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  • American Association for Cancer Research (AACR)  (14)
  • 1
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 2, No. 6 ( 2014-06-01), p. 568-580
    Abstract: Vaccination with irradiated granulocyte macrophage colony-stimulating factor (GM-CSF)–transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity. However, its effectiveness is limited. We therefore attempted to improve the antitumor effect by identifying little-known key pathways in GM-CSF–sensitized dendritic cells (GM-DC) in tumor-draining lymph nodes (TDLN). We initially confirmed that syngeneic mice subcutaneously injected with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) remarkably rejected the tumor growth. Using cDNA microarrays, we found that expression levels of type I interferon (IFN)–related genes, predominantly expressed in plasmacytoid DCs (pDC), were significantly upregulated in TDLN-derived GM-DCs and focused on pDCs. Indeed, mouse experiments demonstrated that the effective induction of GM-CSF–induced antitumor immunity observed in immunocompetent mice treated with LLC/SeV/GM cells was significantly attenuated when pDC-depleted or IFNα receptor knockout (IFNAR−/−) mice were used. Importantly, in both LLC and CT26 colon cancer–bearing mice, the combinational use of imiquimod with autologous GVAX therapy overcame the refractoriness to GVAX monotherapy accompanied by tolerability. Mechanistically, mice treated with the combined vaccination displayed increased expression levels of CD86, CD9, and Siglec-H, which correlate with an antitumor phenotype, in pDCs, but decreased the ratio of CD4+CD25+FoxP3+ regulatory T cells in TDLNs. Collectively, these findings indicate that the additional use of imiquimod to activate pDCs with type I IFN production, as a positive regulator of T-cell priming, could enhance the immunologic antitumor effects of GVAX therapy, shedding promising light on the understanding and treatment of GM-CSF–based cancer immunotherapy. Cancer Immunol Res; 2(6); 568–80. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 14 ( 2021-07-15), p. 3916-3929
    Abstract: Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9–FGFR axis as a therapeutic target for transdifferentiated SCLC. Significance: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 410466-3
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  • 3
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    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P5-15-09-P5-15-09
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P5-15-09-P5-15-09
    Abstract: Background: Many breast cancer patients suffer hair loss due to chemotherapy, and not only scalp hair loss, but also eyebrow loss, eyelash loss and nail changes induced by chemotherapy are traumatic for patients. These side effects diminish self-esteem and greatly reduce quality of life. However, there has been little research in this field until now. To clarify the actual situation concerning appearance issues in breast cancer patients who received adjuvant chemotherapy, and to consider a support system for these patients, we conducted a questionnaire survey. Methods: Disease-free breast cancer patients who have received adjuvant chemotherapy containing anthracycline and/or taxane within 5 years were recruited from 47 hospitals or clinics in Japan from April to October 2013. The patients participating in this survey completed a 65-question questionnaire concerning appearance issues (48) and their perception of physical and non-physical side effects (17). The drugs administered and treatment period were filled out by their doctors beforehand. The completed questionnaires were mailed directly to the data center by the patients. Results: A total of 1511 patients returned the questionnaire to the data center with a response rate of 82% (1511/1853). Since 33 patients did not meet the entry criteria, the questionnaires returned by 1478 patients were analyzed in this survey. The mean age was 54.7 years (+-10.4, range 17-79). The distribution of the patients by time from the end of chemotherapy to this survey was as follows: & lt; 1 year: 28%; 1 to 2 years: 24%; 2 to 3 years: 19%; 3 to 4 years: 15%; 4 to 5 years: 13%. In this survey, the side effect that most patients (92%) considered traumatic was hair loss. The second most traumatic side effect was fatigue (83%), while the 7th place was taken by nail changes (72%) and nausea/vomiting was in the 10th place (56%). During chemotherapy, scalp hair loss occurred in 98% of patients. Eyebrows fell out in 90% and complete eyebrow loss occurred in 36%. Eyelashes fell out in 88% and complete eyelash loss occurred in 37%. Fingernail changes occurred in 77% and toenail changes in 62%. In 60-70%, scalp hair, eyebrow and eyelashes recovered to the original appearance by 1 to 1.5 years after chemotherapy, but in 3-7%, scalp and face hair loss did not recover at all by 1 to 1.5 years. This proportion remained almost the same for 1.5 to 5 years too. During or after chemotherapy, 84% of patients used