One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene.

BACKGROUND: Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations. METHODS: To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case-control analysis. RESULTS: Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively. CONCLUSION: Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

Tumor molecular profiling of NSCLC patients using next generation sequencing.

Non­small cell lung cancer (NSCLC) is the most common type of lung cancer and a tumor with a broad spectrum of targeted therapies already available or in clinical trials. Thus, molecular characterization of the tumor using next generation sequencing (NGS) technology, has become a key tool for facilitating treatment decisions and the clinical management of NSCLC patients. The performance of a custom 23 gene multiplex amplification hot spot panel, based on Ion AmpliSeq™ technology, was evaluated for the analysis of tumor DNA extracted from formalin-fixed and paraffin-embedded (FFPE) tissues. Furthermore, the Ion AmpliSeq™ RNA Fusion Lung Cancer Research Panel was used for fusion RNA transcript analysis. The mutation spectrum of the tumors was determined in a cohort of 502 patients with NSCLC using the aforementioned targeted gene panels. The panel used for tumor DNA analysis in this study exhibited high rates (100%) of sensitivity, specificity and reproducibility at a mutation allelic frequency of 3%. At least one DNA mutation was detected in 374 patients (74.5%) and an RNA fusion was identified in 16 patients, (3.2%). In total, alterations in a cancer-driver gene were identified (including point mutations, gene rearrangements and MET amplifications) in 77.6% of the tumors tested. Among the NSCLC patients, 23% presented a mutation in a gene associated with approved or emerging targeted therapy. More specifically, 13.5% (68/502) presented a mutation in a gene with approved targeted therapy (EGFR, ALK, ROS1) and 9.4% (47/502) had an alteration in a gene related to emerging targeted therapies (ERBB2, BRAF, MET and RET). Furthermore, 51.6% of the patients had a mutation in a gene that could be related to an off label therapy or indicative for access to a clinical trial. Thus, the targeted NGS panel used in this study is a reliable approach for tumor molecular profiling and can be applied in personalized treatment decision making for NSCLC patients.

A collecting duct carcinoma producing carcinoembryonic antigen and Ca-125 in a 29-year-old woman.

Collecting duct carcinoma is a rare renal malignant neoplasm, arising from the medullary collecting duct and accounting for less than 1% of renal cell carcinomas. It is more common in middle-aged men and is usually presented with hematuria, abdominal mass and back or flank pain. Its immunohistochemical analysis detects the expression of various markers, such as low and high molecular weight keratins, Ulex europaeus agglutinin-1, epithelial membrane antigen and peanut lectin. Here, we present a case of a 29-year-old woman with CDC presented with back pain and supraclavicular lymphadenopathy that produced carcinoembryonic antigen and CA-125.

Submerged goiter proven to be metastatic infiltration of a neuro-endocrine Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon neuroendocrine cutaneous carcinoma. Metastases to the thyroid gland are rare and may present diagnostic difficulties. CASE PRESENTATION: A 73-year-old woman presented with a hard mass in the adipose tissue of the right inguinal area. This mass was surgically excised and the histology examination showed the existence of a MCC. CT scans revealed a sizable lesion with imaging features of a submerged goiter, invasive to the upper mediastinum. The patient received chemotherapy following by locoregional radiotherapy at the bed of the excised lesion. During the next 10 months the patient was asymptomatic, serum markers values were normal and CT scans findings were stable. However, afterwards NSE and chromogranin values raised and CT scans revealed an enlargement of the submerged goiter. The patient became symptomatic, mainly experiencing respiratory inconvenience. Surgical excision of the right lobe of the thyroid gland was decided and performed without any complications. The histopathology examination showed infiltration of the thyroid gland by a neuroendocrine carcinoma with characteristics compatible with MCC. CONCLUSIONS: The rare case of metastatic infiltration of the thyroid gland by a MCC based on histological and immunohistochemical findings was described. This case report is of clinical significance indicating that by any abnormal finding in the thyroid gland in patients with a malignant disease, the diagnostic approach should always contain consideration of metastasis from the primary tumor.

Neoplastic pericarditis as the initial manifestation of a papillary thyroid carcinoma.

Neoplastic pericarditis represents approximately 5%-7% of the cases with acute pericarditis and is rarely the initial manifestation of malignancy. The most common cause is lung cancer, followed by breast cancer, lymphomas, leukemia, and esophageal cancer. Neoplastic pericardial disease is extremely rare in thyroid cancer, especially as the first manifestation. Here, we present a papillary thyroid carcinoma that was manifested with pericarditis and cardiac tamponade in a 49-year-old female.

Coexistence of intracranial germ cell tumor and craniopharyngioma in an adolescent: case report and review of the literature.

PURPOSE: We present the case of a patient treated for intracranial germ cell tumor in which elements of craniopharyngioma were found in the residual tumor mass. FINDINGS: A 17 year old patient presented with a history of secondary amenorrhea. She deteriorated with headache and left eyelid drop, paresis of the abducent nerve and convergent strabismus (Parinaud syndrome). ß-HCG was 722mIU/ml and pregnancy was excluded. AFP was 6322 ng/ml. Brain CT scan showed a large endosellar tumor to the hypersellar region. There was left papillary atrophy. MRI confirmed a tumor to dorsum sellae. Primary germ cell intracranial tumor was diagnosed. Severe clinically evident pituitary failure developed with signs of increased intracranial pressure and brain edema as well as diabetes insipidus, while AFP increased to 15786,3ng/ml. Urgent treatment with combination chemotherapy including cisplatin etoposide and bleomycin (ΡEB) was administered for 4 courses. As a result her clinical condition improved and tumor markers dropped but nevertheless did not become normal. In addition CT scans revealed a remaining endocranial mass and therefore the patient was subjected to high-dose chemotherapy followed by autologous stemcell rescue which resulted in complete clinical and biochemical remission. Due to the persisting mass in the area, it was delivered radiotherapy. CONCLUSIONS: The above case is extremely rare in worldwide literature. Dysgerminoma may coexist with craniopharyngioma which in fact may be part of a germ cell tumor in the context of dysembryogenesis and benign "teratoma".

Bilateral de quervain syndrome after aromatase inhibitor administration: a case report and review of the literature.

Aromatase inhibitors are widely used as one of the main treatment options of both early and advanced hormone receptor-positive breast cancer in postmenopausal women. Unfortunately, musculoskeletal symptoms are often presented in patients treated with aromatase inhibitors (AIs), and, although the pathogenesis is unknown, postulated mechanisms have been described. Herein, to our knowledge, we present the first report of bilateral De Quervain syndrome related with AIs therapy with a review of the relevant literature.