The Clinical and Molecular Profile of Lung Cancer Patients Harboring the TP53 R337H Germline Variant in a Brazilian Cancer Center: The Possible Mechanism of Carcinogenesis

Abstract

In southern and southeastern Brazil, the TP53 founder variant c.1010G>A (R337H) has been previously documented with a prevalence of 0.3% within the general population and linked to a heightened incidence of lung adenocarcinomas (LUADs). In the present investigation, we cover clinical and molecular characterizations of lung cancer patients from the Brazilian Li-Fraumeni Syndrome Study (BLISS) database. Among the 175 diagnosed malignant neoplasms, 28 (16%) were classified as LUADs, predominantly occurring in females (68%), aged above 50 years, and never-smokers (78.6%). Significantly, LUADs manifested as the initial clinical presentation of Li-Fraumeni Syndrome in 78.6% of cases. Molecular profiling was available for 20 patients, with 14 (70%) revealing EGFR family alterations. In total, 23 alterations in cancer driver genes were identified, comprising 7 actionable mutations and 4 linked to resistance against systemic treatments. In conclusion, the carriers of TP53 R337H demonstrate a predisposition to LUAD development. Furthermore, our results indicate that environmental pollution potentially impacts the carcinogenesis of lung tumors in the carriers of TP53 R337H.

Keywords: Li-Fraumeni syndrome; TP53 R337H variant; environmental pollution; lung adenocarcinoma; lung cancer; molecular profiling; particulate matter.

Figure 1

Patients included in the BLISS database: (A) proportion of patients with cancer diagnosis; (B) proportion of lung cancer from all tumors.

Figure 2

Genomic landscape of lung adenocarcinomas. Genomic profile of the 20 patients submitted to tumoral multigenic next-generation sequencing (NGS) platforms or real-time PCR (rtPCR) for EGFR and ALK. NGS was performed in 16 patients and rtPCR was performed in 4 (indicated by *). Most cases indicated mutations in driver genes. A total of 23 alterations, comprising 7 actionable and 4 related to systemic treatment resistance, were described. In horizontal lines, individual characteristics of the patients are listed, such as average levels of exposure to PM_2.5, gender, smoking, and evaluated genes. Each column indicates an individual patient. On the right, the genetic alterations are described and illustrated with colored squares. Abbreviations: del—deletion; indel—insertion or deletion; inser—insertion; PM_2.5—particulate matter < 2.5mm of diameter.

Figure 3

Clinical outcomes of 16 patients with early disease submitted to surgery: (a) median disease-free survival of the sixteen patients assessed; (b) overall survival of these patients. None of them had died due to LC. Abbreviation: NR—not reached.

Figure 4

Clinical outcomes in 11 patients with advanced disease treated with EGFR inhibitors: (a) median progression-free survival on first-generation EGFR inhibitor treatment (n = 6; median follow-up of 15.7 months); (b) median progression-free survival on third-generation EGFR inhibitor treatment (n = 5; median of follow-up of 12 months); (c) median overall survival on first-generation EGFR inhibitor treatment (n = 6; median of follow-up of 50.3 months); (d) median overall survival on third-generation EGFR inhibitor treatment (n = 5; median of follow-up of 67.6 months).

Figure 5

Clinical evolution on systemic treatments of patients #6 and #11: (a) a 41-year-old man with metastatic LC to bone and lungs with EGFR exon 20 insertion was submitted to six lines of treatment with clinical and radiologic benefit until multisystemic progression after seven months of an experimental EGFR oral inhibitor for exon 20 alterations; (b) a 33-year-old man with previous resected LC harboring, HER 2 exon 20 insertion, and submitted to four cycles of platinum doublet experienced a hepatic recurrence 13 months after. Then, he received three lines of systemic treatment, as represented above, with clinical and radiographic benefits for 25 months until CNS progression. Abbreviations: carbo—carboplatin; CDDP—cisplatin; pmtx—pemetrexed; TDM-1—trastuzumab–emtansine; x followed by a number indicates the number of treatment cycles.

Figure 6

Distribution of cases in Brazil and average daily values of PM_2.5: (a) location of patients diagnosed with LC according to the PM_2.5 heat map obtained via satellite (the redder the colors, the higher the PM_2.5 value); (b) daily mean values are represented in box plots of cities with cases and comparison with the value established by the European Society for the Environment as poor air quality (EAQI poor). We applied logarithmic scaling to the values for better graphical representation. Note that most values are above the levels designated as EAQI poor.