疯狂克隆是癌细胞的基本特征之一。其中，有些克隆可能来自先天遗传的癌基因，有些克隆可能来自后天突变的正常组织细胞。而且，肿瘤的克隆进化还存在不同模式，例如线性进化、分支进化、爆发进化、干细胞型进化、平行进化、中性进化、间断进化……如同每个兵团的士兵可能来自五湖四海，存在不同派系，年龄、身高、体重、体质、体力、饭量、口味、性格、作风各不相同。因此，同样是乳腺癌，不同患者各不相同，即使同一患者同一肿瘤内部不同部位乃至不同时期也可能不同，即所谓的肿瘤异质性。不过，正常组织的一个或多个克隆最终进化为肿瘤之前，目前尚不明确哪些额外的驱动事件以什么顺序发生，这些对于肿瘤的诊断与治疗至关重要。
2023年7月26日，全球自然科学三大旗舰期刊之首、英国《自然》正刊在线发表日本京都大学、东京国立癌研究中心、大阪红十字医院、岩手医科大学、熊本大学、京都足立医院、东京癌研究会有明医院、东京大学、庆应义塾大学医学院、大冢制药、神户市立医疗中心中央市民医院、东京医科齿科大学、瑞典卡罗林斯卡学院的研究报告，深入分析了乳腺癌及其相关克隆的时空进化史。
该研究通过对来自癌症和非癌症病变的多个激光捕获显微切割标本进行系统发育分析，发现了der(1;16)阳性乳腺癌的独特进化史。der(1;16)是指1号染色体和16号染色体发生易位或融合等改变，可见于大约20%的乳腺癌，是常见的驱动基因改变。随后，通过测定正常上皮细胞的突变率，对早期进化事件的大致时间进行推算。对于der(1;16)阳性乳腺癌，衍生染色体获得于发育早期至发育后期，随后于患者30岁出头时出现共同原始细胞，癌症和非癌症克隆都从该原始细胞进化而来。在随后几年，这些克隆取代了原先存在的乳腺上皮，至乳腺癌被诊断出时，这些克隆在绝经前乳腺组织占据了大量区域。从非癌症原始细胞进化出多个独立的癌症生成细胞十分常见，这导致了肿瘤内部异质性。驱动事件的数量与组织学无关，表明局部微环境和/或表观遗传驱动事件的作用。在另一例由AKT1基因突变生成细胞进化而来者也观察到类似的进化模式。
Nature. 2023 Jul 26. IF: 64.8
Evolutionary histories of breast cancer and related clones.
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, Tomoe Nakagawa, Yukiko Inagaki-Kawata, Kosuke Aoki, Masahiro Hirata, Kosaku Nanki, Mami Matano, Megumu Saito, Eiji Suzuki, Masahiro Takada, Masahiro Kawashima, Kosuke Kawaguchi, Kenichi Chiba, Yuichi Shiraishi, Junko Takita, Satoru Miyano, Masaki Mandai, Toshiro Sato, Kengo Takeuchi, Hironori Haga, Masakazu Toi, Seishi Ogawa.
Kyoto University, Kyoto, Japan; National Cancer Center Research Institute, Tokyo, Japan; Kyoto University Hospital, Kyoto, Japan; Osaka Red Cross Hospital, Osaka, Japan; Iwate Medical University, Iwate, Japan; Kumamoto University, Kumamoto, Japan; Adachi Hospital, Kyoto, Japan; Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; The University of Tokyo, Tokyo, Japan; Keio University School of Medicine, Tokyo, Japan; Otsuka Pharmaceutical Company, Limited, Osaka, Japan; Kobe City Medical Center General Hospital, Hyogo, Japan; Tokyo Medical and Dental University, Tokyo, Japan; Karolinska Institute, Stockholm, Sweden.
Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
DOI: 10.1038/s41586-023-06333-9
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