Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach. The systematic review included articles published between 2000 and 2023 in the databases: PubMed, EMBASE, and Cochrane. After a detailed analysis of the available publications, we qualified for the systematic review: 28 publications on proto-oncogenes: BRAF, KRAS, NRAS, ERBB2, and PIK3CA, 20 publications on tumour suppressor genes: BRCA1/2, ARID1A, CHEK2, PTEN, 4 on adhesion molecules: CADM1, 8 on proteins: B-catenin, claudin-1, and 5 on glycoproteins: E-Cadherin. In addition, in the further part of the systematic review, we included eight publications on microsatellite instability and three describing loss of heterozygosity in BOT. Molecular changes found in BOTs can vary on a case-by-case basis, identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. Molecular studies have contributed significantly to our understanding of BOT pathogenesis, but substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease related to germline mutations in VHL. In VHL disease, pheochromocytoma develops in 10%-20% of patients because of germline mutations and loss of heterozygosity of VHL. However, the rate of paraganglioma associated with VHL is low compared with that of pheochromocytoma, and the reason is unknown. In this study, we performed germline and somatic mutation analyses of retroperitoneal paraganglioma that developed in a patient with clinically diagnosed VHL disease and investigated the tumorigenic mechanism of paraganglioma. The patient was a 25-year-old woman who was considered to have VHL disease on the basis of her family history. She was referred to our clinic to investigate a tumor at the bifurcation of the common iliac artery. The tumor was diagnosed as retroperitoneal paraganglioma by clinical evaluations. A left renal cell carcinoma was also suspected. Polymerase chain reaction direct sequencing analysis and polymorphic microsatellite analysis within the VHL locus suggested that loss of heterozygosity of VHL was associated with paraganglioma and renal cell carcinoma. Multiplex ligation-dependent probe amplification analysis showed a loss of the copy number of VHL exons in paraganglioma. These results suggest that VHL disease contributes to the development of paraganglioma. A literature review showed no reported common missense variants involved in the progression of paraganglioma. The loss of heterozygosity of VHL can be a tumorigenic mechanism of retroperitoneal paraganglioma in VHL disease. However, the low rate of paraganglioma compared with pheochromocytoma is not explained by their genetic background alone.

HLA loss in hematologic malignancies is rare at diagnosis but may occur in leukemic cells at disease relapse. Although HLA mismatched hematopoietic cell transplant (HCT) is useful in exploiting graft vs. leukemia (GvL) effects, alloreactive T cells may exert immune pressure on leukemic cells, leading to immune escape. Roughly 10-30% of relapses after HLA mismatched hematopoietic cell transplant (HCT) involve loss of recipient-specific HLA genes, thereby rendering leukemic cells resistant to donor GvL effects. The use of alloreactive T cells, i.e., donor lymphocyte infusions (DLI) to control relapse following HCT will not be effective in the context of recipient-specific HLA loss and will instead carry all the risk of graft versus host disease (GvHD). Additionally, the source of the lost HLA, maternal or paternal, is important in informing the best donor choice for rescue HCT. The growing body of evidence, together with developments in laboratory testing for genomic loss of HLA, has highlighted the importance of routine testing for HLA loss in patients who relapse post HLA-mismatched HCT. Assessment of HLA loss allows transplant centers to make quick decisions regarding the most appropriate therapies and/or alternative donor selection for rescue HCT.

Epithelioid sarcoma (EpS) is a rare malignant neoplasm that accounts for < 1% of adult soft tissue sarcomas. Primary EpS of the bone is extremely rare and only a few cases have been reported to date. We report a case of primary distal-type EpS of the lumbar vertebra. A 30-year-old man without any history of malignant tumors had complained of lumbago for 3 months before visiting the hospital. Magnetic resonance imaging (MRI) of the lumbar spine showed a high signal intensity on the fat-suppressed T2-weighted image (WI) and a low signal on the T1WI at the L1 vertebral body. The tumor protruded toward the anterior components. Systemic radiological examination revealed no other lesion. A biopsy revealed a primary malignant tumor with epithelioid features. After chemotherapy, total en bloc spondylectomy was performed. Macroscopically, the tumor replaced the entire L1 with necrosis. Histologically, the tumor showed nodules of epithelioid cells that were strongly positive for epithelial markers, but a lack of INI1 expression. Central necrosis in the tumor nodule was also observed. This tumor showed loss of heterozygosity at the SMARCB1 locus but without the SMARCB1 mutation. The result of Foundation One ®CDx showed no actionable mutations. Seven months after surgery, a subcutaneous metastasis to the left cheek and bilateral lung metastasis with pleural dissemination were observed on radiological examination. A final diagnosis of distal-type EpS was made based on these findings. The patient died of the disease 8 months after surgery.

