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  • American Association for Cancer Research (AACR)  (34)
  • 1
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    Abstract P5-13-04: Clonal evolution of mammary epithelial cells into breast cancers
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P5-13-04-P5-13-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P5-13-04-P5-13-04
    Abstract: [Introduction] Proliferative lesions in the breast have been implicated in the development of breast cancer. Previous studies showed that some proliferative lesions and adjacent breast cancers shared common genetic alterations, suggesting that these originated from the same ancestral cell. However, the clonal structure of normal epithelia and their clonal history during evolution to cancer are poorly understood. In this study, we analyzed genetic profiles of normal epithelia and proliferative lesions in the cancer-borne breast to illustrate the clonal evolution of cancer from a normal epithelial cell. [Methods] Single cell-derived organoids (n=47) were established from breast milk of 4 healthy women aged 22–36 and normal breast tissue of 15 breast cancer patients aged 29–83 to evaluate somatic mutation rate in normal epithelial cells. Multiple normal lobules and proliferative lesions together with cancer lesions were collected using laser-capture micro-dissection (LCM) from fresh frozen (n=3) or formalin-fixed paraffin-embedded (n=5) surgical specimens in 9 premenopausal breast cancer patients. Somatic mutations and copy number alterations were evaluated using whole-genome sequencing. [Results] The mutation profile of single cell-derived organoids suggests that somatic mutations accumulate in normal mammary epithelial cells at a constant rate of 19.4/genome/year before menopause, and the mutation rate decreases to 6.9/genome/year after menopause. Parity was negatively associated with mutation number (-49.3 per life birth). In total, we analyzed 143 LCM samples, including those from 72 normal lobules, 43 proliferative lesions, and 19 non-invasive and 9 invasive cancer samples. Five cases showed a large expansion of proliferative lesions sharing a substantial number of somatic mutations with cancer. These lesions expanded over a distance of 35-90 mm, sharing tens to hundreds of mutations including those in breast cancer-related driver genes, such as PIK3CA, AKT1, GATA3, CBFB and PTEN, while harboring private mutations or copy number alterations of their own. Of interest, the cancers in 4 out of these 5 cases was luminal-A type invasive ducal carcinoma or ER-positive HER2-negative ductal carcinoma in situ, and characterized in common by the presence of der(1;16), concurrent whole-arm 1q gain and 16q loss, in both cancer and proliferative lesions. Phylogenetic analysis adapted with the mutation rate in normal cells predicted that der(1;16) had been acquired between puberty and early 20’s, and the common ancestors of non-cancerous and cancerous lesions emerged by early 30’s, & gt;10 years earlier than at the time of cancer diagnosis. By contrast, analysis of non-cancerous lobules unrelated to cancer showed that der(1;16)-negative non-cancer clones that had emerged after puberty stayed within a single lobule or spatially confined to adjacent lobules and rarely expanded to a large area as observed for those carrying der(1;16), even if the clones had acquired mutations in driver genes such as PIK3CA and PIK3R1, which highlighted the role of der(1;16) in wide clonal expansion. [Conclusions] Our results suggest that in some breast cancer cases, particularly in those with der(1;16), a highly recurrent translocation accounting for the major subset of Luminal A breast cancer, the clones with the funder driver alterations expanded macroscopically long before the onset of cancer, in which further clonal evolutions recursively occur multi-focally, giving rise to multiple proliferative lesions and ultimately, invasive cancers. Our findings provide new insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida, Takaki Sakurai, Tatsuki R. Kataoka, Eiji Kondoh, Yoshitsugu Chigusa, Masahiko Kawai, Morio Sawada, Takuya Inoue, Yasuhide Takeuchi, Hirona Maeda, Satoko Baba, Yusuke Shiozawa, Ryunosuke Saiki, Masahiro M. Nakagawa, Yasuhito Nannya, Yotaro Ochi, Tomonori Hirano, Yukiko Inagaki-Kawata, Kosuke Aoki, Masahiro Hirata, Eiji Suzuki, Masahiro Takada, Masahiro Kawashima, Kosuke Kawaguchi, Kenichi Chiba, Yuichi Shiraishi, Junko Takita, Satoru Miyano, Masaki Mandai, Kengo Takeuchi, Hironori Haga, Masakazu Toi, Seishi Ogawa. Clonal evolution of mammary epithelial cells into breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl) :Abstract nr P5-13-04.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P5-13-04
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Abstract P2-10-12: Relationship between predicted risks of carrying breast cancer susceptibility genes and the presence of germline variants in Japanese patients with primary breast cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-10-12-P2-10-12
