Highlights
- •Presence of gBRCA2 mutations was not associated with IDC and CRIB patterns.
- •Results do not support germline BRCA2 testing only based on presence of IDC and/or CRIB.
- •IDC and CRIB patterns were associated with bi-allelic BRCA2 alterations in our study.
Abstract
Background
Intraductal (IDC) and cribriform (CRIB) histologies in prostate cancer have been associated
with germline BRCA2 (gBRCA2) mutations in small retrospective series, leading to the recommendation of genetic
testing for patients with IDC in the primary tumour.
Patients and methods
To examine the association of gBRCA2 mutations and other tumour molecular features with IDC and/or cribriform (CRIB) histologies,
we conducted a case–control study in which primary prostate tumours from 58 gBRCA2 carriers were matched (1:2) by Gleason Grade Group and specimen type to 116 non-carriers.
Presence/absence of IDC and CRIB morphologies was established by two expert uropathologists
blinded to gBRCA2 status. Fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS)
were used to detect BRCA2 alterations, PTEN deletions and TMPRSS2-ERG fusions. Chi-squared tests were used to compare the frequency of IDC and CRIB in
gBRCA2 carriers and controls and to assess associations with other variables. Logistic regression
models were constructed to identify independent factors associated with both histology
patterns.
Results
No significant differences between gBRCA2 carriers and non-carriers were observed in the prevalence of IDC (36% gBRCA2 versus 50% non-carriers, p = 0.085) or CRIB (53% gBRCA2 versus 43% non-carriers p = 0.197) patterns. However, IDC histology was independently
associated with bi-allelic BRCA2 alterations (OR 4.3, 95%CI 1.1–16.2) and PTEN homozygous loss (OR 5.2, 95%CI 2.1–13.1). CRIB morphology was also independently
associated with bi-allelic BRCA2 alterations (OR 5.6, 95%CI 1.7–19.3).
Conclusions
While we found no association between gBRCA2 mutations and IDC or CRIB histologies, bi-allelic BRCA2 loss in primary prostate tumours was significantly associated with both variant morphologies,
independently of other clinical-pathologic factors.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Integrative clinical genomics of advanced prostate cancer.Cell. 2015; 161: 1215-1228
- Survival with olaparib in metastatic castration-resistant prostate cancer.N Engl J Med. 2020; 383: 2345-2357
- Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making.JCO Precis Oncol. 2017; https://doi.org/10.1200/PO.17.00029
- Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration.J Clin Oncol. 2020; 38: 3763-3772
- BRCA2 and other DDR genes in prostate cancer.Cancers (Basel). 2019; 11
- Inherited DNA-repair gene mutations in men with metastatic prostate cancer.N Engl J Med. 2016; 375: 443-453
- Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines.JAMA Oncol. 2019; 5: 523-528
- PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer.J Clin Oncol. 2019; 37: 490-503
- Patient-derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis.Eur Urol. 2015; 67: 496-503
- Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer.Prostate. 2018; 78: 401-407
- Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations.Eur Urol. 2019; 75: 378-382
- Systematic review links the prevalence of intraductal carcinoma of the prostate to prostate cancer risk categories.Eur Urol. 2017; 72: 492-495
- Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer.Mod Pathol. 2015; 28: 457-464
- Disease-specific survival of patients with invasive cribriform and intraductal prostate cancer at diagnostic biopsy.Mod Pathol. 2016; 29: 630-636
- A prostate cancer "Nimbosus": genomic instability and SChLAP1 dysregulation underpin aggression of intraductal and cribriform subpathologies.Eur Urol. 2017; 72: 665-674
- Genetic and epigenetic determinants of aggressiveness in cribriform carcinoma of the prostate.Mol Canc Res. 2019; 17: 446-456
- Intraductal carcinoma of the prostate is an aggressive form of invasive carcinoma and should be graded.Pathology. 2020; 52: 192-196
- Improved prostate cancer biopsy grading by incorporation of invasive cribriform and intraductal carcinoma in the 2014 Grade groups.Eur Urol. 2020; 77: 191-198
- NCCN: prostate cancer.2020Version: Version 2.2020
- Role of genetic testing for inherited prostate cancer risk.in: Philadelphia prostate cancer consensus conference 2017. vol. 36. 2018: 414-424
- Clinical and molecular characterization study of prostate cancer (PC) patients with and without previously known germline BRCA1/2 mutations.J Clin Oncol. 2020; 38
- Intraductal carcinoma of the prostate on needle biopsy: histologic features and clinical significance.Mod Pathol. 2006; 19: 1528-1535
- Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization.Lab Invest. 2006; 86: 398-408
- Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer.Oncogene. 2008; 27: 253-263
- Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer.Mod Pathol. 2012; 25: 902-910
- Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations.BMC Canc. 2018; 18
- Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.Nat Genet. 1997; 15: 103-105
- Tumour lineage shapes BRCA-mediated phenotypes.Nature. 2019; 571: 576-579
- High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers.Ann Oncol. 2015; 26: 2293-2300
- Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.Nat Commun. 2017; 8: 13671
- Cytoplasmic PTEN protein loss distinguishes intraductal carcinoma of the prostate from high-grade prostatic intraepithelial neoplasia.Mod Pathol. 2013; 26: 587-603
- Analytic validation of a clinical-grade PTEN immunohistochemistry assay in prostate cancer by comparison with PTEN FISH.Mod Pathol. 2016; 29: 904-914
Article info
Publication history
Published online: February 21, 2021
Accepted:
January 16,
2021
Received in revised form:
December 29,
2020
Received:
October 18,
2020
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
