Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Palisading neutrophilic and granulomatous dermatitis as a presentation of Hodgkin lymphoma: A case and review.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a histopathological diagnosis, characterized by a pattern of granulomatosis, which may be associated with leukocytoclastic vasculitis. PNGD most commonly occurs in association with systemic inflammatory disorders, typically autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythromatosus. There are very rare reports of PNGD in patients with lymphoma. We report the case of a 53-year-old female with an erythematous, papular eruption occurring in association with Hodgkin lymphoma. Histopathological evaluation of the rash confirmed PNGD. To the best of our knowledge, this is the first case of PNGD occurring in association with Hodgkin lymphoma. Although extremely rare, underlying malignancy should be considered in patients with PNGD, particularly in individuals with constitutional symptoms and the absence of an obvious inflammatory etiology.

Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study.

BACKGROUND: The absence of trial data comparing robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy is a crucial knowledge gap in uro-oncology. We aimed to compare these two approaches in terms of functional and oncological outcomes and report the early postoperative outcomes at 12 weeks. METHOD: In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, were able to read and speak English, had no previous history of head injury, dementia, or psychiatric illness or no other concurrent cancer, had an estimated life expectancy of 10 years or more, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women's Hospital (Brisbane, QLD). Participants were randomly assigned (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient's condition. Further, a masked central pathologist reviewed the biopsy and radical prostatectomy specimens. Primary outcomes were urinary function (urinary domain of EPIC) and sexual function (sexual domain of EPIC and IIEF) at 6 weeks, 12 weeks, and 24 months and oncological outcome (positive surgical margin status and biochemical and imaging evidence of progression at 24 months). The trial was powered to assess health-related and domain-specific quality of life outcomes over 24 months. We report here the early outcomes at 6 weeks and 12 weeks. The per-protocol populations were included in the primary and safety analyses. This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12611000661976. FINDINGS: Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to radical retropubic prostatectomy and 163 to robot-assisted laparoscopic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group proceeded to surgery and 157 in the robot-assisted laparoscopic prostatectomy group. 121 assigned to radical retropubic prostatectomy completed the 12 week questionnaire versus 131 assigned to robot-assisted laparoscopic prostatectomy. Urinary function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (74·50 vs 71·10; p=0·09) or 12 weeks post-surgery (83·80 vs 82·50; p=0·48). Sexual function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (30·70 vs 32·70; p=0·45) or 12 weeks post-surgery (35·00 vs 38·90; p=0·18). Equivalence testing on the difference between the proportion of positive surgical margins between the two groups (15 [10%] in the radical retropubic prostatectomy group vs 23 [15%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a Δ of 10%. However, a superiority test showed that the two proportions were not significantly different (p=0·21). 14 patients (9%) in the radical retropubic prostatectomy group versus six (4%) in the robot-assisted laparoscopic prostatectomy group had postoperative complications (p=0·052). 12 (8%) men receiving radical retropubic prostatectomy and three (2%) men receiving robot-assisted laparoscopic prostatectomy experienced intraoperative adverse events. INTERPRETATION: These two techniques yield similar functional outcomes at 12 weeks. Longer term follow-up is needed. In the interim, we encourage patients to choose an experienced surgeon they trust and with whom they have rapport, rather than a specific surgical approach. FUNDING: Cancer Council Queensland.

Fusion transcript loci share many genomic features with non-fusion loci.