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-10-12-P2-10-12
    Abstract: Background: Breast cancer risk models are used to predict the risk of carrying a variant, for one of the most common breast cancer susceptibility genes such as BRCA1 and BRCA2, and the lifetime risk of developing breast cancer. The prediction of harboring a germline variant of the BRCA gene and the development of breast or ovarian cancer over time affects the decision-making for undergoing genetic testing and screening using imaging techniques as the common practice. For instance, the American Cancer Society and the National Comprehensive Cancer Network (NCCN) recommends screening using MRI in women with 20% or greater lifetime risk of having breast cancer. We aimed to investigate the prediction of these risks in Japanese women, particularly on the relationship between the presence of pathogenic germline variants and breast cancer susceptibility genes, using a cohort of 1016 primary breast cancer patients. Patients and Methods: We analyzed a cohort of Japanese patients with primary breast cancer who were treated at the Kyoto University Hospital and the related institutions or hospitals from the period of 2011 to 2016. The germline variants were examined for a set of 13 breast cancer susceptibility genes, using targeted-capture sequencing of pooled DNA, and it was found that 66 out of 1016 patients had pathogenic variants. These included 11 functionally well-established genes (BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, NF1, PALB2, ATM, CHEK2, and NBN) and two additional genes (BARD1 and BRIP1), which are recommended for the screening of high-risk patients with hereditary breast cancer in the NCCN guidelines. Using this cohort, we studied the association of the calculated risk of carrying a germline variant of BRCA1/ BRCA2, using the Tyrer-Cuzick model Breast Cancer Risk Evaluation Tool, within the laboratory germline test results. Results: Pathogenic germline variants of BRCA1/ BRCA2 were carried by 54 (5.3%) out of the 1016 patients (12 cases of BRCA1 and 42 cases of BRCA2). According to the NCCN guidelines, which focus on Genetic/ Familial High-Risk Assessment: Breast and Ovarian, it was found that 500 out of 1016 (49.2%)patients were categorized for considering germline testing. In fact, 38 (7.6%) of the 500 patients, harbored a pathogenic germline variant of BRCA1/ BRCA2. In the remaining 516 patients, 16 (3.1%) harbored the pathogenic germline variant of BRCA1/ BRCA2. The predictive risks of the Tyrer-Cuzick model Breast Cancer Risk Evaluation Tool were recorded as follows: Area under the ROC curve, BRCA1 (area 0.750, 95% CI- 0.581-0.919), BRCA2 (area 0.741, 95% CI- 0.661-0.820), BRCA1 or BRCA2 (Area 0.749, 95% CI: 0.675-0.822), suggesting that the Tyrer-Cuzick model may be useful for the Japanese population. In the mammography breast density analysis, 484 patients showed almost entirely fat or scattered fibroglandular breast tissue, and 362 cases had heterogeneous or extreme fibroglandular breast tissue. In this study, the correlations of breast tissue density with age and breast or ovarian cancer familial history have been reported in greater detail. Discussion and Conclusions: In a retrospective cohort of 1016 Japanese patients with primary breast cancer, 5.3% had pathogenic germline variants of BRCA1/ BRCA2. In a group recommended by NCCN guidelines for considering genetic testing, the BRCA1/ BRCA2 variant rate was 7.6%. Predictive risks calculated by the Tyrer-Cuzick model similar with the known data. Further data are reported. Citation Format: Noriko Senda, Nobuko Kawaguchi-Sakita, Masahiro Kawashima, Yukiko Inagaki-Kawata, Kenichi Yoshida, Tomomi Nishimura, Masahiro Takada, Eiji Suzuki, Yuki Kataoka, Fumiaki Sato, Yoshiaki Matsumoto, Masae Torii, Hiroshi Yoshibayashi, Kazuhiro Yamagami, Shigeru Tsuyuki, Akira Yamauchi, Nobuhiko Shinkura, Hironori Kato, Yoshio Moriguchi, Ryuji Okamura, Norimichi Kan, Hirofumi Suwa, Shingo Sakata, Susumu Mashima, Fumiaki Yotsumoto, Tsuyoshi Tachibana, Mitsuru Tanaka, Takashi Inamoto, Masahiro Sugimoto, Seishi Ogawa, Masakazu Toi. Relationship between predicted risks of carrying breast cancer susceptibility genes and the presence of germline variants in Japanese patients with primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-12.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P2-10-12
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Abstract 131: Clonal expansion in bile duct associated with chronic inflammation
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 131-131
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 131-131