wigs. This decreased to 47% by 1 year after chemotherapy and 15.2% by 1.5 years. However 10% of patients were still using a wig 4 to 5 years after chemotherapy. Approximately 30% of the patients had trouble using and selecting a wig. In 51% of the patients, sufficient information on scalp hair loss was obtained. However, sufficient information on eyebrow loss, eyelash loss and nail changes was only obtained from 28%, 25% and 31%, respectively. Conclusions: Our survey demonstrated the outline of hair loss and appearance issues in breast cancer patients who received chemotherapy. Hair loss is the most distressing and occasionally long-lasting side effect. Lack of information is a serious problem. These facts suggested a need for long-time and careful support of these patients. Citation Format: Takanori Watanabe, Hiroshi Yagata, Mitsue Saito, Hiroko Okada, Tomoko Takayama, Hirohisa Imai, Yuko Yoshida, Nao Tamai, Keiko Nozawa, Tamiko Yajima, Kojiro Shimozuma. National survey of chemotherapy-induced appearance issues in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-09.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 8 ( 2017-04-15), p. 2019-2026
    Abstract: Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy. Experimental Design: We enrolled 279 patients with hormone receptor–positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele). Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 5
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    American Association for Cancer Research (AACR) ; 2010
    In:  Molecular Cancer Research Vol. 8, No. 11 ( 2010-11-01), p. 1547-1557
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 8, No. 11 ( 2010-11-01), p. 1547-1557
    Abstract: Many cancer cells exhibit increased rates of uptake and metabolism of glucose compared with normal cells. Glucose uptake in mammalian cells is mediated by the glucose transporter (GLUT) family. Here, we report that DNA-damaging anticancer agents such as Adriamycin and etoposide suppressed the expression of GLUT3, but not GLUT1, in HeLa cells and a tumorigenic HeLa cell hybrid. Suppression of GLUT3 expression determined by the real-time PCR was also evident with another DNA-damaging agent, camptothecin, which reduced the promoter's activity as determined with a luciferase-linked assay. The suppression by these agents seemed to be induced independently of p53, and it was evident when wild-type p53 was overproduced in these cells. In contrast, the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) kinase (MEK) inhibitor U0126 (but not the phosphoinositide 3-kinase inhibitor LY294002) prevented the drug-induced suppression as determined by reverse transcription-PCR and promoter assays. Furthermore, overexpression of GLUT3 in HeLa cell hybrids increased resistance to these drugs, whereas depletion of the gene by small interfering RNA rendered the cells more sensitive to the drugs, decreasing glucose consumption. The results suggest that DNA-damaging agents reduce GLUT3 expression in cancer cells through activation of the MEK–ERK pathway independently of p53, leading to cell death or apoptosis. The findings may contribute to the development of new chemotherapeutic drugs based on the GLUT3-dependent metabolism of glucose. Mol Cancer Res; 8(11); 1547–57. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1458-1458
    Abstract: Background: We have developed a microcavity array (MCA) system integrated with a miniaturized device for the isolation of circulating tumor cells (CTC) without relying on EpCAM expression. The MCA system allows the filtration of tumor cells from whole blood on the basis of differences in the size between tumor and blood cells. The previous study has shown that the MCA system is potentially superior to the conventional epithelial antigen-based method for detecting CTCs in non-small cell lung cancer. Recently, we further optimized the shape and porosity of MCA to efficiently isolate smaller tumor cells as in small cell lung cancer (SCLC). Here we report the results of clinical study in SCLC patients comparing MCA system to CellSearch system and exploratory study of novel rectangular-shaped MCA system. Methods: The MCA is made of nickel by electroforming and circular MCA is fabricated with 8-9 μm diameter pores. Meanwhile, novel rectangular-shaped MCA is fabricated with 5-9 μm-wide and 30-60 μm-long pores. NCI-H69 (12 μm in diameter) SCLC cells were used for spike-in experiments. CTCs were defined as cells with round to oval morphology, a visible nucleus, positive for cytokeratin and negative for CD45. For the clinical evaluation, paired peripheral blood samples were collected from 18 SCLC patients to compare the performance of the CellSearch system and the MCA system for CTC detection. Results: The recovery rate of spiked NCI-H69 cells with the rectangular-shaped MCA (80 ± 2%) was significantly higher than that with the circular MCA (67 ± 4%) (p=0.01, t-test). In addition, the carryover of leukocytes on the rectangular-shaped MCA was 7-fold lower than that on the circular MCA in the experiment