BACKGROUND: Fusion transcripts are found in many tissues and have the potential to create novel functional products. Here, we investigate the genomic sequences around fusion junctions to better understand the transcriptional mechanisms mediating fusion transcription/splicing. We analyzed data from prostate (cancer) cells as previous studies have shown extensively that these cells readily undergo fusion transcription. RESULTS: We used the FusionMap program to identify high-confidence fusion transcripts from RNAseq data. The RNAseq datasets were from our (N = 8) and other (N = 14) clinical prostate tumors with adjacent non-cancer cells, and from the LNCaP prostate cancer cell line that were mock-, androgen- (DHT), and anti-androgen- (bicalutamide, enzalutamide) treated. In total, 185 fusion transcripts were identified from all RNAseq datasets. The majority (76%) of these fusion transcripts were 'read-through chimeras' derived from adjacent genes in the genome. Characterization of sequences at fusion loci were carried out using a combination of the FusionMap program, custom Perl scripts, and the RNAfold program. Our computational analysis indicated that most fusion junctions (76%) use the consensus GT-AG intron donor-acceptor splice site, and most fusion transcripts (85%) maintained the open reading frame. We assessed whether parental genes of fusion transcripts have the potential to form complementary base pairing between parental genes which might bring them into physical proximity. Our computational analysis of sequences flanking fusion junctions at parental loci indicate that these loci have a similar propensity as non-fusion loci to hybridize. The abundance of repetitive sequences at fusion and non-fusion loci was also investigated given that SINE repeats are involved in aberrant gene transcription. We found few instances of repetitive sequences at both fusion and non-fusion junctions. Finally, RT-qPCR was performed on RNA from both clinical prostate tumors and adjacent non-cancer cells (N = 7), and LNCaP cells treated as above to validate the expression of seven fusion transcripts and their respective parental genes. We reveal that fusion transcript expression is similar to the expression of parental genes. CONCLUSIONS: Fusion transcripts maintain the open reading frame, and likely use the same transcriptional machinery as non-fusion transcripts as they share many genomic features at splice/fusion junctions.

Diagnostic performance of expression of PCA3, Hepsin and miR biomarkers inejaculate in combination with serum PSA for the detection of prostate cancer.

BACKGROUND AND METHODS: Here, we report on the evaluation of the diagnostic performance of ejaculate-derived PCA3, Hepsin, and miRNAs to complement serum PSA to detect prostate cancer. cDNA was prepared from 152 candidate specimens following RNA isolation and amplification for PSA, PCA3 and Hepsin qPCR, with 66 having adequate RNA for all three assays. Small RNA sequencing and examination of PCa-associated miRNAs miR-200b, miR-200c, miR-375 and miR-125b was performed on 20 specimens. We compared findings from prostate biopsies using D'Amico and PRIAS classifications and in relation to whole gland histopathology following radical prostatectomy. Multivariate logistic regression modeling and clinical risk (incorporating standard clinicopathological variables) were performed for all ejaculate-based markers. RESULTS: While Hepsin alone was not of predictive value, the Hepsin:PCA3 ratio together with serum PSA, expressed as a univariate composite score based on multivariate logistic regression, was shown to be a better predictor than PSA alone of prostate cancer status (AUC 0.724 vs. 0.676) and risk, using D'Amico (AUC 0.701 vs. 0.680) and PRIAS (AUC 0.679 vs. 0.659) risk stratification criteria as classified using prostate biopsies. It was also possible to analyse a subgroup of patients for miRNA expression with miR-200c (AUC 0.788) and miR-375 (AUC 0.758) showing best single marker performance, while a combination of serum PSA, miR-200c, and miR-125b further improved prediction for prostate cancer status when compared to PSA alone determined by biopsy (AUC 0.869 vs. 0.672; P < 0.05), and risk (D'Amico/PRIAS) as well as by radical prostatectomy histology (AUC 0.809 vs. 0.690). For prostate cancer status by biopsy, at a sensitivity of 90%, the specificity of the test increased from 11% for PSA alone to 67% for a combination of PSA, miR-200c, and miR-125b. CONCLUSIONS: These results show that use of a combination of different types of genetic markers in ejaculate together with serum PSA are at least as sensitive as those reported in DRE urine. Furthermore, a combination of serum PSA and selected miRNAs improved prediction of prostate cancer status. This approach may be helpful in triaging patients for MRI and biopsy, when confirmed by larger studies.

Total submission of pelvic lymphadenectomy tissues removed during radical prostatectomy for prostate cancer increases lymph node yield and detection of micrometastases.