    Abstract: Introduction: Chronic inflammation has been implicated in cancer development in many tissues and has recently been associated with promoted clonal expansion in non-cancer tissues. Primary sclerosing cholangitis (PSC) is a chronic progressive disease of unknown etiology affecting the bile ducts and has been associated with a substantially increased risk of cholangiocarcinoma. Clonal dynamics in the normal bile duct and PSC epithelium remains poorly understood because of the limited accessibility to normal/inflamed bile ducts. In this study, we established a method to detect somatic mutations accumulated in the bile duct epithelium and investigated a mutation rate in normal bile duct cells and clonal expansion in PSC epithelium. Methods: We established single cell-derived organoids from bile, which were subjected to whole genome sequencing to measure the age-related mutation rate in normal epithelial cell in the bile ducts. We next collected multiple samples from perihilar bile ducts in patients with PSC who underwent total hepatectomy for liver transplantation, for which we performed whole exome sequencing to investigate clonal expansion in PSC-involved bile ducts. Results: In total, 14 single cell-derived organoid lines were established from 2 patients with PSC and 3 control individuals. Based on the whole genome sequencing of those organoids, the number of mutations found in non-PSC bile duct epithelium increases with age at an annual mutation rate of 38.2 mutations per genome per year, which did not substantially differ from the rate in the PSC epithelium, suggesting that the inflammatory process in PSC hardly affected the mutations in PSC epithelium. To further investigate clonal expansion in the PSC epithelium, a total of 126 bulk organoid samples from perihilar bile ducts in 3 PSC patients were analyzed. Somatic mutations were detected in all samples (21 [4-101]/exome/sample on average), some of which showed high variant allele frequencies. In 2 PSC cases, a small number of somatic mutations (n=12[case 1] , 11 and 8[case 2]) were shared between samples that were 13 mm distant apart from each other, suggesting a clonal expansion in PSC epithelium. Expanded clones harbored mutations in known cancer-driver genes, such as ARID2 and PIK3CA, suggesting their role in the expansion in this case. Conclusions: Here, we newly established the method to detect somatic mutations accumulated in the normal/inflamed bile duct epithelium using an organoid-based analysis of clonal somatic mutations. Our results revealed clonal expansion existing in PSC epithelium and open up further potential for approaching carcinogenesis in the bile duct. Citation Format: Hirona Maeda, Nobuyuki Kakiuchi, Takashi Ito, Eri Ogawa, Masahiro Shiokawa, Norimitsu Uza, Hiroko Tanaka, Yasuhito Nannya, Hideki Makishima, Hiroaki Yasuda, Yuzo Kodama, Satoru Miyano, Seishi Ogawa. Clonal expansion in bile duct associated with chronic inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 131.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-131
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Abstract 4902: Clonal evolution of proliferative lesions into breast cancers
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4902-4902
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4902-4902
    Abstract: [Introduction] Proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles of proliferative lesions and cancers from the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from various lesions with different disease-level located in the cancer-borne breast, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were evaluated by whole exome sequencing. [Results] A total of 39 samples from 6 premenopausal females carrying estrogen receptor-positive cancers were analyzed, where the samples were obtained from non-atypical (N = 1) and atypical (N = 8) proliferative lesions, and non-invasive (N = 21) and invasive (N = 4) cancers. The number of somatic mutations per sample increased with disease progression (ranging from 2 to 311). Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining four unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7 - 70 mm, shared one or more driver alterations, such as an AKT1 mutation, a GATA3 mutation, a CBFB mutation and concurrent 1q gain and 16q loss, while harboring private mutations/CNAs of their own. The analysis of phylogenic trees based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. [Conclusions] Our results suggest that early breast cancer development is shaped by the evolution of multiple precancerous clones. In hereditary cases, this process is thought to be substantially promoted multi-focally within the entire breasts, due to innate genomic instability in each mammary epithelial cell for pathogenic germline mutations. By contrast, in sporadic cases, the ancestral cell which has acquired a founder genetic alteration expands macroscopically long before the onset of cancer, most likely in early adolescent. These expanded clones work as the niche predisposed to additional mutations, in which branching evolution occurs multi-focally and raises up multiple proliferative lesions, from which invasive cancer finally evolves. Our findings provide unique insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida, Yasuhide Takeuchi, Hirona Maeda, Yusuke Shiozawa, Masahiro M. Nakagawa, Yotaro Ochi, Yukiko Kawata, Kosuke Aoki, Masahiro Hirata, Tatsuki R. Kataoka, Takaki Sakurai, Satoko Baba, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of proliferative lesions into breast cancers [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 4902.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-4902
