Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis

Abstract

Chromosome 3p and 1p deletions are among the most frequent genetic changes in human lung cancer and although candidate tumor suppressor genes have been identified in these regions, no causative correlations have been drawn between deletion or mutation of these and lung carcinogenesis. We identify XPC and Gadd45a as genes within each of these regions involved in lung tumor initiation and progression, respectively. One hundred percent of XPC-/- mice develop multiple spontaneous lung tumors with a minority progressing to non-small cell lung adenocarcinoma, occasionally with metastasis to adjacent lymph nodes. Deletion of Gadd45a alone does not lead to increased lung tumors in mice, but coupled with an XPC deletion, it results in lung tumor progression. Analysis of published data indicated allelic loss of XPC in most human lung tumors and allelic loss of Gadd45a in some human lung and other cancer types. Because DNA repair capacity is compromised in XPC+/- cells, it is possible that the loss of a single XPC allele in the human lung might confer a mutator phenotype. Coupled with cigarette carcinogens, decreased DNA repair would lead to additional mutations in genes such as p53 that are frequent targets in lung cancer.

Fig. 1.

XPC-/- mice develop lung tumors and additional deletion of Gadd45a results in increased malignancy of lung tumors. (A)26 XPC-/- and 26 XPC-/-Gadd45a-/- mice were allowed to live out their normal lifespan for up to 24 mo. Lungs sections were analyzed for tumor diagnosis. XPC-/- vs. XPC-/-Gadd45-/-, P < 0.0001. (B)18 XPC-/-,21 Gadd45a-/-, and 21 +/+ mice were necropsied at 16-17 mo. Lung surfaces were examined for tumors. No histological analysis of tumors was done for these mice.

Fig. 2.

Lungs from XPC-/- mice show a range of lesions covering the range from early atypia and hyperplasia to metastatic lung adenocarcinoma. (A) Normal lung. (B) Atypia. (C) Atypical adenomatous hyperplasia. (D) Adenoma. (E) Carcinoma in situ. (F and G) Adenocarcinoma. (H) Metastases to adjacent lymph nodes.

Fig. 3.

Lung tumors in XPC-/- and XPC-/-Gadd45a-/- do not lead to decreased lifespan compared with +/+ mice.

Fig. 4.

Increased incidence and multiplicity of lung tumors with age in XPC-/- mice. (A) Incidence of surface lung tumors in XPC-/- mice at various ages (6 mo, 19 mice; 12 mo, 8 mice; 16-17 mo, 18 mice). Surface lung tumor frequency increases with age. (B) Surface lung tumor number per mouse increases with age, each point represents one animal, and means are indicated with horizontal lines. (C) Size of individual surface lung tumors does not increase significantly with age, each point represents one lung tumor, and means are indicated with horizontal lines.