Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

Nature Reviews Cancer | Review
Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

Margaret A. Knowles Carolyn D. Hurst

Nature Reviews Cancer
15,
25–41
(2015)
doi:10.1038/nrc3817

Published online
23 December 2014

Abstract

Urothelial carcinoma of the bladder comprises two long-recognized disease entities with distinct molecular features and clinical outcome. Low-grade non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle-invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy.


At a glance


Bladder cancer is the fifth most common cancer in men in Western countries (male:female ratio is 3:1), and tobacco smoking is a major risk factor.
There are two major groups of patients with distinct prognosis and molecular features. Although local disease recurrence is a major problem for those with low-grade non-muscle-invasive tumours, life expectancy is long and development of invasive disease is infrequent. For those who present with muscle-invasive disease, development of metastatic disease is common, prognosis is dismal and no advances in therapy have been made for decades.
Major unmet clinical needs include non-invasive methods for disease surveillance and novel approaches to eliminate both tumour and widespread intraepithelial preneoplasia in patients with non-muscle-invasive disease. New systemic therapeutic approaches are urgently needed for those with muscle-invasive disease.
Recent studies reveal important biological features of urothelial metastasis and the epithelial–mesenchymal transition that may contribute to metastatic initiation. A key role for inflammatory processes is evident in the development of metastasis.
Heterogeneity in outcome within the two major groups indicates a need for subclassification for more accurate prognostication, prediction of response to current therapies and development of novel therapies.
Recent molecular analyses now provide such subclassification with definition of multiple subgroups that are independent of conventional histopathological definitions. This presents major opportunities for personalized patient care.

Urine Test Improves Prediction of High-Grade Prostate Cancer

Urine Test Improves Prediction of High-Grade Prostate Cancer
New genetic test could spare many men from unnecessary biopsies

March 31, 2016
Posted in: Cancer, Prostate Cancer / Medicine

An experimental urine test that detects genetic changes associated with prostate cancer identified 92 percent of men with elevated PSA (prostate-specific antigen) levels who had high-grade cancers, according to a study published today in JAMA Oncology online.

“The test has the potential to be a significant improvement over PSA alone in distinguishing between low- and high-grade prostate cancer, especially in the PSA gray zone patient. It could reduce hundreds of thousands of invasive biopsies each year. Given the pain and risks associated with performing a prostate biopsy, that’s not a trivial thing,” said first author James McKiernan, MD, the John K. Lattimer Professor and chair of urology at Columbia University Medical Center (CUMC) and urologist-in-chief at NewYork-Presbyterian/Columbia. In addition, the test is the only urine-based assay that does not require a digital rectal exam prior to collection and is easily integrated in the clinic environment.

Although the PSA blood test is commonly used to screen for prostate cancer, its value has come under question. An elevated PSA level—above 4 ng/mL—only indicates that a patient may have cancer and does not reliably distinguish between low-grade cancer, which can be monitored without active treatment, and high-grade disease, which requires aggressive treatment with surgery or radiation therapy. And, because PSA tests yield a high number of false positive results—only 25 percent of men with an elevated PSA level have prostate cancer—the US Preventive Services Task Force recommends against PSA-based screening.

The only way to definitively diagnose prostate cancer is with a tissue biopsy, a painful procedure that carries a substantial risk of bleeding and infection and a very small chance of death.

“Consequently, men with high PSA levels are typically advised to have a biopsy, even though most have no cancer at all, or have a type of disease that can be monitored without treatment,” said Dr. McKiernan. “In other words, a lot of men are undergoing unnecessary biopsies.”

In the study, prostate biopsy results from 774 men with PSA levels between 2 and 10 were compared with a composite score based on results of the urine test plus other risk factors, including PSA level, age, race, and family history of the disease.

Using data from 255 of the men, the researchers first set a cut-off score of 15.6 that identified over 90 percent of men found to have high-grade cancer. The researchers then assessed the test’s performance among the remaining 519 men using the designated cut-off score. A score above 15.6 was used to predict the presence of high-grade cancer (Gleason Score greater or equal to 7); a score equal to or below 15.6 was used to predict the presence of low-grade cancer or no disease.

This analysis showed that the test correctly identified 92 percent of men with high-grade cancer. However, the test also predicted high-grade cancer in 66 percent of men whose biopsies revealed low-grade or no cancer. In clinical practice, use of the test would have spared 27 percent of men from having an unnecessary prostate biopsy.

Among the 138 men who received a low test score, predicting low-grade or no cancer, 91 percent had no cancer or low-grade cancer that didn’t require immediate treatment. “By adding this test to our evaluation, men who receive a low score could potentially choose to forgo a biopsy,” Dr. McKiernan says.