using healthy donor blood. The fluctuation of flow resistance during filtration with the rectangular-shaped MCA ( & lt;1.5 kPa) was smaller than that with the circular MCA (2 kPa); the rectangular-shaped MCA enabled recovery of small tumor cells with high efficiency. In clinical study, compared to the CellSearch, the circular and rectangular-shaped MCA system identified significantly more SCLC patients (9 of 18 vs. 18 of 18 vs. 17 of 18, respectively) as CTC positive. No significant difference was observed in the CTC counts between the rectangular-shaped MCA (median 16, range 0-545 cells/7.5 mL) and the circular MCA (median 23, range 2-2329 cells/7.5 mL) (p=0.77, Wilcoxon test). In contrast, the number of captured leukocytes on the rectangular-shaped MCA was significantly lower than that on the circular MCA (p & lt;0.0001, Wilcoxon test), suggesting that implementing the rectangular-shaped MCA diminishes a considerable number of carryover leukocytes. Conclusion: The MCA system has a potential as a tool for the efficient recovery of CTCs in small cell type tumors with high purity, while offering the additional advantages in cost, portability, and capacity to perform more detailed analyses of CTCs. Citation Format: Masahito Hosokawa, Hirotsugu Kenmotsu, Yasuhiro Koh, Tomoko Yoshino, Tsuyoshi Tanaka, Tateaki Naito, Toshiaki Takahashi, Haruyasu Murakami, Yukiko Nakamura, Asuka Tsuya, Takehito Shukuya, Akira Ono, Hiroaki Akamatsu, Reiko Watanabe, Sachiyo Ono, Hisashige Kanbara, Tadashi Matsunaga, Nobuyuki Yamamoto. Efficient isolation of circulating tumor cells in small cell lung cancer patients using size- and geometry-controlled microcavity array system. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1458. doi:10.1158/1538-7445.AM2013-1458
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P5-15-17-P5-15-17
    Abstract: Background: Altered appearance due to chemotherapy is a very distressing adverse event and can remain unrecovered for a long time after chemotherapy. To clarify the current status of appearance change and its support systems, we conducted a national questionnaire survey of patients with breast cancer who had received chemotherapy in Japan. Here, we report on the long-term recovery of scalp hair loss during and after chemotherapy. Patients and methods: A questionnaire was distributed to patients in hospitals throughout Japan between April and October 2013. The questionnaire was regarding the current status of the patients’ appearance issues (scalp hair, eyebrows, eyelashes, nails, skin) related to chemotherapy and its support systems, including chemotherapy regimens received, endocrine therapy received, and duration after chemotherapy. Eligible patients were women with breast cancer without any recurrence who had received adjuvant or neoadjuvant chemotherapy containing anthracycline (A) and/or taxanes (paclitaxel, P; docetaxel, D) and who were within 5 years from the last chemotherapy treatment. The physicians of each hospital asked their patients to fill out the questionnaire and mail it directly to the data center. The scalp hair status was analyzed in a cross-sectional manner according to the duration from chemotherapy. Results: The questionnaires were returned from 1511 patients in 47 hospitals (response rate, 82%; 1511/1853). Thirty-three patients were excluded, mainly because & gt;5 years had passed since chemotherapy. In total, 1478 questionnaires were ultimately analyzed. The median age was 50 (range, 17–79) years. The distribution of patients according to time from the last chemotherapy treatment was as follows: & lt;1 year, 28%; 1–2 years, 24%; 2–3 years, 19%; 3–4 years, 15%; and 4–5 years, 13%. During chemotherapy, scalp hair loss occurred in 98.4% of the patients, and 94% experienced & gt;80% hair loss. Hair growth began during chemotherapy in 13.1% of patients and after chemotherapy in 80.3% (6.6% left the question unanswered). Within 6 months from the start of hair growth, 65% of patients felt a change in hair thickness, while 82% felt it was becoming thin. Of the patients, 70% felt a change in quality, while 48% felt that it had become unruly; 44% felt a color change, while 80% felt that they were growing more gray hair. Of the patients who answered the questions, & gt;80% hair volume recovery was seen in 52.7% of patients within 1 year; in 63.5%, in 1–3 years; and in 61.7%, even after 3 years. After 3 years, volume recovery was seen in 67.8% of patients after an A+P–containing regimen; in 43.4%, after A+D; in 63.5%, after D; and in 88.9%, after A. Patients who had received A+P, D, and A+D had significantly less volume recovery than patients who had received A (P & lt;0.001 for all). Conclusions: Almost all patients with breast cancer experienced severe hair loss during standard chemotherapy, but a recovery trend was noted after chemotherapy. However, hair remained unrecovered to various degrees in a significant number of patients even 3–5 years after chemotherapy, especially in those who had received taxane-containing regimens. We should consider the support needs of patients who experience chemotherapy-induced hair loss. Citation Format: Hiroshi Yagata, Takanori Watanabe, Hiroko Okada, Mitsue Saito, Tomoko Takayama, Hirohisa Imai, Yuko Yoshida, Nao Tamai, Keiko Nozawa, Tamiko Yajima, Kojiro Shimozuma. National survey of long-term recovery from chemotherapy-induced hair loss in patients with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-17.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2370-2370
