Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D ...imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Expression profiling of clones arising in Pten/Trp53-deficient tumors identified distinct molecular signatures. Strikingly, most clones harbored cells that had undergone an epithelial-to-mesenchymal transition, indicating widespread, inherent plasticity. Hence, an integrative pipeline that combines lineage tracing, 3D imaging, and clonal RNA sequencing technologies offers a comprehensive path for studying mechanisms underlying heterogeneity in whole tumors.
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•A single-step, non-toxic clearing agent for 3D imaging of whole organs and tumors•Derivation of an integrative platform to interrogate intratumoral heterogeneity•Profound clonal restriction occurs during neoplastic progression•The epithelial-mesenchymal transition occurs clonally as a frequent event
Rios et al. develop a rapid, large-scale single-cell resolution 3D imaging protocol and use the protocol together with RNA sequencing to explore the cellular dynamics of mammary tumorigenesis and show that a molecular epithelial-to-mesenchymal transition is a prominent feature of tumor clones.
Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this ...aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
Abstract Intraductal carcinoma of the prostate (IDC-P) is associated with poor prognosis. While it is often regarded as a rare pathology, the prevalence of IDC-P remains unclear, with variable ...reports from small and disparate patient populations. To determine how common IDC-P is across the spectrum of prostate cancer, we conducted a systematic review correlating IDC-P prevalence with prostate cancer risk. Electronic searches of the OVID Medline, PubMed, and Scopus literature databases identified 38 patient cohorts in 24 articles, which were divided between four prostate cancer risk categories (low, moderate, high, and recurrent or metastatic disease). This review, which included radical prostatectomy and prostate biopsy specimens from >7000 patients, revealed an unexpectedly high rate of IDC-P. The IDC-P prevalence increased from 2.1% in low-risk patient cohorts to 23.1%, 36.7%, and 56.0% in moderate-risk, high-risk, and metastatic or recurrent disease risk categories, respectively ( p < 0.0001). IDC-P was also highly prevalent in tumours following androgen deprivation therapy or chemotherapy (60%). Contrary to common perceptions, this study demonstrates a strong association between IDC-P prevalence and aggressive prostate cancer, with a significantly higher frequency in high-risk disease. Greater recognition and systematic reporting of IDC-P may improve patient risk stratification. Patient summary Prostate cancer can grow within ducts of the prostate, as well as in prostate tissue. By reviewing all reports describing prostate cancer growing within ducts, we found that it occurs more commonly than many scientists and clinicians appreciate, especially in aggressive prostate cancers. We conclude that there should be more awareness of this pattern of prostate cancer.
What's known on the subject? and What does the study add?
The clinical presentation and complications of lichen sclerosus are well known. What is less well known is the true incidence of the ...condition. The published figures are all based on attendance at general medical clinics or specialist clinics, but it is likely that the true incidence is much higher than this reported incidence as many men will not present to the doctor for treatment. The other uncertainty is the relationship of lichen sclerosus to the subsequent development of cancer of the penis. As pointed out in the paper, it is likely that between 4% and 8% of men with this condition will develop squamous cell cancer of the penis. However, it is unclear if lichen sclerosus itself causes the development of squamous cell cancer or if it is due to coexistent infection with human papillomavirus.
This review provides a concise summary of the clinical and pathological features of the disease and describes its current medical and surgical treatment. It brings together a number of papers which have addressed the association of lichen sclerosus with squamous cell carcinoma of the penis and shows that the likely incidence of carcinoma is approximately 4–8% in men with this condition.
SUMMARY
Penile lichen sclerosus, also known as balanitis xerotica obliterans, is a chronic inflammatory condition of the penis which can occur at all ages. The inflammation leads to the formation of white plaques most commonly on the foreskin or penis, and can lead to inability to retract the foreskin or blockage to the flow of urine. Cancer may occur rarely.
Penile lichen sclerosus is a progressive, sclerosing, inflammatory dermatosis of the glans penis and foreskin which is of uncertain aetiology. Recent studies have shown a link between lichen sclerosus and squamous cell carcinoma of the penis. In this review, we discuss the clinical presentation, pathology and current approach to treatment of this condition.
Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic ...evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.
Gene panel testing for breast cancer susceptibility has become relatively cheap and accessible. However, the breast cancer risks associated with mutations in many genes included in these panels are ...unknown.
We performed custom-designed targeted sequencing covering the coding exons of 17 known and putative breast cancer susceptibility genes in 660 non-BRCA1/2 women with familial breast cancer. Putative deleterious mutations were genotyped in relevant family members to assess co-segregation of each variant with disease. We used maximum likelihood models to estimate the breast cancer risks associated with mutations in each of the genes.