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
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  • 5
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    Abstract 92: Clonal evolution of proliferative lesions into breast cancers
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 92-92
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 92-92
    Abstract: Introduction: Proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles of proliferative lesions and cancers from the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. Methods: Multiple samples were collected from various lesions with different disease-level located in the cancer-borne breast, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were evaluated by whole exome sequencing. Results: A total of 39 samples from 7 premenopausal females carrying estrogen receptor-positive cancers were analyzed, where the samples were obtained from proliferative lesions (without/with atypia) (N = 3 and 10, respectively), and non-invasive (N = 22) and invasive (N = 4) cancers. The number of somatic mutations per sample increased with disease progression (ranging from 7 to 311). Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining five unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7 - 70 mm, shared one or more driver alterations, such as an AKT1 mutation, a GATA3 mutation, a CBFB mutation, a PTEN mutation and concurrent 1q gain and 16q loss, while harboring private mutations/CNAs of their own. The analysis of phylogenic trees based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. Conclusions: Our results suggest that early breast cancer development is shaped by the evolution of multiple precancerous clones. In hereditary cases, this process is thought to be substantially promoted multi-focally within the entire breasts, due to innate genomic instability in each mammary epithelial cell for pathogenic germline mutations. By contrast, in sporadic cases, the ancestral cell which has acquired a founder genetic alteration expands macroscopically long before the onset of cancer. These expanded clones work as the niche predisposed to additional mutations, in which branching evolution occurs multi-focally and raises up multiple proliferative lesions, from which invasive cancer finally evolves. Our findings provide unique insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida, Yasuhide Takeuchi, Hirona Maeda, Yusuke Shiozawa, Masahiro M. Nakagawa, Yotaro Ochi, Yukiko Kawata, Kosuke Aoki, Masahiro Hirata, Tatsuki R. Kataoka, Takaki Sakurai, Satoko Baba, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of proliferative lesions into breast 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 92.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-92
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
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  • 6
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    Abstract 6085: Clonal evolution of mammary epithelial cells into breast cancers
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6085-6085
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6085-6085
    Abstract: [Introduction] Previous studies suggested that breast cancers (BCs) and some adjacent atypical proliferative lesions evolved from the same ancestral cell. However, the clonal structure of normal epithelial cells and their clonal history during evolution to cancer are poorly understood. In this study, we analyzed genetic profiles of normal epithelia and proliferative lesions in the cancer-borne breast to illustrate the clonal evolution of cancer from a normal epithelial cell. [Methods] Single cell-derived normal epithelial organoids (n=47) were established from breast milk of 4 healthy women aged 22-36 and surgical specimens of 15 BC patients aged 29-83 to evaluate somatic mutation rate. Multiple normal lobules or proliferative lesions together with cancer cells were collected using laser-capture micro-dissection (LCM) from fresh frozen (n=3) or formalin-fixed paraffin-embedded (n=6) surgical specimens in 9 premenopausal BC patients. Somatic mutations and copy number alterations were evaluated using whole-genome sequencing. [Results] On the basis of single cell-derived mammary gland-derived organoids, somatic mutations increased in mammary gland cells at a constant