We observed significant associations between two circulating markers of interstitial lung disease and subsequent lung cancer risk in a large cohort study, the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. After adjustment for cigarette smoking, lung cancer risk was increased 1.9-fold during follow-up for those in the top quartile of SP-D, and 1.6-fold for those in the top quartile of KL-6, compared to people with the lowest levels of these markers.
These associations with lung cancer risk are biologically plausible, because elevated circulating SP-D and KL-6 levels have been detected in patients with a number of pulmonary diseases, including idiopathic pulmonary fibrosis (15
), idiopathic pulmonary alveolar proteinosis (22
), and acute respiratory distress syndrome (16
). Individuals with COPD also have elevated SP-D levels (17
). Both glycoproteins are produced by type II alveolar cells, which proliferate and replace type I alveolar cells during lung injury (27
). Subsequently, the reparative type II cells transform into type I cells or undergo epithelial-to-mesenchymal transition (28
). However, a disproportionately large number of type II alveolar cells persist in the presence of interstitial fibrosis and secrete high SP-D and KL-6 levels detectable in serum or plasma (27
). Idiopathic pulmonary fibrosis has been associated with increased lung cancer risk and mortality in a number of studies (12
), and may cause lung cancer through diffuse pulmonary inflammation (29
). Chronic pulmonary inflammation could be an initiator or a promoter in the development of lung cancer, causing direct genotoxic injury due to a highly oxidative microenvironment, alteration of gene methylation, or increased cellular proliferation during tissue repair (4
In our study, current smoking status was associated with increased SP-D levels. However, we did not observe significant trends with cigarettes smoked per day, pack-years smoked or years since quitting. A prior study also observed increased SP-D levels in smokers (17
), while other studies have not (21
). We found no difference in KL-6 levels by smoking status, consistent with one prior study (31
). The lack of a consistent association between these markers and cigarette smoking suggests SP-D and KL-6 reflect processes that have effects on lung cancer that are independent of smoking, and are not merely markers of smoking-related lung damage.
Participants in PLCO were drawn from the general population, so they were largely healthy and free of severe pulmonary conditions. Thus, it is not surprising that SP-D and KL-6 levels observed in our study were much lower than those observed in patients with interstitial lung disease. For example, in our study the median level of SP-D among matched controls was 105 ng/mL, much lower than the median of approximately 400 ng/mL in a prior study of patients with pulmonary fibrosis (21
), and of 318.5 ng/mL observed in our positive control subjects with pulmonary fibrosis. These considerations highlight that, among our subjects, elevations in SP-D and KL-6 mostly reflect mild pulmonary disease or damage in the absence of clinical illness. CRP was positively correlated with SP-D and KL-6, indicating that levels of SP-D and KL-6 may increase in the setting of lung inflammation. Nonetheless, our results showing independent associations with lung cancer risk suggest that SP-D, KL-6 and CRP each reflect somewhat independent processes that impact lung carcinogenesis.
Along these lines, we found a relationship between SP-D levels and scarring on the baseline CXR, which was particularly strong for bilateral scarring, but KL-6 levels were not associated with CXR scarring. One possible explanation could be that KL-6 is a sensitive marker for the detection and monitoring of certain interstitial lung diseases, but it may not be as sensitive for the detection of much less severe or early pulmonary scarring. It is also important to recognize that a degree of measurement error exists in the detection of scarring by CXRs, as manifest by only fair agreement in the assessment of scarring across consecutive CXRs in PLCO (32
). Thus, it is possible that some scarring diagnoses in our study were misclassified and that some of the CXR findings may correspond to other conditions (e.g., congestive heart failure or atelectasis), which would have biased the associations of SP-D and KL-6 with CXR scarring toward the null.
Our results regarding the time intervals over which the associations between these markers and lung cancer risk were apparent are also informative (). For SP-D, an association with lung cancer risk was observed after more than two years following measurement of serum levels, and no association was observed over a shorter interval. If lung damage promotes cancer over an extended period of time, then perhaps the associations observed at longer latencies represent prolonged exposure to lung damage, while associations observed proximal to cancer diagnosis do not. In contrast, KL-6 was predominantly associated with lung cancer over shorter intervals. The association with lung cancer during the two years immediately following measurement suggests that an alternative explanation for our findings for KL-6 may be reverse causality due to a disease effect, i.e., that the presence of a cancer leads to production of KL-6. Indeed, KL-6 is secreted by some lung cancer tumors and has previously been considered as a possible diagnostic marker of lung adenocarcinoma (33
). Whether reverse causality could explain the associations between KL-6 and lung cancer observed over the longer interval of 2–4 years, or for squamous cell carcinoma, remains unclear.
Significant associations between each fibrosis marker and lung cancer were limited to adenocarcinomas and squamous cell carcinomas. Though we did not observe associations for small and large cell carcinomas, our analyses were limited by a small number of cases. Further, significant trends in lung cancer risk with increasing levels of fibrosis markers were limited to current and former smokers for SP-D, and current smokers only for KL-6. However, the number of cases who were never smokers was small, and because the interactions of SP-D and KL-6 with smoking status were not significant, we cannot conclude that the associations vary by smoking status.
The main strength of our study was the measurement of two circulating markers that are produced in the lung, and are associated with both lung damage and severe pulmonary diseases. We utilized pre-diagnostic sera, so that levels of these markers could be evaluated as predictors of subsequent lung cancer risk. Further, we were able to carefully control for potential confounding factors, including smoking, both in the study design and data analysis. A limitation was the potential measurement error of assessing pulmonary scarring with CXRs (11
). Further, our statistical power was limited for certain sub-analyses, due to a smaller number of cases.
In conclusion, we observed positive associations between circulating levels of SP-D and KL-6 and subsequent risk of lung cancer. Our results add support to a model whereby pulmonary disease, inflammation and scarring contribute to the etiology of lung cancer (4
). Future research should further examine the role of interstitial lung disease and fibrosis in the etiology of lung cancer, and the measurement of serum levels of SP-D and KL-6, particularly in smokers. As KL-6 is secreted by some lung tumors, its use as an early detection marker should be further explored. The use of SP-D and KL-6 has been advocated for the clinical monitoring of interstitial lung diseases. These markers, along with other known predictors, may also offer promise to identify individuals at high risk of developing cancer.