Tag Archive for: genetics

Posts

Article of the week: Nomogram helps the preoperative prediction of early biochemical recurrence after radical prostatectomy

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Ángel Borque discussing his paper.

If you only have time to read one article this week, it should be this one.

Genetic predisposition to early recurrence in clinically localized prostate cancer

Ángel Borque, Jokin del Amo, Luis M. Esteban*, Elisabet Ars§, Carlos Hernández**, Jacques Planas, Antonio Arruza††, Roberto Llarena, Joan Palou§, Felipe Herranz**, Carles X. Raventós, Diego Tejedor, Marta Artieda, Laureano Simon, Antonio Martínez, Elena Carceller, Miguel Suárez, Marta Allué, Gerardo Sanz* and Juan Morote

‘Miguel Servet’ University Hospital, *University of Zaragoza, Zaragoza, Spain, Progenika Biopharma S.A., University Hospital of Cruces, Bilbao, §Puigvert Foundation, ‘Vall d’Hebron’ University Hospital, Barcelona, **‘Gregorio Marañón’ University Hospital, Madrid, and ††Hospital of Txagorritxu, Vitoria, Spain

OBJECTIVES

• To evaluate genetic susceptibility to early biochemical recurrence (EBCR) after radical prostatectomy (RP), as a prognostic factor for early systemic dissemination.

• To build a preoperative nomogram to predict EBCR combining genetic and clinicopathological factors.

PATIENTS AND METHODS

• We evaluated 670 patients from six University Hospitals who underwent RP for clinically localized prostate cancer (PCa), and were followed-up for at least 5 years or until biochemical recurrence.

• EBCR was defined as a level prostate-specific antigen >0.4 ng/mL within 1 year of RP; preoperative variables studied were: age, prostate-specific antigen, clinical stage, biopsy Gleason score, and the genotype of 83 PCa-related single nucleotide polymorphisms (SNPs).

• Univariate allele association tests and multivariate logistic regression were used to generate predictive models for EBCR, with clinicopathological factors and adding SNPs.

• We internally validated the models by bootstrapping and compared their accuracy using the area under the curve (AUC), net reclassification improvement, integrated discrimination improvement, calibration plots and Vickers’ decision curves.

RESULTS

• Four common SNPs at KLK3, KLK2, SULT1A1 and BGLAP genes were independently associated with EBCR.

• A significant increase in AUC was observed when SNPs were added to the model: AUC (95% confidence interval) 0.728 (0.674–0.784) vs 0.763 (0.708–0.817).

• Net reclassification improvement showed a significant increase in probability for events of 60.7% and a decrease for non-events of 63.5%.

• Integrated discrimination improvement and decision curves confirmed the superiority of the new model.

CONCLUSIONS

• Four SNPs associated with EBCR significantly improved the accuracy of clinicopathological factors.

• We present a nomogram for preoperative prediction of EBCR after RP.

 

Read Previous Articles of the Week

Editorial: Prostate cancer families – predicting disease before and after the radical

In this issue of BJUI, Borque et al. discuss a subject that is now very close to my heart. Aged 48 years, I am 6 weeks post radical prostatectomy for a Gleason 3 + 4 prostate adenocarcinoma measuring ~2 mL in volume, with a PSA level of 2.54 ng/mL. Histology reassures me it is organ confined and seminal vesicle negative. My father and his brother both died aged 63 years of Gleason 10 prostate cancer and my brother is awaiting his radical prostatectomy in a few weeks. I have two sons, one of whom has asked me when he should be tested. Any prognostic information is going to help me advise my family.

In all, 85% of prostate cancers appear to be sporadic. The incidence of all prostate cancers is 1 in 8500 under the age of 40 years, rising to 1 in 15 at 60–69 years and 1 in 8 after that. The lifetime risk in the UK for all men is 8–10%.

The genetics of prostate cancer are confused by case clustering; the family members of men with a prostate cancer diagnosis seek out early advice from their physician resulting in detection of some clinically questionable cancers and an apparent higher incidence in certain families. These families do not necessarily have genetically determined prostate cancer.

The lifetime risk is altered dramatically by having two or more first-degree relatives with a diagnosis of prostate cancer; if the disease in the relative is identified before the age of 65 years the risk is increased further. Bratt suggests the risk rises from 15 to 20% when a single first-degree relative is diagnosed aged < 60 years. Zeegers et al., in a meta-analysis, have shown that diagnosing prostate cancer in a relative aged < 65 years increases the relative risk of having prostate cancer by 3.3, and having two first-degree relatives increases the relative risk by a factor of 5.1.

