouse model; HSPCs of WT competitors transplanted with Tet2-hKO cells showed a significant enhancement of IFN-response signatures compared to those transplanted with WT cells. Intriguingly, monocytes of Tet2-hKO donors showed aberrant expression of S100a8/a9, which might contribute to the non-cell intrinsic effect of Tet2-hKO cells. Conclusions In CH, not only mutated cells but also surrounding WT cells show an aberrant gene expression phenotype, suggesting the presence of non-cell autonomous phenotype or an altered bone marrow environment that favors the positive selection of CH-clones. Disclosures Nakagawa: Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Inagaki:Sumitomo Dainippon Pharma Co., Ltd.: Current Employment. Ogawa:Eisai Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-142157
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Online Resource
    TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease‐related hepatocellular carcinoma
    Wiley ; 2016
    In:  International Journal of Cancer Vol. 139, No. 11 ( 2016-12), p. 2512-2518
    Details
    In: International Journal of Cancer, Wiley, Vol. 139, No. 11 ( 2016-12), p. 2512-2518
    Abstract: What's new? While the number of patients with virus‐related hepatocellular carcinoma (HCC) is expected to decline thanks to advanced anti‐virus therapy, the number of patients with nonalcoholic fatty liver disease‐derived HCC (NAFLD‐HCC) has been raising worldwide due to increased prevalence of metabolic syndrome. The molecular features of NAFLD‐HCC remain to be fully determined. Here, the authors analyzed genetic aberrations in NAFLD‐HCC tumor samples by whole‐exome sequencing, targeted sequencing, and copy number variation studies. Although NAFLD‐HCC shared similar genetic aberration profiles with HCC from other etiologies, TERT promoter mutations and chromosome 8p loss emerged as potentially essential factors in NAFLD‐derived liver carcinogenesis.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v139.11
    DOI: 10.1002/ijc.30379
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 5
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    Clonal expansion in non-cancer tissues
    Springer Science and Business Media LLC ; 2021
    In:  Nature Reviews Cancer Vol. 21, No. 4 ( 2021-04), p. 239-256
    Details
    In: Nature Reviews Cancer, Springer Science and Business Media LLC, Vol. 21, No. 4 ( 2021-04), p. 239-256
    Type of Medium: Online Resource
    ISSN: 1474-175X , 1474-1768
    URL: Article
    DOI: 10.1038/s41568-021-00335-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2060549-3
    detail.hit.zdb_id: 2062767-1
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  • 6
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    Abstract 1683: Mutational landscape of colorectal cancer with POLE gene mutation
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1683-1683
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1683-1683
    Abstract: Introduction POLE-mutated tumor is a rare subtype of colorectal cancer (POLE-CRC) and has been poorly understood because of its rarity. In this study, we have investigated the clinical and genetic features of POLE-CRC in the largest cohort of this unique subtype of CRC. Methods We included a total of 3,240 patients who had been treated at the Cancer Institute Hospital of Japanese Foundation for Cancer Research between 2004 and 2017, which were screened for POLE mutations, either by targeted-panel sequencing (n=544) or amplicon-based deep sequencing (n=2,696). POLE mutation-positive samples were further analyzed by whole exome sequencing. Results In total, 74 POLE variants were detected in 69 samples, of which 40 showed prominent hypermutation (median; 5,346, range; 837-16,990) with the predominance of COSMIC signature 10 associated with defective POLE functions. Patients with POLE-CRC were significantly younger (median; 50, range; 33-84), compared with those with non-hypermutated CRC (median; 65, p-value & lt;0.01) and MSI-CRC (median; 70, p-value & lt;0.01). They also showed significantly favorable prognosis than patients with non-hypermutated CRC (p-value & lt;0.01). In accordance with previous reports, mutational hotspots in POLE gene were found at codons 411, 286, 459, and 456, while a previously unreported variant was found in 1 case, which affected an active site of the exonuclease domain on codon 277. Significantly mutated genes or driver genes in 40 POLE-CRC cases were interrogated by evaluating non-synonymous vs. synonymous mutations in each gene, using dNdSCV. We found 9 genes showing significantly deviated dN/dS (q-value & lt;0.1), including B2M, APC, TP53, PTEN, PIK3CA, PIK3R1, ARID1A, TAP1, and CD58 of which most frequently observed was APC (39/40; 97.5%). Of interest, two of these genes, B2M and TAP1, are involved in the antigen presentation machinery (APM). When samples having truncating mutations in HLA-A, B, C, and TAP2 are included, 70% (28/40) of POLE-CRC samples are thought to have compromised neoantigen presentation. Positive selection of mutations in APM was also found in our analysis of POLE-mutated endometrial cancer. Because of an extremely heavy