每天一包烟，赛过活神仙？Nature子刊：重度吸烟者，反而不易患肺癌？

2022-04-17 四五七 MedSci原创

梅斯头条

企业/

Nature Genetics：吸烟量最大的那些人不一定体细胞突变最多，老烟枪为什么吸烟多年而不患癌，原因在于他们拥有限制体细胞突变的强大机制，保护自身免受肺癌侵害

肺癌是全球癌症死亡的首位原因，80%-90%的肺癌发生都是由吸烟导致的，吸烟者患肺癌的风险是不吸烟者的20倍之多。

烟草中含有60多种致癌物，在点燃时随着烟雾进入到肺部，引起肺部细胞DNA损伤，甚至产生致癌突变。

有研究显示，在吸烟者的肺癌细胞中，存在着成千上万个体细胞突变，其中不到20个突变就能驱动肿瘤形成。

按理来说，吸烟的量越多，暴露于这些致癌物的时间越长，吸烟者患肺癌的风险就应该越大，然而现实中一天一包烟，快活似神仙，活到80岁而不患肺癌的人比比皆是，这又作何解释呢？

近期，来自美国阿尔伯特爱因斯坦医学院的一项研究或能解答这一疑问，研究人员通过比较各年龄段的吸烟者和非吸烟者近端支气管基底细胞的突变情况，发现吸烟量最大的那些人不一定体细胞突变最多，老烟枪为什么吸烟多年而不患癌，原因在于他们拥有限制体细胞突变的强大机制，保护自身免受肺癌侵害。该研究于2022年4月11日发表于Nature Genetics。

已知衰老和吸烟都会导致体细胞突变积累，为了区分这两种因素对体细胞突变的影响，研究人员特意选择了14名年龄在11-86岁的非吸烟者以及19名年龄在44-81岁的吸烟者，利用支气管镜进行肺部取材，并通过单细胞全基因组测序来分析支气管基底细胞发生突变的情况。

本研究中，体细胞突变的类型主要涉及到单核苷酸变异（single-nucleotide variants, SNVs）以及小的插入和缺失（small insertions and deletions, INDELs）。

通过比较不同年龄的非吸烟者支气管基底细胞的突变频率，研究人员发现，随着年龄增长，细胞内单核苷酸变异的数量也在不断增加，11岁的参与者细胞内SNVs中位数为464 ± 108，而86岁的参与者细胞内SNVs中位数则为2,739 ± 778，平均下来，每个细胞每一年会新增28个SNVs。

相比之下，支气管基底细胞出现小的插入和缺失突变的频率就比较低，从59 ± 18 (11岁)到304 ± 94 (86岁)，相当于每个细胞每年只新增2个INDELs。

图注：非吸烟者，随着年龄增长，支气管基底细胞内SNVs和INDELs数量变化

接下来，对不同年龄的吸烟者支气管基底细胞突变频率进行分析，也得到了类似的结论——随着年龄增长，体细胞突变数目上升，区别在于，吸烟者的细胞以更高的频率在发生突变，每个细胞每年发生91个单核苷酸变异，比非吸烟者多了63个。吸烟者细胞发生小的插入和缺失频率同样高于非吸烟者，但是未达到统计学意义。

探明了衰老与体细胞突变数量的关联，下一步就是研究吸烟量与体细胞突变的关系，这里研究者用“包年（pack-year）”作为吸烟量的单位，1包年定义为每天吸20支烟（相当于一包烟）/年。19名吸烟者的吸烟量范围在5.6-116包年之间。

出人意料的是，研究人员发现体细胞突变并不会随着吸烟量的增加一直上升，而是以“23包年”作为拐点，在“23包年”后，体细胞突变数量停止上升，趋向于平稳甚至下滑。

从下图也可看出，重度吸烟者（吸烟量＞60包年）体细胞突变数目甚至要低于中度吸烟者（吸烟量20.1-60包年）。

重度吸烟者没有最高的突变负担，对于这一现象，研究人员提出了两点可能原因：

一是这些重度吸烟者对DNA损伤的修复能力很强，当然这一点还有待证明。

二是他们能迅速代谢掉香烟中的有害物质，降低致癌风险。

在研究中，有两名参与者存在AKR1C2基因多态性，导致他们对香烟中的多环芳烃（PAHs）解毒能力下降，这两个人发生C>A/G>T碱基替换（在吸烟者肺腺癌中常见）的频率是其他人的两倍以上，说明AKR1C2基因多态性在一定程度上决定了香烟致癌物对吸烟者的影响。