AIMS: The detection of lymph node metastases has prognostic and therapeutic implications for patients undergoing radical prostatectomy for prostate cancer. Macroscopic identification of pelvic lymph nodes in surgical lymphadenectomy specimens can be difficult, with a potential for incomplete submission of lymph nodes for microscopic examination. This study was undertaken to determine whether complete sampling of lymphadenectomy specimens would improve the detection of metastatic disease in patients undergoing radical prostatectomy. METHODS AND RESULTS: We examined 109 pelvic lymphadenectomies accompanying radical prostatectomy specimens to assess the benefit of complete submission of the lymph node packets to detect extra lymph nodes and metastatic disease. We found that blocking the residual tissue, after all palpable lymph nodes had been identified, increased the mean number of lymph nodes from 3.8 to 10.8, with an average of 0.84 macroscopically undetectable nodes being recovered per block submitted. Metastatic prostate cancer was identified in eight cases, one of which had cancer in an impalpable lymph node only. CONCLUSIONS: Submission of all pelvic lymphadenectomy tissue for histological examination improves the yield of lymph nodes and the detection of metastatic prostate cancer.

A curious case: Concurrent collecting duct renal cell carcinoma and upper tract urothelial carcinoma.

A 71-year-old male presented to Urology with three weeks of overt haematuria and increasing lethargy. Contrast-enhanced CT scans revealed an 8 × 6cm partially exophytic lesion in the left kidney's upper pole, extending beyond the capsule and invading the superior cortical vein, accompanied by abnormal retrocrural lymph nodes. Signs of paraneoplastic syndrome prompted a left radical nephrectomy for symptom relief. Histological analysis identified high-grade collecting duct renal carcinoma and invasive urothelial cell carcinoma. Post-surgery, he was referred for oncological treatment but passed away within two months of the initial diagnosis.

Gleason score 3+3=6 prostatic adenocarcinoma is not benign and the current debate is unhelpful to clinicians and patients.

Prostate adenocarcinoma is a common malignancy associated with a significant morbidity and mortality. In both prostate biopsies and radical prostatectomy specimens Gleason scoring informs both treatment and outcome prediction. The current convention is that in needle biopsies, Gleason patterns 3, 4 and 5 are considered to be malignant. Despite this there is debate as to whether or not Gleason score (GS) 3+3=6 should be diagnosed as cancer due to potential over-treatment and the psychological impact on patients. It is apparent that GS 3+3=6 is indolent disease with a low risk of metastasis. However, it does have the histological features of malignancy and is capable of infiltrating the prostate gland, extraprostatic extension, and metastatic spread. Furthermore GS 3+3=6 carcinoma has immunohistochemical and molecular genetic features similar to those of higher grade prostatic carcinoma. If GS 3+3=6 tumour is considered benign, the question arises should a benign label be given to the Gleason pattern 3 component of tumour that includes Gleason patterns of higher grade? This would seem a logical step as GS 3+3=6 cancers and the pattern 3 component in cancers with multiple patterns are morphologically identical. If pattern 3 is considered to be benign, then Gleason scoring would be limited to 4+4=8, 4+5=9, 5+4=9 and 5+5=10 which is clearly inappropriate. The correct strategy to address potential over-treatment of patients with low-grade cancer is clinician and patient education, not the recalibration of Gleason grading to reclassify malignant tumours as benign.

Peritoneal inclusion cysts in a young male: A case report.

INTRODUCTION AND IMPORTANCE: Peritoneal inclusion cyst is a rare benign condition with low potential for malignant transformation but high recurrence rates. Debulking surgery is the recommended first line management for these patients, however, recurrence rates are up to 50 % (Padmanabhan et al., 2020; Chapel and Husain, 2021). CASE PRESENTATION: A 26-year-old male being worked up for non-specific abdominal pain with cross-sectional imaging showing multiple multicystic lesions in the abdomen and pelvis. There was a pre-operative suspicion of Pseudomyxoma Peritonei and decision was made for diagnostic laparoscopy and biopsy. Mucin and an abnormal small bowel mesentery was found intraoperatively and sampled leading to the diagnosis of peritoneal inclusion cyst. CLINICAL DISCUSSION: Treatment of peritoneal inclusion cyst range from surveillance to aggressive treatment with complete cytoreductive surgery with involved field peritonectomy and hyperthermic intra-peritoneal chemotherapy. CONCLUSION: First line management of peritoneal inclusion cysts is for debulking surgery. Arguments for less invasive and more aggressive management has been proposed, however, further data needs to be collected to determine gold standard of treatment.