burden of somatic mutations in POLE-mutated cancers, this finding suggested an important role of anti-cancer immune evasion in the pathogenesis of these POLE-mutated cancers. Also of note is frequent loss-of-function mutations in CD58, a molecule involved in NK-cell recognition. In 70% (7/10) of CD58 mutated cases, co-occurrence with mutations affecting the APM was detected. Loss of intact CD58 might play a role in the evasion from NK cell surveillance for tumors with defective HLA presentation. Conclusions Similar to MSI-CRC, POLE-CRC shows a favorable prognosis, where the mutations affecting APM are positively selected to evade immune surveillance, suggesting a possible role of checkpoint blockade in its therapeutics. Citation Format: Yoshikage Inoue, Nobuyuki Kakiuchi, Kenichi Yoshida, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Tetsuichi Yoshizato, HIroko Tanaka, Satoshi Nagayama, Satoru Miyano, Yoshiharu Sakai, Seishi Ogawa. Mutational landscape of colorectal cancer with POLE gene mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1683.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1683
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract 164: Clonal evolution in noncancerous esophageal mucosa in normal and cancer-bearing individuals
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 164-164
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 164-164
    Abstract: Background Esophageal squamous cell carcinoma (ESCC) represents the most common form of esophageal cancer worldwide, especially in East Asia, where alcohol drinking and smoking have been implicated in the field carcinogenesis of ESCC. However, the oncogenic process therein has been poorly understood in terms of gene mutations. Patients & Methods A total of 100 samples, including cancer, dysplastic, and non-dysplastic esophageal tissues, were obtained from 24 individual with (N = 14) or without (N = 10) ESCC (a median of 2.5 samples per case: 1−29) either by endoscopy or surgery and were subjected to whole exome sequencing (WES). An additional paired cancer/non-caner samples from 32 patients was analyzed by targeted sequencing (TS). All samples were analyzed for copy number alterations (CNAs) using SNP array- and/or digital sequencing-based karyotyping. Results In WES, clonal evolution in esophageal epithelia, as determined by the presence of somatic mutations, was detected in 21 of 21 cancer, 12 of 12 dysplastic, and 63 of 67 non-dysplastic samples, where the mean number of mutation per sample showed a significant trend to increase in cancer (65) and dysplastic samples (50) compared to non-dysplastic samples (13) (P = 2.1×10-11). CNAs, especially those involving CDKN2A, CCND1, YAP1, and EGFR, were frequently affected in cancer samples, but rarely so in non-dysplastic samples. Non-dysplastic samples tended to have smaller allelic burden and therefore, clone size, compared to dysplastic and cancer samples (P = 2.2×10-16). Mutations had a predominant age-related signature in non-dysplastic samples but increasing APOBEC3A/3B patterns was observed in cancer and dysplastic samples. Shared mutations were found only within cancer tissues but never among dysplastic or non-dysplastic samples, suggesting the latter lesions are clonally independent from each other. In accordance with previous reports, TP53 mutations were found in 21/21 cancer samples and also found in dysplastic (11/12) and non-dysplastic samples at a lower frequency (26/67). Strikingly, non-dysplastic samples harbored a very high frequency of NOTCH1 mutations (51/67), which were also found in cancer (3/21) and non-dysplastic (8/12) samples but at much lower frequencies (P = 6.6×10-7). TS of validation samples confirmed the trend of higher NOTCH1 (84% vs. 25%) and lower TP53 mutation rates (38% vs. 100%) in non-dysplastic samples compared to cancer samples. The number of mutations in non-dysplastic samples was higher in drinkers than non-drinkers. Multiple NOTCH1 mutations were more common in cancer patients and drinkers than non-drinkers. Conclusion Clonal proliferation in non-cancer esophageal epithelia is common even in non-ESCC cases and extensive in ESCC cases. NOTCH1 and TP53 mutations play major roles in clonal evolution in common but may have differential impacts on esophageal carcinogenesis, which is likely to be shaped by APOBEC-induced mutations and CNAs. Citation Format: Akira Yokoyama, Hiromichi Suzuki, Tetsuichi Yoshizato, Kosuke Aoki, Yusuke Shiozawa, Youichi Fujii, Yusuke Sato, Nobuyuki Kakiuchi, Sugi Kin, Keisuke Kataoka, Kenichi Yoshida, Hideki Makishima, Yusuke Amanuma, Shinya Oohashi, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Brown J.B., Masashi Sanada, Shigeru Tsunoda, Sachiko Minamiguchi, Yoshiharu Sakai, Hironori Haga, Tsutome Chiba, Satoru Miyano, Manabu Muto, Seishi Ogawa. Clonal evolution in noncancerous esophageal mucosa in normal and cancer-bearing individuals. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 164.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-164
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract 2342: Tobacco exposure and somatic mutations in normal bronchial epithelia