Background: Archived formalin-fixed paraffin-embedded (FFPE) specimens from nonmalignant tissues derived from cancer patients are a vast and potentially valuable resource for high-quality genotyping analyses and could have a role in establishing inherited cancer risk. Methods: We systematically searched PubMed, Ovid MEDLINE, and Scopus databases for all articles that compared genotyping performance of DNA from nonmalignant FFPE tissue with blood DNA derived from cancer patients irrespective of tumor type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies, and extracted genotyping data from the eligible studies. These studies included, but were not limited to, genotyping technique, reported call rate, and concordance. Results: Thirteen studies were reviewed, in which DNA from nonmalignant FFPE tissues derived from cancer patients was successfully purified and genotyped. All these studies used different approaches for genotyping of DNA from nonmalignant FFPE tissues to amplify single nucleotide polymorphisms (SNPs) and to estimate of loss of heterozygosity. The concordance between genotypes from nonmalignant FFPE tissues and blood derived from cancer patients was observed to be high, whereas the call rate of the tested SNPs was not reported in all included studies. Conclusion: This review illustrates that DNA from nonmalignant FFPE tissues derived from cancer patients can serve as an alternative and reliable source for assessment of germline DNA for various purposes, including assessment of cancer predisposition.

Renal cell neoplasia are heterogeneous with diverse histology, genetic alterations, and clinical behavior that are diagnosed mostly on morphologic features. The Renal Cell Neoplasia Workgroup of the Cancer Genomics Consortium systematically evaluated peer-reviewed literature on genomic studies of renal cell carcinoma (RCC), including clear cell RCC, papillary RCC, chromophobe RCC, and the translocation RCC involving TFE3, TFEB and MITF rearrangements, as well as benign oncocytoma, which together comprise about 95% of all renal cell neoplasia. The Workgroup curated recurrent copy number alterations (CNAs), copy-neutral loss-of-heterozygosity (cnLOH), rearrangements, and mutations, found in each subtype and assigned clinical relevance according to established criteria. In clear cell RCC, loss of 3p has a disease-initiating role and most likely also in progression with mutations detected in VHL and other genes mapped to this arm, and loss of 9p and/or 14q has well-substantiated prognostic utility. Gain of chromosomes 7 and 17 are hallmark CNAs of papillary RCC, but patterns of other CNAs as detected by chromosomal microarray analysis (CMA) afford sub-classification into Type 1 and 2 with prognostic value, and for further sub-stratification of Type 2. Inherent chromosome loss in chromophobe RCC as detected by CMA is useful for distinguishing the eosinophilic variant from benign oncocytoma which in contrast exhibits few CNAs or rearranged CCND1, but share mitochondrial DNA mutations. In morphologically atypical RCCs, rearrangement of TFE3 and TFEB should be considered in the differential diagnosis, portending an aggressive RCC subtype. Overall, this evidence-based review provides a validated role for assessment of CNAs in renal cell neoplasia in the clinical setting to assist in renal cell neoplasm diagnosis and sub-classification within subtypes that is integral to the management of patients, from small incidentally found renal masses to larger surgically resected specimens, and simultaneously identify the presence of key alterations portending outcome in malignant RCC subtypes.

