Owing to advances in treatment paradigms across the last five decades, testicular cancer is now eminently curable. However, current serum tumour and imaging biomarkers lack adequate sensitivity, specificity, and predictive value. Subsequently, their utility in detecting active malignancy and informing treatment decisions is minimal in a large proportion of men with testicular cancer. Micro-ribonucleic acids (miRNA), pertinently miR-371a-3p, offer a new tool, which based on early data, appears to fill many of the gaps that existing biomarkers leave. This paper reviews the evolution of the technology, potential limitations, and discusses the clinical relevance of miRNA as it moves towards the clinic.

https://journals.sagepub.com/doi/pdf/10.1177/17588359211027826

Improving outcomes in germ cell cancers using miRNA.

Abstract The germline cells are essential for the propagation of human beings, thus essential for the survival of mankind. The germline stem cells, as a unique cell type, generate various states of germ stem cells and then differentiate into specialized cells, spermatozoa and ova, for producing offspring, while self-renew to generate more stem cells. Abnormal development of germline stem cells often causes severe diseases in humans, including infertility and cancer. Primordial germ cells (PGCs) first emerge during early embryonic development, migrate into the gentile ridge, and then join in the formation of gonads. In males, they differentiate into spermatogonial stem cells, which give rise to spermatozoa via meiosis from the onset of puberty, while in females, the female germline stem cells (FGSCs) retain stemness in the ovary and initiate meiosis to generate oocytes. Primordial germ cell-like cells (PGCLCs) can be induced in vitro from embryonic stem cells or induced pluripotent stem cells. In this review, we focus on current advances in these embryonic and adult germline stem cells, and the induced PGCLCs in humans, provide an overview of molecular mechanisms underlying the development and differentiation of the germline stem cells and outline their physiological functions, pathological implications, and clinical applications. 

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Germline stem cells in human

Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex–associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome

An Update on Diagnostic Tissue-Based Biomarkers in Testicular Tumors.

https://doi.org/10.1016/j.neo.2021.12.009

Whole-chromosome arm acquired uniparental disomy in cancer development is a consequence of isochromosome formation

Assessment of isochromosome 12p and 12p abnormalities in germ cell tumors using fluorescence in situ hybridization, single-nucleotide polymorphism arrays, and next-generation sequencing/mate-pair sequencing

The routine clinical implementation of molecular methods other than fluorescence in situ hybridization in the evaluation of renal neoplasia is currently limited, as the current standard of care primarily involves a combination of morphologic and immunophenotypic analysis of such tumors. Amongst various molecular techniques, global copy number profiling using single nucleotide polymorphism-based microarrays, colloquially referred to as SNP-arrays, is being increasingly utilized to profile renal tumors, as several subtypes have characteristic recurrent patterns of copy number alterations. Recurrent copy number alterations in common tumor types include loss of chromosome 3p in clear cell renal cell carcinoma (RCC), gain of chromosomes 7 and 17 in papillary RCC and multiple losses in chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe RCC. Such assays are being increasingly utilized in the clinical setting. Herein, we discuss some common clinical applications of such testing that includes high yield diagnostic and prognostic applications. Diagnostic utility includes evaluation of tumor types that are primarily defined by underlying copy number alterations, establishing the underlying subtype in high grade dedifferentiated (unclassified) renal tumors, as well as assessment of loss of heterozygosity, which is an important component in the workup for germline alterations in tumor suppressor genes. Universal adoption of these techniques across clinical laboratories will likely be significantly affected by variables such as cost, reimbursement, and turnaround time.

A contemporary guide to chromosomal copy number profiling in the diagnosis of renal cell carcinoma.

Importance In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. Objective To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. Design, setting, and participants In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Main outcomes and measures Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Results Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dube (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. Conclusions and relevance In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.

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Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia.

Fumarate Hydratase (FH) c.1431_1433dupAAA (p.Lys477dup) variant is not associated with FH protein deficiency and increased 2SC in two separate patients with renal neoplasia

Wei Shen

Papers

Assessment of isochromosome 12p and 12p abnormalities in germ cell tumors using fluorescence in situ hybridization, single-nucleotide polymorphism arrays, and next-generation sequencing/mate-pair sequencing

A contemporary guide to chromosomal copy number profiling in the diagnosis of renal cell carcinoma.

Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia.

Fumarate Hydratase (FH) c.1431_1433dupAAA (p.Lys477dup) variant is not associated with FH protein deficiency and increased 2SC in two separate patients with renal neoplasia