    Abstract: Background: EpCAM-based enumeration of circulating tumor cells (CTCs) has prognostic value in solid tumors such as advanced breast, colon and prostate cancers. However, currently poor sensitivity has limited the use of CTCs in other types of cancers including non-small cell lung cancer (NSCLC). We have developed a microcavity array (MCA) system integrated with microfluidic device for recovery and enumeration of CTC regardless of EpCAM expression level, allowing isolation of tumor cells on the basis of differences in the size and deformability between tumor and hematologic cells. Shapes and sizes of the cavity were optimized in order to trap tumor cells while letting blood cells flow through the microcavities during whole blood filtration. Enrichment of CTCs, fixation, permeabilization, staining, and counting process were implemented in a microfluidic assay within one integrated device. In this study, we evaluated the sensitivity of the MCA system in detecting CTCs with a preclinical model using cell lines and conducted a clinical feasibility study in NSCLC patients. Methods: A wide range of cancer cell lines derived from breast (MCF-7, Hs578T), colon (SW620), gastric (AGS, SNU-1) and lung (A549, HCC-827, NCI-H358, NCI-H441, NCI-H1650, NCI-H1975, NCI-H69, NCI-H82) were used for spike-in experiments. Cells were spiked into 1 mL of healthy donor blood and then introduced into the MCA system. Trapped cells were stained with Hoechst 33342, FITC-labeled anti-pan cytokeratin antibody and PE-labeled anti-CD45 antibody for subsequent imaging analysis. CTCs were defined as cells with round to oval morphology, a visible nucleus, positive staining for pan-cytokeratin and negative staining for CD45. For the clinical evaluation, 16 advanced NSCLC patients were enrolled into the study and we conducted a head-to-head comparison study with CellSearch system. Results: We obtained a quite high recovery rate regardless of tumor types ranging from 80 to 99% in the cell line spike-in experiments containing EpCAM-negative cell lines (Hs578T, SNU-1). Most of recovered cells were viable and were able to proliferate even after isolation process, suggesting the potential for further biological and molecular analyses of CTCs. In the clinical part of the study, CTCs were detectable in 12 out of 16 patients (count β1 per 7.5 ml) with our system. More CTCs were detected by MCA system (median 13, range 0-313 cells/7.5ml blood) than by CellSearch system (median 0, range 0-37 cells/7.5ml blood) demonstrating statistical superiority (p=0.0132, Wilcoxon test). It is also noteworthy that among patients who had negative CTC count by CellSearch system, several patients had positive CTC count by MCA system, suggesting better detection of EpCAM-negative CTCs. Conclusion: Our results suggest the potential of our MCA system for detection of CTCs in solid tumors including NSCLC and further clinical development should be considered. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2370. doi:1538-7445.AM2012-2370
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5364-5364
    Abstract: Background: We have reported DNA methylation alterations in non-cancerous lung tissue obtained from lung cancer patients. These previous data drew our attention to DNA methylation alterations at precancerous stage of lung adenocarcinoma (LADC). However, the impact of DNA methylation alterations at precancerous stage on the characteristics of established LADCs has been unclear. The purpose of this study is to clarify the significance of DNA methylation profiles during lung carcinogenesis. Methods: Using single-CpG resolution Infinium array, genome-wide DNA methylation analysis was performed in 36 samples of normal lung tissue (C), 139 samples of non-cancerous lung tissue (N) obtained from patients with LADCs, and the corresponding 139 samples of tumorous tissue (T) as a learning cohort. As a validation cohort, the 50 paired samples of N and the corresponding T were obtained from patients with primary LADCs. Results: 3,621 probes showed significant differences in DNA methylation levels between the 36 C and 139 N samples in the learning cohort, suggesting that N was at precancerous stage with DNA methylation alterations. Unsupervised hierarchical clustering using DNA methylation levels of N on 26,447 autosomal probes subclustered 139 patients of the learning cohort into Cluster A (n=32), B (n=35) and C (n=72). Most of patients in Cluster A were heavy smokers and frequently showed severe pleural anthracosis which mainly reflects smoking history. LADCs in Cluster A were locally invasive tumors which develop