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Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients.

ABSTRACT: Early-stage non-small cell lung cancer (NSCLC) is potentially curative. Nevertheless, many patients will show disease recurrence after curative treatment. The Wnt signaling pathway is a developmental and stem cell pathway that plays an important role in tumorigenesis and may affect cancer progression. We hypothesize that genetic variants of the Wnt pathway may influence clinical outcome in early-stage NSCLC patients. We genotyped 441 functional and tagging single nucleotide polymorphisms (SNPs) from 54 genes of the Wnt pathway in 535 early-stage NSCLC patients treated with curative intent therapy including surgery and chemotherapy. For validation, 4 top SNPs were genotyped in 301 early-stage NSCLC patients from the Mayo Clinic. Cox proportional hazard model and combined SNP analyses were performed to identify significant SNPs correlated with recurrence-free and overall survival. Results from discovery group showed a total of 40 SNPs in 20 genes correlated with disease recurrence (P < 0.05). After correction for multiple comparisons, rs2536182 near Wnt16 remained significant (q < 0.1), which was validated in the replication population. Thirty-nine SNPs in 16 genes correlated with overall survival (P < 0.05) in the discovery group, and seven remained significant after multiple comparisons were considered (q < 0.1). In patients receiving surgery-only treatment, rs10898563 of FZD4 gene was associated with both recurrence-free and overall survival. Joint SNP analyses identified predictive markers for recurrence stratified by treatment. Our findings suggest inherited genetic variation in the Wnt signaling pathway may contribute to variable clinical outcomes for patients with early-stage NSCLC.

SUBMITTER: Coscio A

PROVIDER: S-EPMC4043238 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients.

Coscio Angela A Chang David W DW Roth Jack A JA Ye Yuanqing Y Gu Jian J Yang Ping P Wu Xifeng X

Carcinogenesis 20140211 6

Early-stage non-small cell lung cancer (NSCLC) is potentially curative. Nevertheless, many patients will show disease recurrence after curative treatment. The Wnt signaling pathway is a developmental and stem cell pathway that plays an important role in tumorigenesis and may affect cancer progression. We hypothesize that genetic variants of the Wnt pathway may influence clinical outcome in early-stage NSCLC patients. We genotyped 441 functional and tagging single nucleotide polymorphisms (SNPs) ...[more]

PMID: 24517998

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Project description:Lobectomy is considered the standard treatment for early-stage non-small cell lung cancer (NSCLC); however, more limited resections are commonly performed. We examined patient and surgeon factors associated with limited resection and compared postoperative and long-term outcomes between sublobar and lobar resections.A population- and health system-based sample of patients newly diagnosed with stage I or II NSCLC between 2003 and 2005 in five geographically defined regions, five integrated health-care delivery systems, and 15 Veterans Affairs hospitals was observed for a median of 55 months, through May 31, 2010. Predictors of limited resection and postoperative outcomes were compared using unadjusted and propensity score-weighted analyses. All P values are from two-sided tests.One hundred fifty-five (23%) patients underwent limited resection and 524 (77%) underwent lobectomy. In adjusted analyses of patient-specific factors, smaller tumor size (P = .004), coverage by Medicare or Medicaid, no insurance or unknown insurance (P = .02), more severe lung disease (P < .001), and a history of stroke (P = .049) were associated with receipt of limited resection. In adjusted analyses of surgeon characteristics, thoracic surgery specialty (P = .02), non-fee-for-service compensation (P = .008), and National Cancer Institute cancer center designation (P = .006) were associated with higher odds of limited resection. Unadjusted 30-day mortality was higher with limited resection than with lobectomy (7.1% vs 1.9%, difference = 5.2%, 95% confidence interval [CI] = 1.5% to 10.8%, P = .003), and the adjusted difference was not statistically significant (6.5% vs 2.9%, difference = 3.6%, 95% CI = -.1% to 9.2%, P = .09). Postoperative complications did not differ by type of surgery (all P > .05). Over the course of the study, a non-statistically significant trend toward improved long-term survival was evident for lobectomy, compared with limited resection, in adjusted analyses (hazard ratio of death = 1.35 for limited resection, 95% CI = 0.99 to 1.84, P = .05).Evidence is statistically inconclusive but suggestive that lobectomy, compared with limited resection, is associated with increased long-term survival for early-stage lung cancer. Clinical, socioeconomic, and surgeon factors appear to be associated with the choice of surgical resection.

Project description:BackgroundThe recurrence site that influences post-recurrence survival (PRS) in patients with non-small cell lung cancer (NSCLC) undergoing surgery and the preoperative predictors of recurrence remain unclear.MethodsCohorts 1 and 2 had 4520 (who underwent complete resection for p-stage 0-IIIA NSCLC) and 727 (who experienced recurrence after surgery) patients, respectively. The initial sites of recurrence were the lungs (309 cases), thoracic lymph nodes (225 cases), pleura (112 cases), bone (110 cases), central nervous system (86 cases), adrenal gland (25 cases), abdomen (60 cases), cervical and axillary lymph nodes (38 cases), chest wall (13 cases), skin (5 cases), and eye and tongue (3 cases). For cohort 2 analysis, the initial recurrence site that resulted in poor PRS was analyzed by multivariable analysis using a Cox proportional hazard model. For cohort 1 analysis, the preoperative predictors of recurrence patterns with poor PRS were analyzed by multivariable analysis using a logistic regression model.ResultsIn cohort 2 analysis, recurrence in the central nervous system (hazard ratio [HR], 1.70; p < 0.001), bone (HR, 1.75; p < 0.001), abdomen (HR, 2.39; p < 0.001), and pleura (HR, 1.69; p < 0.001) were independent poor prognostic recurrent sites for PRS and they were high-risk sites (HRS). Intrathoracic lymph nodes, cervical and axillary lymph nodes, lungs, chest wall, adrenal gland, eye and tongue, and skin were low-risk sites (LRS) that did not affect PRS. Patients with multiple LRS without HRS recurrence had a worse prognosis than those with a single LRS without HRS recurrence (5-year PRS 20.2% vs. 37.7%, p < 0.001) and were comparable to those with HRS recurrence (p = 1.000). In cohort 1 analysis, preoperative predictors for HRS and multiple LRS recurrences were positron emission tomography (PET) maximum standardized uptake value (maxSUV) ≥ 3.2 (HR, 5.09; p < 0.001), clinical nodal metastasis (HR, 2.00; p < 0.001), tumor size ≥ 2.4 cm (HR, 1.96; p < 0.001) and carcinoembryonic antigen (CEA) ≥ 5 ng/ml (HR, 1.41; p = 0.004). The cumulative incidence rates of HRS and multiple LRS recurrences within 5 years were 55.9%, 40.9%, 26.3%, 11.1%, and 3.5% (p < 0.001) in patients with 4, 3, 2, 1 and 0 of the above risks, respectively.ConclusionsHRS and multiple LRS were vital recurrences associated with poor PRS. Preoperative PET maxSUV, clinical nodal metastasis, tumor size, and CEA level predicted the incidence of vital recurrence.

Dataset Information

Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients.

Publications

Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients.

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