|LETTER TO THE EDITOR
|Ahead of print publication
Germline BRCA2 mutation in a case of aggressive prostate cancer accompanied by spinal bulbar muscular atrophy
Hiroshi Hongo1, Takeo Kosaka1, Hideyuki Hayashi2, Kohei Nakamura2, Hiroshi Nishihara2, Shuji Mikami3, Himisha Beltran4, Mototsugu Oya1
1 Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
2 Genomics Unit, Keio Cancer Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
3 Division of Diagnostic Pathology, Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
4 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
|Date of Submission||06-Dec-2020|
|Date of Acceptance||23-Mar-2021|
|Date of Web Publication||21-May-2021|
Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582
Source of Support: None, Conflict of Interest: None
Article in PDF
|How to cite this URL:|
Hongo H, Kosaka T, Hayashi H, Nakamura K, Nishihara H, Mikami S, Beltran H, Oya M. Germline BRCA2 mutation in a case of aggressive prostate cancer accompanied by spinal bulbar muscular atrophy. Asian J Androl [Epub ahead of print] [cited 2021 Jun 12]. Available from: https://www.ajandrology.com/preprintarticle.asp?id=316630
Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a rare X-linked, recessive, lower motor neuron disease caused by a CAG repeat expansion within the first exon of the androgen receptor (AR) gene. Instability of the CAG-triplet repeat impacts AR function; therefore, men with SBMA are thought to be at a very low risk of prostate cancer. We previously reported a case of high-risk prostate cancer with SBMA (repeat length 46). Here, we present the follow-up of this patient along with investigation of his genetic background. The patient was a 54-year-old Japanese man diagnosed with prostatic adenocarcinoma, with a Gleason score of 4 + 5 by prostate needle biopsy at our institute (Keio University Hospital, Tokyo, Japan). Prostate-specific antigen (PSA) concentration was 148.0 ng l-1. Immunohistochemistry showed AR in the nucleus of prostate cancer cells [Supplementary Figure 1 [Additional file 1]]. He exhibited proximal limb weakness, perioral fasciculations, and tongue atrophy since the age of 40 years and had been diagnosed with SBMA by neurologists at our institute. Polymerase chain reaction and Sanger sequencing of its product identified more than 46 CAG repeats in the AR gene. He had a family history of SBMA (his maternal uncle), bladder cancer (his maternal uncle), breast cancer (his sister), lung cancer (his sister), and laryngeal cancer (his father). Magnetic resonance imaging suggested capsular invasion and left internal iliac lymph node metastases. Scintigraphy revealed no obvious bone metastasis. Combined androgen blockade with flutamide and leuprorelin was administered. The patient responded well to this hormonal therapy and the PSA nadir persisted for 8 years. After an increase in PSA level was noted, enzalutamide was begun. After approximately 3 years on enzalutamide, his PSA levels gradually increased and new pleural metastases were detected on computed tomography scan [Figure 1]a. Metastatectomy was performed, and pathological findings were consistent with those of prostate adenocarcinoma with small-cell neuroendocrine prostate cancer (NEPC; [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e). He was initiated on carboplatin and etoposide chemotherapy and was administered eleven cycles. He responded well, with a PSA decline from 148.35 ng ml−1 to <0.02 ng ml−1, and remains without any evidence of progression at 2 years.
|Figure 1: (a) Clinical course of our case. Representative picture of pleural metastasis with (b) hematoxylin and eosin staining and immunohistochemical images of (c) AR, (d) PSA, and (e) synaptophysin. Pathological diagnosis was poorly-differentiated adenocarcinoma with neuroendocrine differentiation. Scale bars = 50 μm. PSA: prostate-specific antigen; AR: androgen receptor; LHRH: luteinizing hormone releasing hormone; iPSA: initial PSA; ENZ: enzalutamide; CBDCA: carboplatin; VP16: etoposide; HE: hematoxylin-eosin; SYP: synaptophysin.|
Click here to view
To understand the aggressiveness of the disease in this patient, we analyzed his genetic profile. This study was approved by the Ethics Committee of Keio University Hospital (approval numbers: 20150285 and 20160084). Written informed consent for this study was obtained from the patient. Metastatic tumor tissue of the pleura and a blood sample were submitted for next-generation sequencing (NGS) genomic testing using the NCC OncoPanel test, which detects genetic mutations in 114 genes [Supplementary Table 1 [Additional file 2]]. Testing of tumor and blood samples identified a breast cancer gene 2 (BRCA2) mutation as a pathogenic variant (c.6952C>T, p.R2318*; allele frequency in the blood, 37.1%). Furthermore, a DNA polymerase epsilon catalytic subunit (POLE) mutation (c.2275C>T, p.R759C) was detected in the tumor sample as a variant of unknown significance.
SBMA is associated with an elongation of CAG repeats within the AR gene, with repeats ranging from 38 to 62, and these repeats disrupt AR gene function. Therefore, patients with SBMA are considered to be at a low risk for prostate cancer with only a few cases reported in the literature. Our patient with SBMA presented with an aggressive prostate cancer. We identified germline BRCA2 mutation which likely contributed to prostate cancer development and progression, despite suppressed AR function by CAG repeats. Notably, the tumor in this patient expressed nuclear AR protein; his PSA level was relatively high; and he responded well to initial androgen deprivation therapy and subsequent enzalutamide. Therefore, prostate cancers that develop in the setting of SBMA are not necessarily AR independent. He subsequently exhibited tumor progression and developed histologic features of NEPC which has been associated with AR independence. Through matched tumor-normal sequencing, we identified two predicted pathogenic alterations of potential clinical relevance involving BRCA2 (germline) and POLE (somatic).