rate of 19.4/genome/year before menopause, which then decreased to 6.9/genome/year after menopause. Parity was negatively associated with mutation number (-49.3 per life birth). In total, we analyzed 113 LCM samples, including those from 66 normal lobules, 28 proliferative lesions, and 14 non-invasive and 5 invasive cancer samples. Phylogenetic analysis showed that most of the neighboring normal lobules (53/66) from 3 BC patients shared no somatic mutations with each other and therefore were clonally independent. In other 13 normal lobules, shared mutations including a PIK3CA mutation were observed across multiple adjacent samples, although they were still confined to & lt;10 mm regions. By contrast, we found a large expansion of proliferative lesions sharing a substantial number of somatic mutations with cancer in 5 out of the 6 remaining BC cases. They were expanded over a distance of 25-85 mm, sharing tens to hundreds of mutations including those in BC-related driver genes, such as PIK3CA, AKT1, GATA3, CBFB and PTEN. Of interest, Tumors in 4 out of these 5 cases was Luminal-A type and characterized in common by the presence of 1q gain and 16q loss (1q+/16q-) in both cancer and proliferative lesions. Phylogenetic analysis adapted with the mutation rate in normal cells predicted that 1q+/16q- had been acquired during adolescence to mid-20s, where the clonal expansion had occurred years to decades before the onset of cancer. [Conclusions] Our results suggest that in some BC cases, particularly in those with 1q+/16q-, the clones with the founder driver mutations expanded macroscopically long before the onset of cancer, in which further clonal evolutions recursively occur multi-focally, giving rise to multiple proliferative lesions and ultimately, i nvasive cancers. Citation Format: Tomomi Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida, Yasuhide Takeuchi, Hirona Maeda, Yusuke Shiozawa, Masahiro M. Nakagawa, Ryunosuke Saiki, Yotaro Ochi, Tomonori Hirano, Yukiko Kawata, Kosuke Aoki, Masahiro Hirata, Tatsuki R. Kataoka, Takaki Sakurai, Satoko Baba, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of mammary epithelial cells into breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6085.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6085
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract 4677: Non-prostate cancer death within 5 years after radical therapy in men with localized prostate cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4677-4677
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4677-4677
    Abstract: Background: As AUA guideline for the Management of Clinically Localized Prostate Cancer: 2007 Update states “An assessment of the patient's life expectancy, overall health status, and tumor characteristics should be undertaken before any treatment decisions can be made," definitive therapy for localized prostate cancer is usually recommended for patients with 5-year life expectancy or more. In some cases, however, unexpected lethal disease is diagnosed and causes death within 5 years after prostate cancer treatment. It seems important to elucidate the characteristics of other causes of death during follow up period after definitive therapy for localized prostate cancer (PCa). Patients and Methods: We reviewed 664 consecutive patients who had received radical prostatectomy (RP, n = 107) or external beam radiotherapy (EBRT, n = 557) and been followed up over 5 years at our institute. Survival status was evaluated and cause of death was identified in dead cases. All cases underwent chest and abdominal computed tomography (CT) and bone scan that were negative for metastasis. Results: At latest follow up, 103 (15.5%) patients were dead of PCa (n = 48) and other causes (n = 55), respectively. Of the 55 patients who died of other causes, 26 did not survive 5 years after radical treatment for PCa. 54% of them died of other malignancies including lung (n = 7) and gastrointestinal (GI) tract (n = 3), lymphoma (n = 2), liver (n = 1), and pancreatic (n = 1) cancers. Non-cancer causes included cerebrovascular disease (n = 3), pulmonary disease (n = 3), ischemic heart disease (n = 2), and unknown (n = 3). Conclusions: Since all patients had negative chest CT for primary lung cancer, some patients with localized PCa seemed to have developed more lethal and rapid malignancy after treatment for PCa. Urologists may need to pay their attention that their patients undergo regular mass screening for common diseases even if they were under urological follow up. Pretreatment test for fecal occult blood may be useful to screen GI tract cancer before treatment initiation. Citation Format: Takashi Kobayashi, Tomomi Kamba, Naoki Terada, Toshinari Yamasaki, Itaru Ikeda, Haruo Inokuchi, Yoshiki Norihisa, Takashi Mizowaki, Takahiro Inoue, Kazutoshi Okubo, Koji Yoshimura, Masahiro Hiraoka, Osamu Ogawa. Non-prostate cancer death within 5 years after radical therapy in men with localized prostate cancer. [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 4677. doi:10.1158/1538-7445.AM2013-4677
