PSC is a rare lung malignancy that accounts for about 2%-3% of all NSCLC cases [1, 7]. The obvious heterogeneity of PSC not only increases the difficulty of clinical diagnosis, but also decreases the efficacy of conventional therapies [8, 9]. Therefore, it is crucial to identify novel prognostic factors and therapeutic factors to improve patient prognosis. The identification of panoramic oncogene exons through NGS has accelerated the development of molecular targeted therapies for lung adenocarcinoma, malignant melanoma, breast cancer and other tumors based on specific gene mutations. This approach is particularly effective for screening mutations associated with rare malignancies, such as PSC.
In this study, the average age of the PSC patients was 60 years, which is consistent with previous reports indicating that PSC is more prevalent in middle-aged and elderly men with 60–66 years of age [1]. In addition, previous studies have shown that clinicopathological features such as tumor diameter > 5 cm, clinical stage > I and lymph node invasion portend worse survival in PSC patients, and early surgical treatment may improve prognosis [10]. However, we did not detect any significant association of smoking status, tumor diameter, clinical stage and surgical treatment with the survival of PSC patients.
Mutations in TP53, PKD1, THADA, RB1 (single copy deletion), KRAS, PIK3CA, EGFR, NF1, PTCH1, BRCA1, BRAF, ARID1A, mTOR, MET, CREBBP, ARID2, ALK, CDK12 and EMLA4-ALK (fusion) were frequent in the tumor specimens obtained from 36 PSC patients. Previous reports on the frequency of gene mutations in PSC were largely focused on the European population, and the mutations were mostly sporadic. Almost 50% of the NSCLC patients harbor mutations in the TP53 gene, which is closely related to the occurrence and development of tumors [11]. However, the frequency of TP53 mutations in our cohort was 69.4%, which was the highest compared to that observed for other genes. Previous studies have shown that TP53 mutations in PSC are accompanied by other mutations, suggesting that mutated TP53 may not be the driver gene for PSC but rather augment genomic instability [12]. Since multiple gene mutations drive tumor growth, recovery of TP53 function can trigger apoptosis and clear the tumor cells [13].
In our study, the frequency of KRAS mutation was 30.6%, which is consistent with the reported mutation rate of 15%-30% in cancer. The PSC patients harboring KRAS mutations had worse overall survival compared to those with wild-type KRAS. Another study conducted on 46 cancer patients found that KRAS mutations increased the risk of metastasis, recurrence and death [14]. In addition, Fallet et al. [15] showed that all cancer patients with KRAS mutation have the wild-type EGFR, which was also observed in our study. However, the underlying mechanism needs to be further clarified. Nevertheless, the frequency of EGFR mutations in cancer patients is ambiguous. For instance, while one study reported that EGFR mutations occur in 9% of cancer patients [16], another study conducted on the Asian population found the mutation frequency of EGFR was 20% [17]. In our study, the frequency of EGFR mutations in the PSC patients was 19.4%, which was similar to the data on the Asian population. This suggests that the EGFR mutation may be closely related to race and ethnicity. Although tyrosine kinase inhibitors targeting EGFR have shown encouraging results, there is no data to support their efficacy against PSC.
Exon 14 skipping in MET occurs in about 3% of the NSCLC patients. Recent studies have shown that MET mutations are more common in sarcomatoid lung cancer than NSCLC [18, 19]. One study reported MET mutation frequency of 22.2% (8/36) among PSC patients [20], which was significantly higher than the 13.9% observed in our study. This can be attributed to differences in ethnicity and the small sample size. Other small sample studies and case reports have demonstrated that c-Met inhibitors (such as crizotinib and capotinib) may be effective against tumors with exon 14 jumping mutations of MET. Since none of patients in our cohort were treated with c-Met inhibitors, we cannot determine their efficacy in patients with PSC. We also detected mutations in PKD1, THADA, RB1, NF1, PTCH1, BRCA1 and BRAF, of which BRCA1 mutations were prognostically relevant, although little is known regarding their role in PSC.
In conclusion, the overall survival of the KRAS wild-type PSC patients was better compared to those harboring the KRAS mutations. Thus, detection of KRAS mutations can not only guide targeted therapy, but also predict prognosis. Although BRCA1 gene mutation was also identified as a prognostic factor, given the small sample size and racial differences, the result may have been biased and thus needs to be clarified in future studies. Therefore, it is worth conducting NGS using blood or tumor tissue specimens to detect germ-line mutations, and provide a basis for diagnosis and individualized treatment.
