High grade prostatic intraepithelial neoplasia does not display loss of heterozygosity at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer

Abstract

What ' s known on the subject? and What does the study add?The risk of developing aggressive prostate cancer is increased for men carrying a pathogenic germline mutation in BRCA2 . An earlier study by the Kathleen Cuningham Consortium for Research into Familial Breast Cancer showed that BRCA2 mutation carriers displayed a loss of heterozygosity (LOH) within their prostate cancer tissue in the majority of cases, thus implying that the prostate cancer in these men occurred as a result of LOH for BRCA2 . High grade prostatic intraepithelial neoplasia (HGPIN) has been considered a precursor to prostate adenocarcinoma in some, but not all, cases of prostate adenocarcinoma.The study found that there was no LOH for BRCA2 in HGPIN. From this small cohort of BRCA2 -positive men, we suggest HGPIN is not necessarily a precursor to their prostate cancer development. The presence of HGPIN in a TRUS biopsy in these men at risk of high risk disease is not an indication for prostatectomy. OBJECTIVES• To determine if high grade prostatic intraepithelial neoplasia (HGPIN), which is considered a precursor to the development of prostate adenocarcinoma, displays the same genetic hallmarks as adenocarcinoma.• To identify, using molecular genetic techniques, if HGPIN is a precursor of tumour development and progression in men carrying a pathogenic germline mutation in BRCA2 . PATIENTS AND METHODS• Ten participants from the Kathleen Cuningham Consortium for Research into Familial Breast Cancer cohort of high-risk breast cancer families were identifi ed, with (i) a diagnosis of aggressive prostate cancer and presence of HGPIN, (ii) a pathogenic BRCA2 mutation, and (iii) access to archival prostate tissue specimens.• Loss of heterozygosity (LOH) at the BRCA2 gene was examined using mutation-specifi c PCR and sequencing of DNA from laser microdissected HGPIN. RESULTS• Within this cohort of 10 pathogenic BRCA2 carriers, no patient displayed LOH at the mutation locus within HGPIN, irrespective of whether or not corresponding adenocarcinoma DNA displayed LOH. CONCLUSIONS• Although HGPIN is considered a precursor to cancer, as no LOH was observed, this assay does not provide a genetic marker that may be considered a positive predictor of tumorigenesis in BRCA2 carriers.• In this group of high-risk men, early screening via prostate-specifi c antigen testing, rectal examination and prostate biopsy may be prudent to permit the detection and the optimum clinical management of prostate cancer. KEYWORDSBRCA2 , loss of heterozygosity , HGPIN , prostate cancer High grade prostatic intraepithelial neoplasia does not display loss of heterozygosity at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer

Loss of heterozygosity for chromosomal regions 15q14-21.1, 17q21.31, and 13q12.3-13.1 and its relevance for prostate cancer

“…Similarly Edwards et al [ 37 ] identified LOH in the majority of tumors of BRCA2 mutation carriers. On the other hand, Willems-Jones et al [ 42 ] note that high-grade prostatic intraepithelial neoplasia, believed to be a precursor to prostate adenocarcinoma in some cases, does not display LOH at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer.…”

Tumour Suppressor Mechanisms in the Control of Chromosome Stability: Insights from BRCA2

“…Lack of LOH has been documented using different methods in up to ∼30% of breast cancers (King et al, 2007), by NGS in ∼25% high-grade serous ovarian carcinomas (Cancer Genome Atlas, 2011), and in up to 55% of prostatic cancers associated with BRCA2 mutation carriers (Willems-Jones et al, 2012). Thus, it will be essential in future clinical trial designs to test for LOH in tumour samples to help stratify likely responders to PARP1i or similar targeted therapies.…”

Chromosome instability and carcinogenesis: Insights from murine models of human pancreatic cancer associated with BRCA2 inactivation

“…Importantly large‐scale, unbiased genomic sequencing of high‐grade serous ovarian carcinomas highlighted the retention of the wild‐type allele in end stage disease from ∼25% of germline Brca2 carriers (Atlas, 2011). Furthermore, a detailed study of prostate tumour progression in BRCA2 germline mutation carriers uncovered no LOH in high‐grade prostatic intraepithelial neoplasias, considered precursor lesions to the development of prostate adenocarcinoma, and up to 55% of the malignant tumours analysed (Willems‐Jones et al., 2012). Collectively, these data suggest that cancers arising in germline BRCA2 mutation carriers frequently fail to exhibit loss of the wildtype allele, and that failure to exhibit LOH occurs in BRCA2 ‐mutant cancers from several different tissues.…”