BRCA2 plays a key role in the homologous recombination (HR) DNA repair pathway. In the nucleus of normal eukaryotic cells, BRCA2 proteins act with other molecules involved in DNA repair. BRCA2 proteins are located in the nuclear foci formed on DNA strands where replication errors are recognized. BRCA2 protects the stalled replication fork from nucleolytic degradation. BRCA2 also regulates DNA repair protein RAD51 homolog 1 (RAD51) recombinase activity and manages HR DNA repair. Loss of BRCA2 function causes double-strand DNA breaks via inactivation of the HR repair pathway and contributes to cancer development. Germline BRCA2 mutations are etiological factors for hereditary breast and ovarian cancer syndrome. BRCA2 loss also causes other cancers, such as those of the stomach, pancreas, and prostate. Regarding prostate cancer, the frequency of BRCA2 alteration was reported to be 3.3% in localized cases and 9.3%–13.1% in aggressive and metastatic cases. Germline BRCA2 variants were identified in 1.1% prostate cancer cases and 0.2% healthy men in a Japanese cohort. Of note, this is the second reported case of SBMA and aggressive prostate cancer with neuroendocrine differentiation found to have a germline BRCA2 mutation, suggesting that BRCA2 loss trumps the need for highly active AR signaling in prostate cancer pathogenesis. Both our patient and the patient previously reported with SBMA and BRCA2-associated prostate cancer had a neuroendocrine pathology. Because AR expression was heterogeneous in our case, some clones appeared to acquire androgen-independence potentially because of genomic instability due to BRCA2 mutation. This also has potential therapeutic implications considering that prostate cancer cases with BRCA2 mutations are reported to have higher response rates to platinum-based chemotherapy or poly (ADP-ribose) polymerase (PARP) inhibitor therapy. The long remission with carboplatin in our case and significant response to PARP inhibitor therapy in the other reported case can be associated with their BRCA2 mutation.
Comparative analysis of the clinical presentation of BRCA2-associated prostate cancer between the case previously reported and our case is shown in [Supplementary Table 2 [Additional file 3]]. Both cases developed metastatic prostate cancer at a young age. Both responded well to platinum-based chemotherapy and lived relatively longer than observed in the general progression of patients with NEPC. Of note, both cases also responded to enzalutamide despite the neuroendocrine pathology. Conteduca et al. attempted the use of a PARP inhibitor, talazoparib, and their case responded well. A PARP inhibitor, olaparib, has just been approved for treating BRCA-associated prostate cancer in Japan; we are currently considering it to treat our patient. Because both patients with SBMA developed aggressive prostate cancer, regular PSA screening is recommended for men with SBMA. In patients with SBMA who are diagnosed with prostate cancer, testing for germline BRCA2 should be considered.
In conclusion, this reported case of aggressive prostate cancer in a patient with SBMA accompanied by a pathogenic germline BRCA2 mutation, likely contributed to prostate cancer initiation and treatment response. Despite predicted disrupted AR function in SBMA, our patient did respond to AR-targeted therapies. Genetic testing should be considered for patients with SBMA and prostate cancer.
| Author Contributions|| |
H Hongo, TK and MO designed the study. H Hongo and TK provided the study materials. H Hongo, TK, H Hayashi, KN, HN and SM conducted and collected data. H Hongo, TK and HB analyzed data and made interpretations. H Hongo, TK and HB wrote manuscript. H Hayashi, KN, HN, SM and MO edited manuscript. All authors read and approved the final manuscript.
| Competing Interests|| |
All authors declare no competing interests.
| Acknowledgments|| |
Yoko Suzuki provided technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research (#17K16813 to H Hongo and #17K11158 and #20H03817 to TK) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The study was supported in part by research Grant to TK from the Takeda Science Foundation, Japan.
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
| References|| |
Kosaka T, Miyajima A, Kikuchi E, Takahashi S, Suzuki N, et al.
A case of spinal and bulbar muscular atrophy with high-stage and high-Gleason score prostate cancer responded to maximal androgen blockade therapy. J Androl
2012; 33: 563–5.
Conteduca V, Sigouros M, Sboner A, Pritchard CC, Beltran H. BRCA2-associated prostate cancer in a patient with spinal and bulbar muscular atrophy. JCO Precis Oncol
2018; 2: PO.18.00115.
Hamann U, Herbold C, Costa S, Solomayer EF, Kaufmann M, et al.
Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2
in sporadic breast cancer. Cancer Res
1996; 56: 1988–90.
Collins N, McManus R, Wooster R, Mangion J, Seal S, et al.
Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2
gene on chromosome 13q12-13. Oncogene
1995; 10: 1673–5.
Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst
1999; 91: 1310–6.
Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell
2015; 163: 1011–25.
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, et al.
Integrative clinical genomics of advanced prostate cancer. Cell
2015; 161: 1215–28.
Momozawa Y, Iwasaki Y, Hirata M, Liu X, Kamatani Y, et al.
Germline pathogenic variants in 7636 Japanese patients with prostate cancer and 12 366 controls. J Natl Cancer Inst
2020; 112: 369–76.
Pomerantz MM, Spisák S, Jia L, Cronin AM, Csabai I, et al.
The association between germline BRCA2
variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer
2017; 123: 3532–9.
Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, et al.
DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med
2015; 373: 1697–708.