Role of DMP1 and its future in lung cancer diagnostics

Abstract

Lung cancer is the most lethal carcinoma worldwide. Mutations of p53, inactivation of p16^INK4a, and overexpression of cyclins E, A and B are independently associated with poor prognoses of patients, while the prognostic value of cyclin D1 or RB expression is inconclusive. Cyclin D binding myb-like protein 1 (Dmp1) encodes a DNA binding protein that receives signals from oncogenic Ras and functions as a tumor suppressor by activating the Arf–p53 pathway. Dmp1 has been shown to be haplo-insufficient for tumor suppression in mouse models including K-ras-mediated lung carcinogenesis. The human DMP1 gene is located on chromosome 7q21, and our recent results revealed that the hDMP1 gene is deleted, but not mutated or silenced, in approximately 40 % of human non-small-cell lung carcinomas. These cases typically retained wild-type ARF and p53 and expressed very low levels of the hDMP1 protein. Thus, hDMP1 loss could be a novel diagnostic marker for non-small-cell lung carcinomas.

Keywords::

• ARF
• DMP1
• haploid insufficiency
• immunohistochemistry
• LOH
• loss of heterozygosity
• lung cancer
• p16^INK4a
• p53
• Ras
• tumor-suppressor gene

Acknowledgements

We thank Charles Sherr, Martine Roussel, John Cleveland, Linda Shapiro, Martin McMahon, Ali Mallakin, Lauren Matise, Sarah Lagedrost, Robert Kendig and Dana Yancey for collaborative work on Dmp1 projects. We are grateful to Bruce Torbett and Mario Tschan for sharing unpublished data.

Financial & competing interests disclosure

Kazushi Inoue is supported by the National Institutes of Health/National Cancer Institute (NIH/NCI) 5R01CA106314, American Cancer Society RSG-07–207–01-MGO and Wake Forest University Golfers against Cancer grant P30CA12197GAC. Donna Frazier was supported by the Ruth L Kirschstein National Research Service Award Institutional Research Training Grant (5T32CA079448, F Torti) from NIH.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this review manuscript.