Molecular genetics of lung cance

Types of lung cancer

  The two broad histological subtypes of lung cancer are small-cell lung cancer (SCLC), which is the cause of 15% of cases, and non-small-cell lung cancer (NSCLC), which accounts for 85% of cases and includes adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma.

The two general types of lung cancer include:

• Small cell lung cancer.
  Small cell lung cancer occurs almost exclusively in heavy smokers and is less common than non-small cell lung cancer.

• Non-small cell lung cancer（NSCLC）.
  Non-small cell lung cancer is an umbrella term for several types of lung cancers. Non-small cell lung cancers include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.

Molecular genetics of lung cancer

  There are at least two distinct genetic components to cellular transformation: there are large, clonal chromosome aberrations (aneuploidy) including translocations, amplifications, and deletions, and there are alterations that occur at the level of the gene, which often include point mutations, small amplifications, and deletions.

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Chromosome aberrations

  Chromosomal instability, aneuploidy, and loss of heterozygosity; There are several types of genetic damage that contribute to lung cancer pathogenesis:

• (i) changes in chromosome number;
• (ii) changes in chromosome structure;
• (iii) allelic alterations and loss of heterozygosity (LOH);
• (iv) sequence alterations in the form of point mutations or small amplifications or deletions .

Alterations that occur at the level of the gene

• Oncogenes and the pathways they regulate

  • Receptor tyrosine kinases

    • The EGFR family
      The EGFR family of receptors are transmembrane TK receptors and are composed of EGFR, HER2, HER3, and HER4 and each has unique properties. EGFR is overexpressed in ∼70% of NSCLCs but rarely expressed in SCLCs.

    • c-KIT
      SCLC but not NSCLC frequently express (40–70%) both the receptor c-KIT and its ligand, stem cell factor (SCF) suggesting an autocrine loop may promote the growth of the SCLC cells. activating c-KIT mutations are very rare in lung cancer.

    • RAS/RAF/MEK/ERK pathway
      The RAS family of proto-oncogenes (HRAS, KRAS, and NRAS) are 21-kD plasma membrane-associated G-proteins that regulate key signal transduction pathways involved in normal cellular differentiation, proliferation, and survival. RAS mutations (nearly always KRAS mutations in lung cancer) are found in 15–20% of NSCLCs, especially in adenocarcinomas(20–30%), but never in SCLCs.

• Epigenetic basis of lung cancer—DNA methylation and tumor suppressor gene inactivation

  There is overwhelming evidence that tumor acquired promoter hypermethylation, leading to loss of expression of the associated gene, is a common event during the multistep pathogenesis of human lung cancer. Over the past decade, nearly 150 genes have been identified that show tumor-specific methylation in primary tumor samples, including many in lung cancer.

• Tumor suppressor genes—Several key tumor-suppressor pathways are frequently inactivated in lung cancer.

  • The p53 pathway
    The tumor suppressor gene p53 is the most frequently mutated gene in human cancer, and p53 is inactivated by mutation in ∼90% of SCLCs and ∼50% of NSCLCs.

  • The RB pathway
    The RB pathway plays a central role in G1/S cell transition. Loss of RB function though deletion or mutation leads to loss of the G1/S checkpoint, and is a common event in lung cancer, particularly SCLCs (>90%), while inactivation of RB is found in 15–30% of NSCLCs.

  • 3p tumor suppressor genes
    Allele loss in 3p, including LOH and homozygous deletion, occurs in nearly 100% of SCLCs and more than 90% of NSCLCs and is one of the earliest events in lung cancer development.

参考资料

1. Oser, M.G., Niederst, M.J., Sequist, L.V. & Engelman, J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. The Lancet Oncology 16, e165-e172 (2015).
2. Shames, D.S., Sato, M. & Minna, J.D. The Molecular Genetics of Lung Cancer. in Lung Cancer 61-83 (2008).