Clinicopathologic Significance of Anterior Prostate Cancer: Comparison With Posterior Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging.

Anterior prostate cancer (APC) has been considered an indolent tumor, most commonly arising in the transition zone (TZ). More recently, detection of APC has been facilitated through multiparametric magnetic resonance imaging and improved biopsy techniques, enabling earlier detection. The pathologic features and clinical significance of pure APC in a large contemporary series of well-characterized tumors have, to date, not been elucidated. Cases with APC defined as cancer present anterior to the urethra only were identified from 1761 consecutive radical prostatectomy specimens accessioned between January 2015 and August 2016. The clinicopathologic features of these cases were compared with those of pure posterior prostate cancer (PPC) and the features of anterior peripheral zone (APZ) cancers were compared with those of TZ cancers. In addition, the tumor series from 2015 to 2016 was compared with a cohort of 1054 patients accessioned before the utilization of multiparametric magnetic resonance imaging in the routine workup of patients with prostate cancer. In the 2015-2016 series, there were 188 (10.7%) patients with APC compared with 5.4% in the series from the pre-multiparametric magnetic resonance imaging era. No difference was observed between APC and PPC with regards to patient age or mean serum prostate-specific antigen at presentation. Mean tumor volume and positive surgical margin (PSM) rates were significantly higher in APC. In contrast, PPC was more commonly high grade with more frequent extraprostatic extension (EPE). None of the cases of APC had infiltration of the seminal vesicle or lymph node involvement, in contrast to PPC, with almost 14% of cases in each category. The 3- and 5-year biochemical recurrence-free survival was significantly higher in APC when compared with PPC, although this was not retained on multivariable analysis which included tumor location. On division of APCs according to anatomic zone of origin, 45% were APZ cancer and 37% TZ cancer. On comparison of APZ and TZ cancers, there were no significant differences in mean age and serum prostate-specific antigen at presentation as well as tumor volume, Gleason score, and PSM rate. High-grade malignancy (Gleason score >3 + 4=7) was seen in 26% of TZ cancers which compared with 44% of APZ cancers and 56% of PPC cancers. The rate of EPE was significantly higher in APZ when compared with TZ cancer ( P< 0.0005); however, the biochemical recurrence rate was not significantly different between the groups. The prevalence of APC in radical prostatectomy specimens has increased in recent times, in association with earlier detection at a stage amenable to curative surgical treatment. APC, when compared with PPC, is less commonly high grade with less frequent EPE, despite the APC group having larger tumors and a higher PSM rate at presentation. However, not all anterior cancers are indolent. Anterior cancers are more commonly seen in the APZ than the TZ and APZ cancers appear more locally aggressive than TZ cancers.

Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer.

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele had reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

A Rare Case of Intraperitoneal Desmoplastic Fibroblastoma.

Desmoplastic fibroblastoma is a benign soft tissue tumor of indolent nature. It is more prevalent in males in their fourth to sixth decades of life and typically presents in the upper extremities, feet, and back. Other, uncommon locations have been reported as well, including the oral cavity and retroperitoneum. Histological examination demonstrates bland spindle cells in a dense collagenous stroma. The tumor neither recurs nor metastasizes. In this report, we discuss a case of a female patient who presented with symptoms concerning for intra-abdominal sepsis and was subsequently diagnosed with an intraperitoneal desmoplastic fibroblastoma. There is no evidence that this condition has been previously reported in the literature in the English language. The lesion was excised during laparoscopy and the patient showed no evidence of recurrence on magnetic resonance elastography (MRE) imaging 12 months later.

Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features.

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.

Lung and liver growth and retinoic acid status in human fetuses with congenital diaphragmatic hernia.