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4677
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 8
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    Abstract 5754: The genetic aberrations in carcinogenic sequence of colitis-associated cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5754-5754
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5754-5754
    Abstract: Colitis-associated cancer (CAC) is a common complication among patients with a long history of ulcerative colitis (UC). Previous studies revealed that dysplasia precedes CAC development, and more than 20% of CACs are multicentric, suggesting the presence of a field effect on colorectal carcinogenesis in UC patients. However, the genetic basis of the field effect in UC patients is poorly understood.To address this issue, we isolated single crypts from non-tumorous colon mucosa from 6 UC patients, as well as those from apparently normal mucosa from non-UC patients, and “single crypt-derived DNA” was analyzed for somatic mutations using whole-exome sequencing (WES). In total, 19 crypts from histologically non-dysplastic, but inflamed mucosa, and 2 from apparently normal mucosa were isolated from 6 UC patients, including 4 with pancolitis, 1 with left-sided colitis and 1 with proctitis, while 32 crypts were obtained from normal mucosa from 20 non-UC patients, including 10 with colorectal cancer, 6 with adenoma and 4 healthy volunteers. Regardless of the disease status, mutations were detected in all crypts analyzed with the median of 43/crypt (3 − 121), showing high variant allele frequencies (VAFs) (~0.5), suggesting that these mutations were shared by all cells within single crypts and therefore by crypt-maintaining stem cells. The number of mutations increased with age, in crypts from both UC and non-UC patients (P & lt; 10-9), showing clear age-related C to T transition in both normal and UC-inflamed crypts. Strikingly, however, the age-adjusted number of mutations was significantly higher in UC-derived crypts than in those from non-UC individuals (P & lt; 10-3). KRAS and TP53 mutations were reported to be the most prevalent alterations in UC-associated CAC, but only rarely seen in UC-derived normal crypts. Next, to evaluate clonal expansion of mutated clones, we performed WES for the bulk specimens composed of 20 - 30 mutually adjacent crypts. However, this time, mutations and copy number alterations (CNAs) with high VAFs were detected only in UC-inflamed mucosa, suggesting that clonal crypt expansion occurred only in UC-derived mucosa. WES was also performed for 14 CACs. The number of non-synonymous mutations (101/sample) in CAC were significantly higher than that in UC-derived normal crypts (38/sample) and recurrently involved known driver genes, such as TP53 (71%) and KRAS (36%). CNAs were also more frequent in CAC than UC-derived, normal crypts. In conclusion, our study revealed that somatic mutations accumulated in normal mucosa of both UC and non-UC cases, but the mutational burden increased in UC-inflamed mucosa. Chronic inflammation caused clonal expansion of crypts even in histologically non-dysplastic mucosa in UC case, accompanied by acquisition of driver mutations and CNAs, which could trigger the development of CAC. Our findings provide novel insights into the carcinogenic sequence in UC-derived CAC. Citation Format: Nobuyuki Kakiuchi, Kenichi Yoshida, Yusuke Shiozawa, Akira Yokoyama, Keisuke Kataoka, Yoshikage Inoue, Yasuhide Takeuchi, Yasunori Kogure, Ayana Kon, Masahiro Nakagawa, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Satoru Miyano, Kenji Kawada, Hideaki Okajima, Yoshiharu Sakai, Takaki Sakurai, Hironori Haga, Hiroshi Nakase, Motoi Uchino, Hiroki Ikeuchi, Takako Kihara, Seiichi Hirota, Takahiro Horimatsu, Minoru Matsuura, Hiroyuki Marusawa, Hiroshi Seno, Seishi Ogawa. The genetic aberrations in carcinogenic sequence of colitis-associated cancer [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5754. doi:10.1158/1538-7445.AM2017-5754
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5754
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 9
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    Abstract 741: Clonal evolution of non-malignant proliferative lesions into breast cancers
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 741-741
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 741-741