Of the 12 men who had high-grade cancer but received a low test score, nine had moderately aggressive cancer that would likely have been detected with follow-up monitoring. The remaining three had a higher risk of cancer.

The test, called ExoDxTM Prostate(IntelliScore), detects RNA from three genes (ERG, PCA3, and SPDEF) that have been linked to the development and progression of prostate cancer. The RNA is encapsulated in lipid membrane-coated structures called exosomes that are excreted by cancer cells into urine. The test, developed by Exosome Diagnostics of Cambridge, MA, is the first urine-based test for prostate cancer that does not require a digital rectal exam or prostate massage before sample collection. Additional clinical trials to obtain FDA approval are being planned.

Based on the current study, the test’s AUROC score, which is a measure of how well the test plus PSA and risk factors distinguishes men with high-grade disease from men without, was superior to that of the current standard of care, at 0.72 versus 0.63. (A test with an AUROC score of 1.0 is perfect; a test that performs no better than random guessing has a score of 0.5.)

Prostate cancer is the most common solid malignancy and the second leading cause of cancer death in men worldwide, with over a million new cases and approximately 300,000 deaths in 2014, according to the researchers. Approximately two million transrectal ultrasound-guided prostate biopsies are performed each year in the US and Europe.

Long working hours and cancer risk: a multi-cohort study

Short Communication
BJC Open article

British Journal of Cancer (2016) 114, 813–818. doi:10.1038/bjc.2016.9 www.bjcancer.com
Published online 18 February 2016
Long working hours and cancer risk: a multi-cohort study

Katriina Heikkila1,2, Solja T Nyberg2, Ida E H Madsen3, Ernest de Vroome4, Lars Alfredsson5,6, Jacob J Bjorner3, Marianne Borritz7, Hermann Burr8, Raimund Erbel9, Jane E Ferrie10,11, Eleonor I Fransson6,12,13, Goedele A Geuskens4, Wendela E Hooftman4, Irene L Houtman4, Karl-Heinz Jöckel14, Anders Knutsson15, Markku Koskenvuo16, Thorsten Lunau17, Martin L Nielsen18, Maria Nordin13,19, Tuula Oksanen2, Jan H Pejtersen20, Jaana Pentti2, Martin J Shipley10, Andrew Steptoe10, Sakari B Suominen21,22,23, Töres Theorell13, Jussi Vahtera2,21,24, Peter J M Westerholm25, Hugo Westerlund13, Nico Dragano17, Reiner Rugulies3,26, Ichiro Kawachi27, G David Batty10,28, Archana Singh-Manoux10,29, Marianna Virtanen2 and Mika Kivimäki2,10,30 for the IPD-Work Consortium

Correspondence: Dr K Heikkila, E-mail: katriina.heikkila@lshtm.ac.uk

Received 22 September 2015; Revised 10 December 2015; Accepted 26 December 2015
Advance online publication 18 February 2016


Abstract


Background:

Working longer than the maximum recommended hours is associated with an increased risk of cardiovascular disease, but the relationship of excess working hours with incident cancer is unclear.
Methods:

This multi-cohort study examined the association between working hours and cancer risk in 116 462 men and women who were free of cancer at baseline. Incident cancers were ascertained from national cancer, hospitalisation and death registers; weekly working hours were self-reported.

Results:

During median follow-up of 10.8 years, 4371 participants developed cancer (n colorectal cancer: 393; n lung cancer: 247; n breast cancer: 833; and n prostate cancer: 534). We found no clear evidence for an association between working hours and the overall cancer risk. Working hours were also unrelated the risk of incident colorectal, lung or prostate cancers. Working greater than or equal to55 h per week was associated with 1.60-fold (95% confidence interval 1.12–2.29) increase in female breast cancer risk independently of age, socioeconomic position, shift- and night-time work and lifestyle factors, but this observation may have been influenced by residual confounding from parity.
Conclusions:

Our findings suggest that working long hours is unrelated to the overall cancer risk or the risk of lung, colorectal or prostate cancers. The observed association with breast cancer would warrant further research.


Epidemiological research suggests that working long hours has a detrimental effect on health. Extended working hours have been reported as being associated with an increased incidence of coronary heart disease and stroke (Kang et al, 2012; Virtanen et al, 2012; Kivimaki et al, 2015a) pre-term delivery (van Melick et al, 2014) and, in manual occupations, type 2 diabetes (Kivimaki et al, 2015b), as well as a high prevalence of anxiety, depression, sleeping difficulties and accidental injuries at work. (Dembe et al, 2005; Bannai and Tamakoshi, 2014). The relationship between long working hours and cancer, however, is unclear.