BACKGROUND: According to the 2016 World Health Organization classification of central nervous system tumors, meningiomas are classified into 3 grades: I, II, and III. It has been reported that 2%-10% of meningiomas exhibit aggressive behavior, and 0.1%-1% of all patients with primary meningiomas develop distant metastases. Past studies have shown that genomic instability is strongly correlated with the risk of meningioma recurrence. Because of the rarity of this tumor, few papers have reported the prognosis and treatment of anaplastic meningioma. Under these circumstances, we present a case of multiple pulmonary and pleural metastases from a recurrent intracranial meningioma with some genetic changes.
METHODS: In the case, a previously healthy man aged 39 years was diagnosed with anaplastic meningioma. Postoperatively, due to multiple pulmonary and pleural metastases, adjuvant radiation, chemotherapy, and Gamma knife radiosurgery was subsequently performed. Molecular genetic examination with chromosomal microarray analysis showed that there were chromosomal abnormalities, including amplification in 1q and chr12; loss in 1p, 9p, and 22q; and catastrophe in chr8 and chr17 in both the previous brain meningioma and lung tissues, confirming the diagnosis of pulmonary metastasis of the initial grade III meningioma.
CONCLUSIONS: The molecular characterization of meningiomas has identified genetic biomarkers that influence tumor characteristics, such as tumor behavior, malignancy, and location. The combined analyses of genetic and epigenetic changes in meningiomas may allow researchers to unveil a more comprehensive understanding of tumor progression mechanisms.

The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment.
To expand current knowledge of the MEN4 phenotype including assessment of penetrance.
This is a case report and a brief review of previously published MEN4 cases.
We report a large Danish family with multiple cases of endocrine tumors that segregated with a pathogenic variant in the CDKN1B gene.
The medical history of the proband included primary hyperparathyroidism and Cushing disease. Genetic analysis identified a pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another 12 individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcemia due to primary hyperparathyroidism occurred in all 13 of the available carriers of the genetic variant, and 4 patients also had functioning or nonfunctioning pituitary adenomas, whereas 1 patient had a metastatic neuroendocrine tumor (carcinoid). Loss-of-heterozygosity was detected in two of five parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. Thirty cases representing 16 different CDKN1B variants have previously been reported, and these cases presented primarily with primary hyperparathyroidism and functioning and nonfunctioning pituitary tumors.
Hypercalcemia due to primary hyperparathyroidism and pituitary tumors are common in MEN4. Gastrointestinal neuroendocrine tumors appear to be less prevalent in MEN4 than in MEN1.

Hürthle cell tumors (HCT), including Hürthle cell adenomas (HCA) and Hürthle cell carcinomas (HCCs), arise in the thyroid gland and are defined in part by an accumulation of mitochondria. These neoplasms were long considered a subtype of follicular neoplasm, although HCT is now generally considered a distinct entity. HCTs exhibit overlapping but distinct clinical features compared to follicular tumors, and several studies have demonstrated that HCTs harbor distinct genomic alterations compared to other forms of thyroid cancer. Two studies recently reported the most complete characterization of the HCC genome to date. These studies assessed complementary cohorts of HCC specimens. The study by Ganly et al. consisted of a large panel of primary HCCs, including 32 widely invasive and 24 minimally invasive primary tumors. Exome and RNA sequencing of material isolated from fresh-frozen tumor specimens was performed. The study by Gopal et al. utilized exome and targeted sequencing to characterize the nuclear and mitochondrial genomes of 32 primary tumors and 38 resected regional and distant metastases using DNA isolated from formalin-fixed paraffin-embedded tissues. Here, HCC is briefly reviewed in the context of these studies.

The prognostic role of cytogenetic analysis is well-established in B-cell chronic lymphocytic leukemia (CLL). Approximately 80% of patients have a cytogenetic aberration. Interphase FISH panels have been the gold standard for cytogenetic evaluation, but conventional cytogenetics allows detection of additional abnormalities, including translocations, complex karyotypes and multiple clones. Whole genome copy number assessment, currently performed by chromosomal microarray analysis (CMA), is particularly relevant in CLL for the following reasons: (1) copy number alterations (CNAs) represent key events with biologic and prognostic significance; (2) DNA from fresh samples is generally available; and (3) the tumor burden tends to be relatively high in peripheral blood. CMA also identifies novel copy number variants and copy-neutral loss-of-heterozygosity (CN-LOH), and can refine deletion breakpoints. The Cancer Genomics Consortium (CGC) Working Group for CLL has performed an extensive literature review to describe the evidence-based clinical utility of CMA in CLL. We provide suggestions for the integration of CMA into clinical use and list recurrent copy number alterations, regions of CN-LOH and mutated genes to aid in interpretation.