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2342-2342
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2342-2342
    Abstract: Background Lung cancer is the leading cause of cancer death, of which 80-90% are attributed to tobacco smoking. Our understanding of how tobacco exposure affects mutational burden, mutational signatures, driver mutations and clonal dynamics in normal lung tissue is limited. Also, genetic differences between normal cells and cancer cells in lung has not been fully elucidated. Methods To access the landscape of somatic mutations in normal bronchial epithelia, we sequenced whole genomes of 632 single-cell-derived colonies of lung basal cells from 16 patients, including 3 children, 4 never-smokers, 6 ex-smokers and 3 current smokers. Five patients had squamous cell carcinomas or carcinoma in situ, which we also sequenced to compare the genetic alteration between normal and cancer cells. Results A positive correlation between the number of base substitutions and age was observed, and 22 somatic mutations accumulated per year (95% confidence interval:20-25; P=10−8). Previous or current smoking significantly increased mutational burden: 2330 substitutions in ex-smokers and 5300 in current smokers. In addition, tobacco smoking is massively increasing both between-subject and within-subject variance of mutation burden. A population of cells in subjects with smoking history had mutation burdens equivalent to that expected for never-smokers: these cells had less damage from tobacco-specific mutational processes, and were four-fold more frequent in ex-smokers than current smokers. Signature analysis revealed that the same mutational signatures seen in lung cancers operate both in patients with and without smoking history: endogeneous signatures, including COSMIC signatures 1 and 5, and APOBEC-related signatures. Three mutational signatures were largely restricted to current or ex-smokers, including known smoking-related COSMIC signature 4 characterized by C & gt;A transversions, signature 16 characterized by T & gt;C mutations with extremely strong transcription strand bias and a new signature characterized by T & gt;A and T & gt;C mutations. dN/dS method identified driver genes in normal bronchial epithelium, including NOTCH1, TP53 and FAT1, which were overlapped with those seen in squamous cell lung cancers and other normal squamous tissues such as esophagus and skin. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged never-smokers. In current smokers, ≥25% of cells carried driver mutations and 0-6% cells had 2 or even 3 drivers. Layering driver mutations onto phylogenetic trees revealed that driver mutations occurred in early life. Compared to the normal bronchial epithelial cells, lung cancers and precancerous lesions were characterized by extensive copy number changes or structural variants and distinct set of driver mutations. Conclusions Tobacco smoking increases mutation burden, cell-to-cell heterogeneity and driver mutations. Our data of genetic lesions in normal bronchial cells provides insights into genetic alterations that drive carcinogenesis in lung. Citation Format: Kenichi Yoshida, Kate HC Gowers, Henry Lee-Six, Deepak P. Chandrasekharan, Tim Coorens, Elizabeth F. Maughan, Kathryn Beal, Andrew Menzies, Fraser R. Millar, Elizabeth Anderson, Sarah E. Clarke, Adam Pennycuick, Ricky M. Thackeray, Colin R. Butler, Nobuyuki Kakiuchi, Tomonori Hirano, Robert E. Hynds, Michael R. Stratton, Inigo Martincorena, Sam M. Janes, Peter J. Campbell. Tobacco exposure and somatic mutations in normal bronchial epithelia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2342.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2342
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Abstract 2185: Genetic analysis of metachronous pancreatic cancers
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2185-2185
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2185-2185
    Abstract: [Introduction] Early detection of pancreatic cancer is a key to curable surgery. However, many patients are diagnosed with an advanced disease and even in those who have an early stage tumor successfully resected, the development of metachronous cancer in the residual pancreas prevents a long-term survival. Thus, it is important to control metachronous tumors to improve clinical outcomes, whose pathogenesis, however, is poorly understood. In this study, we aimed to reveal the origin of metachronous tumors using an unbiased detection of somatic mutations in primary and metachronous tumors as well as adjacent precursor lesions. [Methods] Serially obtained formalin-fixed paraffin-embedded surgical specimens from 12 patients who had undergone curative surgery for an early-stage pancreatic cancer were subjected to laser microdissection for enrichment of tumor and precancerous components, from which DNA was extracted and analyzed for somatic mutations using whole-exome sequencing (WES) with matched normal DNA. Based on shared and private mutations across different samples, we interrogated history of clonal evolution of these lesions. [Results] Pathology for resected primary cancer was