    Abstract: [Introduction] Non-malignant proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles of normal ducts, non-malignant proliferative lesions and cancers in the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from different proliferative lesions within the cancer-borne breast, including invasive cancers, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. [Results] A total of 39 samples from 6 premenopausal females carrying estrogen receptor-positive cancers were analyzed, where the samples were obtained from normal ducts (N = 5), non-malignant proliferative lesions (N = 9), and non-invasive (N = 21) and invasive (N = 4) cancers. The number of somatic mutations per sample was ranging from 1 to 311 and increased with pathological disease progression. Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining four unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7-33 mm, shared one or more driver alterations, such as an AKT1 mutation (UID: KU01), a GATA3 mutation (UID: KU03 and KU06), a CBFB mutation (UID: KU06) and concurrent 1q gain and 16q loss (UID: KU02, KU03 and KU06), while harboring private mutations/CNAs of their own. The analysis of phylogenic trees based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. [Conclusions] Early breast cancer development is thought to be shaped by a simultaneous evolution of multiple precancerous clones. It may be multi-focally initiated by a germline mutation, frequently terminated in bilateral cancers. By contrast, in unilateral cases, cancer clones might be derived from a common ancestral clone, which has acquired a driver founder mutation long before the onset of cancer, and undergo independent evolution, giving rise to multiple proliferative lesions, from which invasive cancer finally evolves. Our findings provide unique insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Kenichi Yoshida, Yukiko Kawata, Yasuhide Takeuchi, Nobuyuki Kakiuchi, Yusuke Shiozawa, Kosuke Aoki, Masahiro Hirata, Tatsuki R. Kataoka, Takaki Sakurai, Satoko Baba, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of non-malignant proliferative lesions into breast cancers [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 741.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-741
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Abstract P4-05-15: Clonal evolution of proliferative lesions into breast cancers
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-05-15-P4-05-15
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-05-15-P4-05-15
    Abstract: [Introduction] Proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that atypical proliferative lesions and adjacent breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles of proliferative lesions and cancer tissues from the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from various lesions with different disease-level located in the cancer-borne breast, including invasive cancers, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. [Results] We analyzed a total of 39 samples from 6 premenopausal females carrying estrogen receptor-positive cancers, where the samples were obtained from non-atypical (N = 1) and atypical (N = 8) proliferative lesions, and non-invasive (N = 21) and invasive (N = 4) cancers. The number of somatic mutations per sample ranged from 2 to 311 and increased with disease progression. Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining four unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions and cancers, which were separated by a distance of 7- 33 mm, shared one or more driver alterations, such as an AKT1 mutation (UID: KU01), a GATA3 mutation (UID: KU03 and KU06), a CBFB mutation (UID: KU06) and concurrent 1q gain and 16q loss (UID: KU02, KU03 and KU06), while harboring private mutations/CNAs of their own. The phylogenetic analysis based on the number of shared mutations predicted an early origin of these founder genetic alterations, which frequently predated decades before the onset of cancer. [Conclusions] Our results suggest that early breast cancer development is shaped by the evolution of multiple precancerous clones. In hereditary cases, this process is thought to be substantially promoted multi-focally within the entire breasts, due to innate genomic instability in each mammary epithelial cell for pathogenic germline mutations. By contrast, in sporadic cases, the ancestral cell which has acquired a founder genetic alteration expands macroscopically long before the onset of cancer, most likely in early adolescent. These expanded clones work as the niche predisposed to additional mutations, in which branching evolution occurs multi-focally and raises up multiple proliferative lesions, from which invasive cancer finally evolves. Our findings provide unique insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Kenichi Yoshida, Nobuyuki Kakiuchi, Yasuhide Takeuchi, Yukiko Kawata, Hirona Maeda, Yusuke Shiozawa, Kosuke Aoki, Masahiro Hirata, Tatsuki R Kataoka, Takaki Sakurai, Satoko Baba, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of proliferative lesions into breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-15.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P4-05-15
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 410466-3
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