Long working hours could impact on cancer risk via their association with lifestyle-related exposures. Observational evidence suggests that working longer than recommended hours is linked to many behavioural cancer risk factors, such as excessive alcohol intake (Virtanen et al, 2015) and physical inactivity (Kirk and Rhodes, 2011; Angrave et al, 2015), possibly because individuals feel that they lack time to exercise because they spend extensive time at work (Escoto et al, 2012). As far as we are aware, the association between long working hours and incident cancer has been examined in only one previous investigation, which had inconclusive findings: in that prospective cohort study the association between working 45 h or longer per week and breast cancer was imprecisely estimated (hazard ratio (HR): 0.93, 95% confidence interval (CI): 0.54, 1.58) and no other cancer outcomes were examined (Nielsen et al, 2008).

To address this evidence gap, we examined the relationship between weekly working hours and the overall incident cancer as well as incident colorectal, lung, breast and prostate cancers using individual participant data from 116 000 men and women from 12 prospective cohort studies from six European countries.

Materials and Methods


The 12 studies in our analyses were conducted between 1992 and 2004 in Denmark, Finland, Germany, Sweden, The Netherlands and UK. All were a part of the Individual-Participant-Data Meta-analysis of Working Populations (IPD-Work) Consortium, a collaborative research effort to investigate the health impact of work-related exposures (Kivimaki et al, 2012). Details of each study’s design, recruitment of participants, data collection and ethics committee approval are provided in Supplementary eAppendix 1.
Participants

Our analyses were based on 116 462 men and women who were working and free of cancer at study baseline, whose records were linked to register-based information on incident cancers and who had complete data available on covariates (Supplementary eAppendix 1 and Supplementary Table S1).


Exposures and outcomes

Weekly working hours were ascertained from baseline self-report questions on usual weekly working hours and defined as the total number of hours in the main job and any secondary jobs (Supplementary eAppendix 2 and Supplementary Table S2).

Cancer events were identified from national cancer, hospitalisation and death registers in all studies apart from one (for details, see Supplementary eAppendix 2). The date of the cancer event was defined as the date of diagnosis or hospital admission due to cancer, whichever was earlier. Cancer cases were categorised according to the type and time of diagnosis of their first cancer. We excluded individuals whose first cancer record came from their death certificate (n=10), as the date of diagnosis for these cancers was uncertain. Codes for the incident cancer events were harmonised using ICD-10 (International Classification of Diseases, version 10) as any cancer (ICD-10 codes C00-C97), colorectal (C18-C20), lung (C34), female breast (C50) and prostate (C61) cancers.


Potential confounders and mediators

Details of the selection and ascertainment of the covariates included in our models are provided in Supplementary eAppendix 2. Briefly, potential confounders were age, sex, socioeconomic position, shift work and night-time work. Potential mediators were smoking, alcohol intake and body mass index (BMI). All covariates, measured at baseline, were harmonised across the studies as reported previously (Heikkila et al, 2012; Heikkilä et al, 2012; Nyberg et al, 2012, 2014).


Statistical analysis

Weekly working hours were analysed as a categorical exposure: <35 h, 35–40 h (reference category: standard working hours for the majority of the workforce in Europe), 41–48 h (the upper limit for the European Union Working Time Directive), 49–54 h and greater than or equal to55 h. Incident cancers (any cancer, colorectal, lung, female breast and prostate cancers) were analysed as binary outcomes. Each participant was followed-up from the date of their baseline assessment to the earliest of the following: incident cancer, death or the end of the registry follow-up. We modelled the associations between working hours and each cancer outcome in each study using Cox proportional hazards regression with the participant's age (i.e., time since birth) as the time scale in the model. Study-specific results were combined using random effects meta-analyses. All statistical analyses were conducted using Stata MP 13 (Stata Corporation, College Station, TX, USA) bar the study-specific analyses in the Danish studies, which were conducted using SAS 9.3 (SAS Institute Inc., Cary, NC, USA) and POLS, which were conducted using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Results



The characteristics of the 116 462 participants are summarised in Table 1. Overall, these men and women were aged 15–73 at baseline and the majority worked a standard 35–40 h per week, with the study-specific proportions varying from 31 to 71%. During a follow-up ranging from 4 to 22 years (median of study-specific medians: 10.8), 4371 individuals were diagnosed with cancer. Of these, 393 men and women had colorectal cancer and 247 had lung cancer; 833 women developed breast cancer and 534 men prostate cancer.