margin-negative in all patients. The median interval between the initial and second surgery was 34.6 months (12 - 65.1 months). Paired primary and metachronous cancers were analyzed in all 12 patients. An additional 5 pancreatic intraepithelial neoplasia (PanIN) samples were also analyzed in one case. We identified a median of 86 (range: 40-145) and 20 (14-42) somatic mutations using WES in cancers and PanIN lesions, respectively. None of the patients have known pathogenic germline variants. All samples had one or more driver mutations. In each patient, all driver mutations and many passenger mutations were shared between primary and metachronous cancer samples, suggesting that those metachronous tumors are evolutionally closely related to the primary cancer, despite long years before recurrence. Negative pathology of the margins at the initial surgery suggested that those metachronous lesions originated from distant dissemination or metastasis, rather than contiguous, intraductal invasion. By contrast, none of the mutations other than hotspot KRAS mutations were shared between precursor lesions and cancer samples. Despite multiple independent clones in the precancerous lesion, all metachronous tumors originated from the primary lesions in this study. [Conclusions] Our study suggests that even early pancreatic cancer might be disseminated within the pancreas and give rise to metachronous cancers, suggesting the importance of close monitoring of recurrence in the residual pancreas. Citation Format: Tomonori Hirano, Nobuyuki Kakiuchi, Yasuhide Takeuchi, Tomomi Nishimura, Toshihiko Masui, Sachiko Minamiguhi, Hironori Haga, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Satoru Miyano, Uza Norimitsu, Yuzo Kodama, Hiroshi Seno, Seishi Ogawa. Genetic analysis of metachronous pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2185.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2185
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract 3132: Tumorigenesis of MEN2 pheochromocytoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3132-3132
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3132-3132
    Abstract: Backgrounds: Pheochromocytomas are catecholamine-secreting neuroendocrine tumors, which occur sporadically or as part of inherited syndromes, such as multiple endocrine neoplasia type2 (MEN2), caused by deleterious mutations within the RET protooncogene. Although the RET mutation is implicated in the development of MEN2-associated pheochromocytoma, there is a long (typically 40 years) latency period before the disease onset, suggesting the need of the acquisition of secondary hits. However, little is known about such secondary alterations involved in the pathogenesis of MEN2. In this study, we compared genetic profiles of MEN2 pheochromocytoma and its precursor lesion, adrenal medullary hyperplasia (AMH). Materials and methods: Samples were collected from surgical specimens in 6 MEN2 pheochromocytoma cases, including a MEN2B case with RET p.M918T and 5 MEN2A cases with RET p.C634F, p.C634F, p.C634Y, p.E768D and p.C620S, and 1 AMH case with MEN2A carrying RET p.C634Y. Spatially separated samples were collected from a tumor slice (“tumor parts”). Multiple microscale sampling was also performed from apparently normal adrenal medulla (“non-tumor parts”). Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. Result: Regarding “tumor parts”, a total of 20 samples from 6 MEN2 pheochromocytomas was analyzed. The number of somatic mutations per sample was ranging from 2 to 10. No somatic mutations commonly implicated in sporadic pheochromocytomas were detected. In a case with MEN2B, 1p, 3q and 21q losses were shared across all 3 samples, while 11p and 11q losses and 5p, 5q, 12p, 12q and 15q gains were private, suggesting that 1p, 3q and 21q losses occurred early in the tumorigenesis. In 5 MEN2A cases, 1p (80%), 3q (100%), 21q (60%) and 22q (60%) losses were frequently shared across all samples in each case. As for “non-tumor parts”, a total of 12 samples from 2 MEN2 pheochromocytoma cases and 1 AMH case were analyzed. The number of somatic mutations per sample ranged from 0 to 15. In 2 MEN2 pheochromocytoma cases, no somatic mutations were shared across the samples or no CNAs were detected, while 12 mutations were shared in two samples derived from an AMH case. Interestingly, these samples harbored 17p loss alone, while 1p, 3q, 21q or 22q losses were not found. Conclusion and perspective: MEN2 pheochromocytoma and AMH had different genetic characteristics, where 1p, 3q, 21q and 22q losses could have a role in early tumorigenesis. Further studies involving an increasing number of patients with MEN2 pheochromocytoma and AMH are warranted. Citation Format: Tatsuki Ogasawara, Yoichi Fujii, Nobuyuki Kakiuchi, Yusuke Shiozawa, Hiromichi Suzuki, Ryuichi Sakamoto, Yusaku Yoshida, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa. Tumorigenesis of MEN2 pheochromocytoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3132.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-3132
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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