依稀看到图像，肺内结节基因组学大纲进展为癌

Small precancerous growths in the lungs are capable of progressing to invasivelung cancer, but so little has been known about them that understanding the risk of progression and how to deal with it has remained a puzzle.

一个188bet体育网址研究小组由MD安德森医生和科学家领导进行了这些结节的首次大规模多区域外显子组测序，建立自己的基因组学的照片是推出了一些惊喜，但也强化了癌前生长具有更简单的分子概况，将使他们更容易治疗的肿瘤相比。

“更多这些结节被发现为‘偶发’通过CT显像在事故和低剂量CT肺癌长期重度吸烟者的筛选伤，”说Jianjun Zhang, M.D., Ph.D., assistant professor ofThoracic/Head and Neck Medical Oncology和的资深作者纸in Nature Communications. “They have become endemic, and their discovery has been technology-driven.”

Based on imaging, many of these growths are characterized as indeterminate pulmonary modules. These nodules are too small to biopsy, so U.S. practice has been to observe them rather than remove them. “Because we don’t know what they are, we don’t know how to treat them,” Zhang says.

Oncologists in other countries take an aggressive approach, surgically removing these growths, which provided Zhang and colleagues an opportunity to study them. From collaborators in Japan and China, they gained access to 116 resected IPNS from 53 patients, which were histologically characterized by pathologists.

There are four types of nodule, listed in ascending order of malignancy:

· Atypical adenomatous hyperplasia (AAH), 22 precancerous growths

· Adenocarcinoma in situ (AIS) 27 nodules

· Minimally invasive adenocarcinoma (MIA) 54 tumors

· Invasive adenocarcinoma (ADC) 13 tumors

It’s not known whether every one of these states is achieved by precancerous growths that progress to invasive lung cancer, Zhang says.

肿瘤或癌前生长的多个区域的全基因组测序可以帮助研究人员确定在癌症发展的早期步骤已发生的突变。188bet体育网址那些在每一个地区发现是早期的事件，而那些只是少数地区发现后发生。

The majority of cancer driver gene mutations found by studying invasive cancers are early events. The current study using precancerous specimens demonstrated some of these driver mutations occur relatively late in the cancer development process, providing a far more detailed road map, Zhang says.

Genetic heterogeneity grows

The team found a number of distinct differences or patterns in genetic mutations.

总突变负担通过评估的单核苷酸变异分析。该研究小组发现突变的负担逐渐增加通过的浸润性腺癌的癌前AAH开始。尽管这一结果是意料之中的，团队的研究是第一个文件前进到更大的突变负担。

They identified six mutational signatures that have potential roles in early lung carcinogenesis.

Chromosomal analysis revealed a more complex picture, with possible chromosomal macroevolution during transitions from AAH, the simplest stage, to AIS, the next stage and then from AIS to minimally invasive disease (MIA).

This study provides new molecular evidence to support the evolution of lung adenocarcinoma from AAH, AIS, MIA and ADC, a model that was long proposed, Zhang explains, but constantly debated for lack of molecular evidence.

克隆复杂性

该小组探讨每种类型的克隆架构。克隆突变存在于一个结节或肿瘤和亚克隆突变的每一个细胞不太普遍出现。

总体而言，研究的结节的平均的48.8％的克隆基因突变，而在侵袭性肺癌平均68.2个百分点。

Precancerous AAH was surprisingly complex, with more subclonal than clonal mutations. Both clonal and subclonal mutations progressively increased, with invasive adenocarcinoma having the highest clonal mutational burden but also the highest subclonal burden, a surprising finding.

当突变变得更加克隆，显性突变忍受而较常见的基因突变被淘汰 - 一个叫克隆扫描模式 - 罕见突变的负担通常会降低，张某解释说。在这种情况下，无论是常见和不常见的突变在更先进的结节增大。遗传异质性跨越结节型增加，是患者在每个阶段中可观。

A variety of commonly mutated cancer genes were identified, including EGFR, KRAS, RBM10, TP52, as well as chromosomal loss of two common tumor suppressors: STK11 and CDKN2A.

EGFR was the most commonly mutated cancer gene found at levels ranging from 29.6% to 46.2% of the three advanced types of growth, but not found at all in the 22 precancerous AAH lesions. A second analysis found EGFR mutations present as minor subclones in AAH, but as major subclones in each of the more advanced growths, implying an advantage for cells with EGFR mutations.

Future research

Zhang notes larger studies will be needed to further illuminate the progression between stages and to shed light on tumor heterogeneity among patients. Additional endpoints, such as recurrence and overall survival would also better define the molecular subtypes and assess their prognostic values.

进一步解密与进展的基因组格局的变化如何需要的临床试验，其包括纵向活检。张有一个这样的clinical trial open. He and colleagues also study immune surveillance across the spectrum of preneoplasia to lung cancer.

This study was supported by the MD Anderson Khalifa Scholar Award, a grant from the National Cancer Institute of the National Institutes of Health (R01CA234629-01), an AACR-Johnson & Johnson Lung Cancer Innovation Science Grant, the MD Anderson Physician Scientist Program, the MD Anderson Lung Cancer Moon Shot®, T.J. Martell Foundation Award, Sabin Family Foundation Award, Duncan Family Institute Cancer Prevention Research Seed Funding Program, the Major Science and Technology Project of Zhejiang Province of China, the Cancer Prevention and Research Institute of Texas, the University of Texas Systems Stars Award, the Welch Foundation, the U.S. Department of Defense, and the UT Lung Specialized Programs of Research Excellence Grant from the NCI (P50CA70907).