BACKGROUND: Abnormal retinoic acid (RA) signalling is considered a major cause of congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia and pulmonary hypertension are the major causes of morbidity and mortality in infants born with CDH. Experimental studies in animals have found that RA signalling is involved in lung and liver development, but animal models of CDH do not directly correlate with CDH in human fetuses. This study investigated if RA status is also linked to lung and liver growth in human fetuses with CDH. STUDY DESIGN AND PATIENTS: Hepatic stellate cells (HSC) in autopsy human fetal liver tissue were identified using cRBP-1 immunohistochemistry and the numbers of HSC manually counted. In mammals, RA is principally stored in HSC complexed to cRBP-1 and therefore cRBP-1+ HSC numbers were used as an indicator of fetal RA status. The number of HSCs was correlated with liver and lung weights, calculated relative to either normal biometric values or fetal body weight. RESULTS: The number of cRBP-1+ HSCs correlated with lung weight contralateral to the side of the diaphragmatic hernia (r=0.82, p=0.025) and combined lung weight (r=0.78, p=0.039) but not with ipsilateral lung weight (r=0.43, p=0.33), in fetuses with right and left CDH and a case of giant omphalocoele. Liver growth was influenced by contact with diaphragm but not significantly correlated with cRBP-1 expression (r=0.52, p=0.056). CONCLUSION: Fetal RA stores, reflected in the number of cRBP-1+ HSCs, influence lung growth as well as diaphragm development in human fetuses with CDH. Contact with diaphragm influenced liver growth.

Intraoperative Consultation and Macroscopic Handling: The International Society of Urological Pathology (ISUP) Testicular Cancer Consultation Conference Recommendations.

The International Society of Urological Pathology held a conference on issues in testicular and penile pathology in Boston in March 2015, which included a presentation by the testis macroscopic features working group. The presentation focused on current published guidance for macroscopic handling of testicular tumors and retroperitoneal lymph node dissections with a summary of results from an online survey of members preceding the conference. The survey results were used to initiate discussions, but decisions on practice were made by expert consensus rather than voting. The importance of comprehensive assessment at the time of gross dissection with confirmation of findings by microscopic assessment was underscored. For example, the anatomic landmarks denoting the distinction of hilar soft tissue invasion (pT2) from spermatic cord invasion (pT3 category) can only be determined by careful macroscopic assessment in many cases. Other recommendations were to routinely sample epididymis, rete testis, hilar soft tissue, and tunica vaginalis in order to confirm macroscopic invasion of these structures or if not macroscopically evident, to exclude subtle microscopic invasion. Tumors 2 cm or less in greatest dimension should be completely embedded. If the tumor is >2 cm in greatest dimension, 10 blocks or a minimum of 1 to 2 additional blocks per centimeter should be taken (whichever is greater).

A microsatellite repeat in PCA3 long non-coding RNA is associated with prostate cancer risk and aggressiveness.

Short tandem repeats (STRs) are repetitive sequences of a polymorphic stretch of two to six nucleotides. We hypothesized that STRs are associated with prostate cancer development and/or progression. We undertook RNA sequencing analysis of prostate tumors and adjacent non-malignant cells to identify polymorphic STRs that are readily expressed in these cells. Most of the expressed STRs in the clinical samples mapped to intronic and intergenic DNA. Our analysis indicated that three of these STRs (TAAA-ACTG2, TTTTG-TRIB1, and TG-PCA3) are polymorphic and differentially expressed in prostate tumors compared to adjacent non-malignant cells. TG-PCA3 STR expression was repressed by the anti-androgen drug enzalutamide in prostate cancer cells. Genetic analysis of prostate cancer patients and healthy controls (N > 2,000) showed a significant association of the most common 11 repeat allele of TG-PCA3 STR with prostate cancer risk (OR = 1.49; 95% CI 1.11-1.99; P = 0.008). A significant association was also observed with aggressive disease (OR = 2.00; 95% CI 1.06-3.76; P = 0.031) and high mortality rates (HR = 3.0; 95% CI 1.03-8.77; P = 0.045). We propose that TG-PCA3 STR has both diagnostic and prognostic potential for prostate cancer. We provided a proof of concept to be applied to other RNA sequencing datasets to identify disease-associated STRs for future clinical exploratory studies.