NSCLC驱动基因：特性、检测方法与靶向治疗

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非小细胞肺癌（Non-Small Cell Lung Cancer, NSCLC）是全球癌症死亡的主要原因之一，占肺癌病例的大约75%。近年来，对NSCLC分子生物学的理解已经取得了显著进步，其中驱动基因的角色尤为重要。驱动基因是指在肿瘤发生和发展过程中起关键作用的基因，它们通常导致细胞增殖、侵袭、转移和抵抗治疗。本文将深入探讨NSCLC中的驱动基因特性、检测方法以及靶向疗法的发展。首先，驱动基因的特性包括： 1. **功能改变**：这些基因通常是抑癌基因突变或肿瘤基因过表达，如EGFR、KRAS、ALK等，它们的异常活动会导致细胞信号传导异常，促进肿瘤生长。 2. **高度特异性**：某些驱动基因突变具有较高的特异性和频率，例如EGFR突变在亚洲人群中较为常见，而ALK融合基因则在部分腺癌中存在。 3. **临床意义**：驱动基因的存在与患者预后、生存率和对治疗的反应性密切相关，识别特定的驱动基因有助于制定个体化治疗策略。对于驱动基因的检测方法，目前主要有以下几种： 1. **基因测序**：通过全基因组测序或靶向区域测序技术，如Next-Generation Sequencing (NGS)，可以检测到基因的点突变、插入/缺失变异以及拷贝数变异。 2. **基因表达分析**：RNA测序或微阵列技术可以评估基因的转录水平，揭示基因表达模式的改变。 3. **蛋白质标志物检测**：免疫组化和蛋白芯片技术可检测驱动蛋白的表达或突变状态。 4. **液体 biopsy**：通过血液检测肿瘤DNA或蛋白质片段，实现对循环肿瘤细胞DNA（ctDNA）或循环肿瘤细胞（CTCs）的分析，监测驱动基因动态变化。针对NSCLC的驱动基因，靶向疗法成为治疗的新策略。这些疗法主要包括： 1. **酪氨酸激酶抑制剂（TKIs）**：如EGFR-TKIs（吉非替尼、厄洛替尼）针对EGFR突变，ALK抑制剂（克唑替尼）针对ALK融合基因。 2. **抗血管生成药物**：如贝伐珠单抗针对VEGF通路的抑制，减少肿瘤供血。 3. **免疫检查点抑制剂**：如PD-1/PD-L1抑制剂（帕博利珠单抗、纳武利尤单抗）激活免疫系统对肿瘤的攻击。 4. **CAR-T细胞疗法**：通过工程化的T细胞针对特定的驱动基因表达的肿瘤抗原进行定向杀伤。理解并鉴定NSCLC中的驱动基因对于改善患者治疗选择和预后至关重要。随着新技术的不断进步，未来有望发现更多的驱动基因，并开发出更精准的靶向疗法，以期提高NSCLC患者的生存率和生活质量。

Oncotarget3

www.impactjournals.com/oncotarget

The detection of driver genes

Besides the above methods, experimental methods

can detect and conform driver genes, and have the more

far-reaching signicant. For example, EGFR mutation

and ALK gene rearrangement, the driver genes of

pulmonary adenocarcinomas, have been well tested and

veried by experimental methods [21, 22]. On genome,

most laboratories usually believe uorescence in situ

hybridization (FISH) assays. Originally, the detection of

ROS1 gene rearrangement is by the mean of dual break-

part uorescence in situ hybridization (FISH) probes.

Recently non-in situ testing approaches, including next-

generation sequencing (NGS) and real-time PCR assays,

have been much potential to be independent methods

or supplementary tests to detect driver genes. As for

transcription, the course about mRNA resulting from

the rearrangement gene, RTPCR have been the another

approach. It is known that the ROS1 rearrangements only

account for 1–2% of occurrence in NSCLC [19], which

decreased the accuracy of laboratory ndings. However,

immunohistochemistry can solve the dilemma by detecting

the increased ROS1 protein levels, providing a supplement

for FISH screening test.

Fluorescence in situ hybridization

Fluorescence in situ hybridization (FISH), rooting in

radioactivity in situ hybridization technique during the late

1980s, is a nonradioactive molecular and cellular genetic

technique with uorescent tags instead of isotope labeling.

From December 2007 to April 2011, uorescence in-situ

hybridization (FISH) have been screening EGFR gene

variation from tumor samples derived from 149 subjects.

And FISH test were successfully treated in the majority

of 49 patients who conferred positive EGFR [23]. Thus,

FISH play an unshakable role in detection and screening

of driver genes. In general, the abnormalities about EGFR,

ALK, RET and ROS1 are well validated by FISH because

the results were widely accepted. The important portion in

FISH is the design about dual-colour break-apart probes,

which have the completely different uorochromes in the

3′end and the 5′ end. In order to distinguish two genes

such as ROS1(green uorochrome at 3′end) and ALK

(orange luorochrome at 3′) when they are run together on

the same side, the selection about the uorochrome color

at 3′ end need to be cautious [24]. Otherwise, some reports

indicate that the experimental material older than 6 months

may induce the low binding efciency of probes [25].

Immunohistochemistry

Immunohistochemistry (IHC) is the course

detecting special antigens (e.g. proteins) in some cells of

a tissue section according to the rationale that antibodies

specically bind to proteins in biological tissues. Its

name originates from the roots “immuno”, antibodies

participating in the method, and “histo” meaning tissue.

Albert Coons is the rst person to conceptualize IHC and

apply to practical laboratory in 1941.

If the level of detected genes is low, IHC with

relatively sensitivity, depending on how to dene the

threshold, is a much effective screening tool. However,

scoring IHC results have been not reaching a consensus due

to the different outcomes from different scoring approaches,

which is perfectly similar to FISH one [25]. In NSCLC,

Immunohistochemistry often acts as a supplemented trial

for the reason that IHC cannot quickly meanwhile test

multiple samples and have higher cost than FISH.

Non-in situ technologies

Compared with these experimental methods above,

non-in situ technologies have been, to some extent, more

meaningful and convenient. For now, there are RTPCR and

NGS applied to detect driver genes in NSCLC [26–29].

Making easily, meanwhile processing multiple

samples, relatively low-cost, and having high sensitivity

even reaching 100% are the reason why most laboratories

adopted RTPCR. To get the perfect outcome, we need

to prudently design primers (a key factor to PCR) and

assure easily depredated and polluted RNA quality.

Although RTPCR, as with FISH, easily leaves out low

expressed genes, a new method according to RTPCR

Table 1: Current treatment recommendation of NSCLCs

Stage* General treatment recommendations

IA Surgical resection

IB Surgical resection, can consider adjuvant chemotherapy in selected cases (e.g. tumor size > 4 cm)

IIA Surgical resection followed by adjuvant chemotherapy

IIB Surgical resection followed by adjuvant chemotherapy

IIIA Multimodality treatment: chemotherapy, radiation, +/− surgery

IIIB Multimodality treatment: chemotherapy and radiation

IV Chemotherapy, consider targeted therapies according to driver mutations

*described according to TNM.

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NSCLC驱动基因：特性、检测方法与靶向治疗

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