Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer

Abstract

Next generation sequencing is transforming patient care by allowing physicians to customize and match treatment to their patients’ tumor alterations. Our goal was to study the association between key molecular alterations and outcome parameters. We evaluated the characteristics and outcomes (overall survival (OS), time to metastasis/recurrence, and best progression-free survival (PFS)) of 392 patients for whom next generation sequencing (182 or 236 genes) had been performed. The Kaplan-Meier method and Cox regression models were used for our analysis, and results were subjected to internal validation using a resampling method (bootstrap analysis). In a multivariable analysis (Cox regression model), the parameters that were statistically associated with a poorer overall survival were the presence of metastases at diagnosis (P = 0.014), gastrointestinal histology (P < 0.0001), PTEN (P < 0.0001), and CDKN2A alterations (P = 0.0001). The variables associated with a shorter time to metastases/recurrence were gastrointestinal histology (P = 0.004), APC (P = 0.008), PTEN (P = 0.026) and TP53 (P = 0.044) alterations. TP53 (P = 0.003) and PTEN (P = 0.034) alterations were independent predictors of a shorter best PFS. A personalized treatment approach (matching the molecular aberration with a cognate targeted drug) also correlated with a longer best PFS (P = 0.046). Our study demonstrated that, across diverse cancers, anomalies in specific tumor suppressor genes (PTEN, CDKN2A, APC, and/or TP53) were independently associated with a worse outcome, as reflected by time to metastases/recurrence, best PFS on treatment, and/or overall survival. These observations suggest that molecular diagnostic tests may provide important prognostic information in patients with cancer.

Telomerase reverse transcriptase promoter alterations across cancer types as detected by next‐generation sequencing: A clinical and molecular analysis of 423 patients

“…Finally, TERT promoter mutations were associated with alterations in CDKN2A, and the latter anomalies have also been associated with a poor prognosis. 25,26 TERT promoter alterations were significantly associated with an increased median number of alterations (5 vs 3; P < .0001) in our population. These results may be of importance because a larger total number of aberrations is of prognostic value in several tumor types, with more aberrations predicting shorter progression-free survival.…”

“…However, in our study, only a higher number of alterations was retained as a significant independent variable correlating with survival in the multivariate analysis. Finally, TERT promoter mutations were associated with alterations in CDKN2A , and the latter anomalies have also been associated with a poor prognosis . TERT promoter alterations were significantly associated with an increased median number of alterations (5 vs 3; P < .0001) in our population.…”

Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics

“…Aberrations in the cell-cycle pathway may also have prognostic value. For instance, it has been reported that cell-cycle pathway gene alterations are independently associated with poor clinical outcomes, including overall survival (13)(14)(15). Further study will be required to elucidate the impact of each of the diverse cell-cycle pathway genes and their correlation to response with the various inhibitors being deployed in the clinic, including but not limited to palbociclib (PD0332991; ref.…”

“…Alterations in the cell-cycle pathway have been described in multiple cancers (8)(9)(10)(11)(12) and are associated with poorer clinical outcome in some tumor types (13)(14)(15), including acute lymphoblastic leukemia (9), ovarian (10), colon cancer (12), and medulloblastoma (11).…”

Massive parallel sequencing of solid tumours – challenges and opportunities for pathologists

“…In addition to directing the use of targeted therapies, recent papers highlight the ability of MPS to provide prognostic information on tumours. Changes in tumour suppressor genes PTEN , TP53 , APC and CDKN2A correlated significantly with poorer patient outcomes in multivariate analysis across multiple primary sites using a 236 gene panel, and Kim et al . were able to use capture‐based sequencing to separate prognostic groups of high‐grade urothelial carcinoma post‐cystectomy .…”