We found 31 putative deleterious mutations in 7 known breast cancer susceptibility genes (TP53, PALB2, ATM, CHEK2, CDH1, PTEN and STK11) in 45 cases, and 22 potential deleterious mutations in 31 cases in 8 other genes (BARD1, BRIP1, MRE11, NBN, RAD50, RAD51C, RAD51D and CDK4). The relevant variants were then genotyped in 558 family members. Assuming a constant relative risk of breast cancer across age groups, only variants in CDH1, CHEK2, PALB2 and TP53 showed evidence of a significantly increased risk of breast cancer, with some supportive evidence that mutations in ATM confer moderate risk.
Panel testing for these breast cancer families provided additional relevant clinical information for <2% of families. We demonstrated that segregation analysis has some potential to help estimate the breast cancer risks associated with mutations in breast cancer susceptibility genes, but very large case-control sequencing studies and/or larger family-based studies will be needed to define the risks more accurately.
The Gleason Grading system has been used for over 50 years to prognosticate and guide the treatment for patients with prostate cancer. At consensus conferences in 2005 and 2014 under the guidance of ...the International Society of Urological Pathology (ISUP), the system has undergone major modifications to reflect modern diagnostic and therapeutic practices. The 2014 consensus conference yielded recommendations regarding cribriform, mucinous, glomeruloid and intraductal patterns, the most significant of which was the removal of any cribriform pattern from Gleason grade 3. Furthermore, a Gleason score grouping system was endorsed which consisted of five grades where Gleason score 6 (3+3) was classified as grade 1 which better reflected the mostly indolent behaviour of these tumours. Another issue discussed at the meeting and subsequently endorsed was that in Gleason score 7 cases, the percentage pattern 4 should be recorded. This is especially important in situations where modern active surveillance protocols expand to include men with low volume pattern 4. While major progress was made at the conference, several issues were either not resolved or not discussed at all. Most of these items relate to details of assignment of Gleason score and ISUP grade in specific specimen types and grading scenarios. This detailed review looks at the 2014 ISUP conference results and subsequent literature from an international perspective and proposes several recommendations. The specific issues addressed are percentage pattern 4 in Gleason score 7 tumours, percentage patterns 4 and 5 or 4/5 in Gleason score 8–10 disease, minor (≤5%) high grade patterns when either 2 or 3 patterns are present, level of reporting (core, specimen, case), dealing with grade diversity among site (highest and composite scores) and reporting scores in radical prostatectomy specimens with multifocal disease. It is recognised that for many of these issues, a strong evidence base does not exist, and further research studies are required. The proposed recommendations mostly reflect consolidated expert opinion and they are classified as established if there was prior agreement by consensus and provisional if there was no previous agreement or if the item was not discussed at prior consensus conferences. For some items there are reporting options that reflect the local requirements and diverse practice models of the international urological pathology community. The proposed recommendations provide a framework for discussion at future consensus meetings.
Triple negative BCa (TNBC) is defined by a lack of expression of estrogen (ERα), progesterone (PgR) receptors and human epidermal growth factor receptor 2 (HER2) as assessed by protein expression ...and/or gene amplification. It makes up ~ 15% of all BCa and often has a poor prognosis. TNBC is not treated with endocrine therapies as ERα and PR negative tumors in general do not show benefit. However, a small fraction of the true TNBC tumors do show tamoxifen sensitivity, with those expressing the most common isoform of ERβ1 having the most benefit. Recently, the antibodies commonly used to assess ERβ1 in TNBC have been found to lack specificity, which calls into question available data regarding the proportion of TNBC that express ERβ1 and any relationship to clinical outcome.
To confirm the true frequency of ERβ1 in TNBC we performed robust ERβ1 immunohistochemistry using the specific antibody CWK-F12 ERβ1 on 156 primary TNBC cancers from patients with a median of 78 months (range 0.2-155 months) follow up.
We found that high expression of ERβ1 was not associated with increased recurrence or survival when assessed as percentage of ERβ1 positive tumor cells or as Allred > 5. In contrast, the non-specific PPG5-10 antibody did show an association with recurrence and survival.
Our data indicate that ERβ1 expression in TNBC tumours does not associate with prognosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The authors report the earliest time frame (six and a half months) between exposure to textured breast implant and the development of breast implant-associated anaplastic large cell lymphoma.
Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate ...cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.
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