Analysis of a huge database from Sweden including data on 182 000 fathers and 3700 sons with prostate cancer suggest a standardised incidence ratio of 9.4 in men with a father and brother diagnosed with prostate cancer, with further analysis also showing unsurprisingly that the risk increases as an individual ages. Some true ‘prostate cancer families’ have been identified. These families have three or more relatives with prostate cancer often associated with a diagnosis at a young age, possibly with an increased tendency to an aggressive
phenotype; my uncle was 18 months from diagnosis to death from his disease, my father 4 years. In these families, the relative risk in male family members is 3.39 in those where the diagnosis of identified sufferers was made aged > 65 years, and 7.33 where the diagnosis is in men aged < 65 years. These risks which effectively give a lifetime risk in the individual of 45–50% are associated with carriage of a gene identified as increasing the prostate cancer risk. The best identified of these genes is the BRCA2 (breast cancer type 2 susceptibility protein) gene, which is associated with an increased risk of other cancers including breast, ovarian, gallbladder and pancreatic cancer, as well as malignant melanoma. This gene, carried in 1% of
Ashkenazi Jewish families, is associated with prostate cancer families in this population.

Now my prostate has been removed, I need to determine my chance of treatment failure. It would be interesting to know whether my genes and my single nucleotide polymorphisms (SNPs), which have almost certainly been responsible for me developing prostate cancer, can also predict my chance of developing early biochemical recurrence (EBCR) and the possibility of needing further treatment. In the Borque et al. article, I would appear on the first model (Fig. 1) to have a chance of ECBR of between 1 and 5%. This risk, according to this study, could increase to up to 30%, if I was to have four SNPs associated with prostate cancer (Fig. 2). Furthermore, we need to know whether identification of SNPs is any better than other possible predictors of EBCR and disease progression, such as the identification of lymphovascular invasion and tumour volume in the final specimen and the presence of extraprostatic extension, data not included in this study. Incidentally, I had no evidence of lymphovascular invasion.

The authors identify that this study needs repeating, particularly in a more ethnically diverse group (this study included Caucasian origin as an entry criterion), and we await longer term data to see how SNPs predict metastasis and prostate cancer-related death.

Jonathan M. Glass
Department of Urology, Guys & St Thomas’ Hospital Trust, London, UK

Read the full article

Video: Genetic predisposition to early recurrence in clinically localized prostate cancer

 

 

Genetic predisposition to early recurrence in clinically localized prostate cancer

Ángel Borque, Jokin del Amo, Luis M. Esteban*, Elisabet Ars§, Carlos Hernández**, Jacques Planas, Antonio Arruza††, Roberto Llarena, Joan Palou§, Felipe Herranz**, Carles X. Raventós, Diego Tejedor, Marta Artieda, Laureano Simon, Antonio Martínez, Elena Carceller, Miguel Suárez, Marta Allué, Gerardo Sanz* and Juan Morote

‘Miguel Servet’ University Hospital, *University of Zaragoza, Zaragoza, Spain, Progenika Biopharma S.A., University Hospital of Cruces, Bilbao, §Puigvert Foundation, ‘Vall d’Hebron’ University Hospital, Barcelona, **‘Gregorio Marañón’ University Hospital, Madrid, and ††Hospital of Txagorritxu, Vitoria, Spain


• To evaluate genetic susceptibility to early biochemical recurrence (EBCR) after radical prostatectomy (RP), as a prognostic factor for early systemic dissemination.

• To build a preoperative nomogram to predict EBCR combining genetic and clinicopathological factors.

PATIENTS AND METHODS

• We evaluated 670 patients from six University Hospitals who underwent RP for clinically localized prostate cancer (PCa), and were followed-up for at least 5 years or until biochemical recurrence.

• EBCR was defined as a level prostate-specific antigen >0.4 ng/mL within 1 year of RP; preoperative variables studied were: age, prostate-specific antigen, clinical stage, biopsy Gleason score, and the genotype of 83 PCa-related single nucleotide polymorphisms (SNPs).

• Univariate allele association tests and multivariate logistic regression were used to generate predictive models for EBCR, with clinicopathological factors and adding SNPs.

• We internally validated the models by bootstrapping and compared their accuracy using the area under the curve (AUC), net reclassification improvement, integrated discrimination improvement, calibration plots and Vickers’ decision curves.

RESULTS

• Four common SNPs at KLK3, KLK2, SULT1A1 and BGLAP genes were independently associated with EBCR.

• A significant increase in AUC was observed when SNPs were added to the model: AUC (95% confidence interval) 0.728 (0.674–0.784) vs 0.763 (0.708–0.817).

• Net reclassification improvement showed a significant increase in probability for events of 60.7% and a decrease for non-events of 63.5%.

• Integrated discrimination improvement and decision curves confirmed the superiority of the new model.

CONCLUSIONS

• Four SNPs associated with EBCR significantly improved the accuracy of clinicopathological factors.

• We present a nomogram for preoperative prediction of EBCR after RP.

© 2022 BJU International. All Rights Reserved.