in emphysematous lung tissue associated with inflammation. Most of patients in Cluster B were non-smokers and LADCs in Cluster B showed less aggressive features. Most of patients in Cluster C were light smokers and LADCs in Cluster C showed more frequent lymph node metastasis and higher Tumor-Node-Metastasis (TNM) stages. The cancer-free and overall survival rates of patients in Cluster C were significantly lower than those of Cluster B. We indetified 21, 26 and 35 probes as markers which characterize Clusters A, B and C, respectively. In the validation cohort, DNA methylation levels of Cluster A, B and C marker probes were significantly correlated with pleural anthracosis, never-smoking history, and lymph node metastases and higher TNM stages, respectively, i.e. correlation between DNA methylation profiles and each clinicopathological parameter were validated in the validation cohort. Conclusion: DNA methylation profiles of Clusters A and C at precancerous stage may be established by the effects of smoking through or not thorough inflammation, respectively, whereas those of Cluster B may be associated with carcinogenesis in non-smokers. DNA methylation profiles at precancerous stage may underlie distinct pathways of lung carcinogenesis and determine tumor aggressiveness and patient outcome. Citation Format: Takashi Sato, Eri Arai, Takashi Kohno, Koji Tsuta, Shun-ichi Watanabe, Kenzo Soejima, Tomoko Betsuyaku, Yae Kanai. DNA methylation profiles at precancerous stage cluster lung adenocarcinomas into subclusters associated with carcinogenetic pathway, clinicopathological aggressiveness and patient outcome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5364. doi:10.1158/1538-7445.AM2013-5364
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3551-3551
    Abstract: Homologous recombination deficiency (HRD) phenotype often observed in tumors with BRCA1/2 deficiency is considered to be associated with efficacy of PARP inhibitors and platinum-based therapies. However, analysis on the degree of HRD requires comprehensive “genomic scar” analyses like Myriad MyChoice, therefore, we sought to develop a simple HRD prediction model in breast cancer patients without compromising its predictive value. HRD score as a consequence of genomic scars was calculated counting loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI), and large-scale state transition score (LST) for three independent breast cancer cohorts; TCGA (n= 744), ICGA (International Cancer Genome Consortium, n= 477), and Japanese AYA cohorts (n= 46). The HRD-high phenotype was defined as HRD scores ≥ 42. Genetic and pathological factors in HRD-high cases were determined by analyzing the sequencing data and DNA methylation chip analysis data as well as clinico-pathological information of the cohorts. The sequencing data comprised somatic mutation status of 82 significantly mutated genes (SMGs), germline/somatic mutations of 25 cancer susceptibility genes and three other HR-related genes. First, we adopted an Elastic Net regularized regression approach that controls for co-varying features within high-dimensional data in a TCGA breast cancer (Area under the curve [AUC] = 0.876), then applied the model onto two validation datasets. Among 16 selected features in the model, features with top-10 coefficient values were hypermethylation status, germline mutations of BRCA1, BRCA2, and PALB2, somatic mutations of BRCA1, BRCA2, PALB2 and TP53, triple negative subtype, and higher nuclear grade. The AUC values in ICGC and Japanese AYA were 0.899 and 0.941, respectively. Second, a simple predictive model for the HRD-high phenotype was developed using a TCGA data set (Area under the curve [AUC] = 0.838) based on only 5 features which were statistically significant (P & lt; 0.01) in logistic regression analysis; germline BRCA1, BRCA2 and somatic TP53 mutations, triple negative subtype and higher nuclear grades. Its prediction power was validated in ICGC (AUC = 0.873) and Japanese AYA cohorts (AUC = 0.936). After excluding most features in the comprehensive Elastic Net model, the simple prediction model derived from five features still showed high AUC values comparable to those from the comprehensive models in the validation sets. These five features can be assessed by gene panel tests and daily pathological analyses. Thus, this study clarifies genomic and pathological factors associated with HRD phenotype of breast cancer and provides a simple predictive model of HRD to identify breast cancer patients who would benefit from PARP and/or platinum therapies in the clinical setting. Citation Format: Maki Tanioka, Tomoko Watanabe, Takayuki Honda, Hirohiko Totsuka, Eri Arai, Yae Kanai, Kouya Shiraishi, Kenji Tamura, Takashi Kohno. Simple vs. comprehensive prediction models of homologous recombination deficiency based on mutational and clinical features in three independent breast cancer datasets [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 3551.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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