Uncovering the Profile of Somatic mtDNA Mutations in Chinese Colorectal Cancer Patients

In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues (namely, cancerous tissue, para-cancerous tissue, and distant normal tissue) from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues (cancerous, para-cancerous and normal tissues) respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients.

过去十年来，学界已在多种癌组织中观测到高发生率的体细胞线粒体DNA（mtDNA）突变，此类研究大多仅针对线粒体基因组的部分片段展开；然而受数据质量问题影响，其中部分突变的真实性受到质疑。显然，若无法全面了解特定患者癌组织中的mtDNA突变谱，则难以阐明体细胞mtDNA突变与肿瘤发生之间的真实关联。为达成这一研究目标，最直接的路径是直接比对同一患者的三类组织——癌组织、癌旁组织及远端正常组织——的全mtDNA基因组变异情况。鉴于既往多数关于mtDNA在结直肠肿瘤中作用的研究仅聚焦于线粒体基因组的D环（D-loop）或部分片段，本研究纳入20例结直肠肿瘤患者的三类组织（癌组织、癌旁组织及正常组织），并对每例组织的线粒体基因组进行了全序列测定。本研究结果显示，此类患者的体细胞突变发生率相对较低；值得关注的是，所有体细胞突变均呈异质性（heteroplasmic）状态。令人意外的是，观测到的体细胞突变并非仅局限于癌组织：癌旁组织与远端正常组织中同样存在体细胞mtDNA突变，其突变频率虽低于癌组织，但高于普通人群中的观测水平。本研究结果表明，癌组织中的体细胞mtDNA突变无法简单归因于肿瘤发生过程；与此同时，正常组织中的体细胞mtDNA突变或可反映癌症患者体内生理环境的改变。