研究人员认为这一发现将导致一个新的研究方向，比如开发新的检测方法，用来检测某人的DNA修复或香烟致癌物的解毒能力，以此评估吸烟者的肺癌风险，比起投入大量努力去攻克肺癌，更好的办法是早期识别出那些面临更高患癌风险的吸烟者，并定期检测。

值得注意的是，这篇研究并不是说明吸烟越多患癌风险越低——和非吸烟者相比，所有吸烟者的体细胞突变数目都是更多的，肺癌风险也更大。

在本研究中，体细胞突变数目最多的，竟然是一个吸烟量6包年的轻度吸烟者。因此，在没有弄清楚自己是不是“DNA修复超强者”或是“香烟致癌物解毒小能手”之前，吸烟有风险，最好的建议是不吸烟。

参考文献

[1]Huang Z, Sun S, Lee M, et al. Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nat Genet. 2022;54(4):492-498. doi:10.1038/s41588-022-01035-w

[2]Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD. Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e1S-e29S. doi:10.1378/chest.12-2345

[3]Yoshida K, Gowers KHC, Lee-Six H, et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature. 2020;578(7794):266-272. doi:10.1038/s41586-020-1961-1

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2022-04-21 liye789132251

#Nat#

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2022-04-20 1361e94681m

样本量太小，能说明什么问题？！

44 0
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2022-04-18 124984e7m89暂无昵称

#吸烟者#

50 0
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2022-04-17 ms3000000235780593

要么不吸烟，要么拼命吸?

92 0
[GetPortalCommentsPageByObjectIdResponse(id=1885736, encodeId=8d811885e36c0, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Thu Apr 21 07:15:38 CST 2022, time=2022-04-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1212930, encodeId=c56c1212930c0, content=样本量太小，能说明什么问题？！, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4ee2039139, createdName=1361e94681m, createdTime=Wed Apr 20 19:48:40 CST 2022, time=2022-04-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1605150, encodeId=b5f2160515086, content=<a href='/topic/show?id=5cba39435fd' target=_blank style='color:#2F92EE;'>#吸烟者#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=39435, encryptionId=5cba39435fd, topicName=吸烟者)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=cc8619318136, createdName=124984e7m89暂无昵称, createdTime=Mon Apr 18 12:15:38 CST 2022, time=2022-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1211828, encodeId=2e651211828a9, content=要么不吸烟，要么拼命吸?, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=48e46488127, createdName=ms3000000235780593, createdTime=Sun Apr 17 10:07:55 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1211826, encodeId=1ce5121182671, content=真的吗, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b8ba6319857, createdName=1064510_1039, createdTime=Sun Apr 17 09:58:20 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1211825, encodeId=67d7121182524, content=<a href='/topic/show?id=aa0582e6946' target=_blank style='color:#2F92EE;'>#肿瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=100, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=82769, encryptionId=aa0582e6946, topicName=肿瘤)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b8ba6319857, createdName=1064510_1039, createdTime=Sun Apr 17 09:58:07 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1211819, encodeId=2ce5121181958, content=吸烟一定是有害的，但是不吸烟的人得肺癌的比例也是很高。, beContent=null, objectType=article, channel=null, level=null, likeNumber=89, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=031e2276097, createdName=121b609dm52(暂无昵称), createdTime=Sun Apr 17 09:25:51 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1211818, encodeId=6cf21211818cb, content=认真学习～, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=cfb41991958, createdName=xulv123, createdTime=Sun Apr 17 09:25:50 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1211807, encodeId=1880121180e8a, content=因为只有那些dna修复超强者才在日复一日的吸烟中活到了现在, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=24295730690, createdName=ms9000001783460538, createdTime=Sun Apr 17 08:15:50 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1211904, encodeId=b0e81211904fc, content=烟草公司赞助的吧, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3c2b1620925, createdName=泽9867, createdTime=Sun Apr 17 14:33:28 CST 2022, time=2022-04-17, status=1, ipAttribution=)]
2022-04-17 1064510_1039

真的吗

83 0
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2022-04-17 1064510_1039

#肿瘤#

100 0
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2022-04-17 121b609dm52(暂无昵称)

吸烟一定是有害的，但是不吸烟的人得肺癌的比例也是很高。

89 0
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2022-04-17 xulv123

认真学习～

47 0
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2022-04-17 ms9000001783460538

因为只有那些dna修复超强者才在日复一日的吸烟中活到了现在

36 0
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2022-04-17 泽9867

烟草公司赞助的吧

51 0

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肿瘤

每天一包烟，赛过活神仙？Nature子刊：重度吸烟者，反而不易患肺癌？

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