Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury

Purpose: To investigate the relationship between loss of heterozygosity (LO H) at the mannose 6-phosphate/ insulin-like growth factor 2 receptor (M6P/I GF2R) gene locus and the development of radiation-induced lung injury. Material and Methods: Thirty-five lung cancer patients with both stored pla sma for Transforming Growth Factor beta1 (TGF beta1) analysis and sufficien t quantities of archival pathology tissue to screen for LOH were studied. A ll patients had been treated with thoracic radiotherapy for their malignanc y and had radiographically detectable tumor present before beginning radiot herapy. Tumor and normal cells were microdissected from archival lung cance r pathology specimens. Two polymorphisms in the 3' untranslated region of t he M6P/IGF2R were used to screen for LOH. Plasma TGF beta1 levels were meas ured using acid-ethanol extraction and an ELISA. TGF beta1 and M6P/IGF2R pr otein expression was estimated by immunofluorescence and immunohistochemica l staining. Symptomatic radiation pneumonitis was scored according to Natio nal Cancer Institute Common Toxicity Criteria without knowledge of the resu lts of TGF beta or LOH analyses. Results: Of the 35 patients, 10 were homozygous for this polymorphism (noni nformative) and were excluded. Of the 25 informative patients, 13 had LOH. Twelve of 13 patients with LOH had increased pretreatment plasma TGF beta1 levels, vs. 3/12 patients without LOH (p < 0.01). A decrease or loss of M6P /IGF2R protein in the malignant cell accompanied by increased latent TGF<be ta>1 protein in extracellular matrix and tumor stroma was found in tumors w ith LOH, suggesting that this mutation resulted in loss of function of the receptor. Seven of 13 (54%) LOH patients developed symptomatic radiation-in duced lung injury vs. 1/12 (8%) of patients without LOH (p = 0.05). Conclusions: Loss of the M6P/IGF2R gene strongly correlates with the develo pment of radiation pneumonitis after thoracic radiotherapy (RT). Furthermor e, patients,vith LOH tin the setting of measurable tumor) are much more lik ely to have elevated plasma TGF beta, suggesting an inability to normally p rocess this cytokine. Thus, loss of the M6P/IGF2R gene may predispose patie nts to the development of radiation-induced lung injury. (C) 2001 Elsevier Science Inc.