DNA Methylation of
            <i>PITX2</i>
            Predicts Poor Survival in Men with Prostate Cancer

Vasiljević, Nataša; Ahmad, Amar; Carter, Paul D.; Fisher, Gabrielle; Berney, Daniel M.; Foster, Christopher S.; Cuzick, Jack; Lörincz, Attila T.

doi:10.2217/bmm.14.41

Cited by 25 publications

(18 citation statements)

References 33 publications

(32 reference statements)

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“…Methylation data from 367 patients was obtained from previous studies [11, 12]. Methylation measurements for HSPB1, CCND2, TIG1, DPYS, PITX2, and MAL were performed on bisulfite converted DNA from an additional 352 patients as previously described [11, 12].…”

Section: Methodsmentioning

confidence: 99%

“…In a recent report, we demonstrated that changes in methylation of HSPB1, CCND2 , TIG1, DPYS , and, MAL, had significant prognostic effects in multivariate Cox models where death from prostate cancer was the study endpoint [11]. In an additional matched case-control study using a subset of patients with low and intermediate Gleason score, methylation of the PITX2 gene was informative for identification of men at high risk of aggressive prostate cancer [12]. Here we propose a new risk stratification score utilizing the methylation levels of the six genes: HSPB1, CCND2, TIG1, DPYS, PITX2, and MAL, that enhance identification of men with aggressive cancer who would otherwise be considered of low or intermediate risk based on clinical variables.…”

Section: Introductionmentioning

confidence: 99%

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A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors

et al. 2016

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Clinically aggressive disease behavior is difficult to predict in men with low to intermediate clinical risk prostate cancer and methylation biomarkers may be a valuable adjunct for assessing the management of these patients. We set to evaluate the utility of DNA methylation to identify high risk disease in men currently considered as low or intermediate risk. DNA was extracted from formalin-fixed paraffin-embedded transurethral prostate resection tissues collected during the years 1990−96 in a watchful-waiting cohort of men in the UK. The primary end point was death of prostate cancer, assessed by reviewing cancer registry records from 2009. Methylation was quantified by pyrosequencing assays for six genes (HSPB1, CCND2, TIG1, DPYS, PITX2, and MAL) with established biomarker value in prostate cancer. A novel prognostic methylation score was developed by multivariate Cox modelling using the six methylation biomarkers in 385 men with low-and-intermediate clinical risk variables and its prognostic value compared to two previously defined clinically-derived risk scores. Methylation score was the most significant variable in univariate and bivariate analysis in men with low-to-intermediate CAPRA risk score. When combined with CAPRA score the hazard ratio was 2.02; 95% confidence interval, 1.40−2.92. For a methylation score sensitivity of 83% the specificity was 44%, while the maximum achieved sensitivity by CAPRA was 68% at a specificity of 44%. The derived methylation score is a strong predictor of aggressive prostate cancer that could have an important role in directing the management of patients with low-to-intermediate risk disease. The estimated areas under the curve (AUC) at 10 years of follow-up were 0.62 (95% CI: 0.51, 0.70) and 0.74 (95% CI: 0.65, 0.82) for CAPRA, and combined (CAPRA + methylation) risk score (CRS) respectively.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors

et al. 2016

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“…90 For prostate cancer, a variety of genes has been suggested as prognostic methylation marker in smaller studies with PITX2 being most extensively verified so far. [91][92][93][94][95][96][97][98][99] A commercialized diagnostic test, that measures gene methylation in tissues of an initial negative biopsy to estimate the likelihood of a cancer diagnosis on subsequent biopsy is the ConfirmDX test (MDx Health). The histological demonstration of carcinoma is still the diagnostic gold standard to allow for curative therapy.…”

Section: Dna-methylationmentioning

confidence: 99%

Markers of clinical utility in the differential diagnosis and prognosis of prostate cancer

