Homozygous mutations causing SMAD4 loss are found in approximately 3% of lung adenocarcinomas and squamous cell carcinomas cases. SMAD4 loss tends to act synergistically with TP53 and KRAS mutations to increase lymphatic metastasis and tumor size. Experimental work in a mouse model has demonstrated increased susceptibility to DNA topoisomerase inhibitors with homozygous SMAD4 loss of function mutation coupled with KRAS G12D activating mutations.
C. Kandoth, M. D. McLellan et al, Mutational landscape and significance across 12 major cancer types. Nature. 502, 2013
SM Haeger, JJ Tompson et al, Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors. Oncogene. 1-10, 2015
C. Bian, Z. Li et al, Clinical outcome and expression of mutant P53, P16, and Smad4 in lung adenocarcinoma: a prospective study. World Journal of Surgical Oncology. 13:128, 2015
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