Kristiansen

2018

Modern Pathology

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Molecular diagnostics is a rapidly evolving area of surgical pathology, that is gradually beginning to transform our diagnostical procedures for a variety of tumors. Next to molecular prognostication that has begun to complement our histological diagnosis in breast cancer, additional testing to detect targets and to predict therapy response has become common practice in breast and lung cancer. Prostate cancer is a bit slower in this respect, as it is still largely diagnosed and classified on morphological grounds. Our diagnostic immunohistochemical armamentarium of basal cell markers and positive markers of malignancy now allows to clarify the majority of lesions, if applied to the appropriate morphological context (and step sections). Prognostic immunohistochemistry remains a problematic and erratic yet tempting research field that provides information on tumor relevance of proteins, but little hard data to integrate into our diagnostic workflow. Main reasons are various issues of standardization that hamper the reproducibility of cut-off values to delineate risk categories. Molecular testing of DNA-methylation or transcript profiling may be much better standardized and this review discusses a couple of commercially available tests: The ConfirmDX test measures DNA-methylation to estimate the likelihood of cancer detection on a repeat biopsy and may help to reduce unnecessary biopsies. The tests Prolaris, OncotypeDX Prostate, and Decipher all are transcript tests that have shown to provide prognostic data independent of clinico-pathological parameters and that may aid in therapy planning. However, further validation and more comparative studies will be needed to clarify the many open questions concerning sampling bias and tumor heterogeneity.

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“…The same phenomenon has been shown for NSCLC [28], a tumor which, like HNSCC, is known for its strong association with a history of smoking. Interestingly, in hormonally dependent tumors like breast and prostate cancer, PITX2 DNA hypermethylation has been associated with adverse overall survival [25–27, 29]. This might point at a role of PITX2 in tumorigenesis which lies beyond cell cycle regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Therawis GmbH (Munich, Germany) in collaboration with Qiagen N.V. (Venlo, The Netherlands) have recently announced the development of a commercially available assay exploiting the additional predictive potential of PITX2 methylation in breast cancer patients. In prostate cancer, PITX2 hypermethylation has been associated with biochemical recurrence, contributing to individualized risk assessment as a single assay and in combination with PITX3 methylation analysis [20, 22–23, 29]. In addition to its known role in the development of several organs, PITX2 also mediates cell cycle progression by regulating the transcription of cyclin A1, cyclin D2, and p21, therefore providing sufficient evidence to implicate PITX2 in tumorigenesis [30–32].…”

Section: Introductionmentioning

confidence: 99%

Clinical performance validation of PITX2 DNA methylation as prognostic biomarker in patients with head and neck squamous cell carcinoma

et al. 2017

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BackgroundDespite advances in combined modality therapy, outcomes in head and neck squamous cell cancer (HNSCC) remain dismal with five-year overall survival rates of less than 50%. Prognostic biomarkers are urgently needed to identify patients with a high risk of death after initial curative treatment. Methylation status of the paired-like homeodomain transcription factor 2 (PITX2) has recently emerged as a powerful prognostic biomarker in various cancers. In the present study, the clinical performance of PITX2 methylation was validated in a HNSCC cohort by means of an independent analytical platform (Infinium HumanMethylation450 BeadChip, Illumina, Inc.).MethodsA total of 528 HNSCC patients from The Cancer Genome Atlas (TCGA) were included in the study. Death was defined as primary endpoint. PITX2 methylation was correlated with overall survival and clinicopathological parameters.ResultsPITX2 methylation was significantly associated with sex, tumor site, p16 status, and grade. In univariate Cox proportional hazards analysis, PITX2 hypermethylation analyzed as continuous and dichotomized variable was significantly associated with prolonged overall survival of HNSCC patients (continuous: hazard ratio (HR) = 0.19 [95%CI: 0.04–0.88], p = 0.034; dichotomized: HR = 0.52 [95%CI: 0.33–0.84], p = 0.007). In multivariate Cox analysis including established clinicopathological parameters, PITX2 promoter methylation was confirmed as prognostic factor (HR = 0.28 [95%CI: 0.09–0.84], p = 0.023).ConclusionUsing an independent analytical platform, PITX2 methylation was validated as a prognostic biomarker in HNSCC patients, identifying patients that potentially benefit from intensified surveillance and/or administration of adjuvant/neodjuvant treatment, i.e. immunotherapy.

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DNA Methylation of PITX2 Predicts Poor Survival in Men with Prostate Cancer

Abstract: Our study strengthens prior findings that PITX2 methylation is useful as a biomarker of poor outcome of PCa and in addition we also suggest that it may be particularly useful in men with low Gleason score.

Cited by 25 publications

References 33 publications

A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors

A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors

Markers of clinical utility in the differential diagnosis and prognosis of prostate cancer

Clinical performance validation of PITX2 DNA methylation as prognostic biomarker in patients with head and neck squamous cell carcinoma

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