BRCA1/2 Pathogenic Variants Are Not Common in Merkel Cell Carcinoma: Comprehensive Molecular Study of 30 Cases and Meta-Analysis of the Literature.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer. Management of advanced MCC is mainly based on immune-checkpoint inhibitors. The high failure rate warrants an investigation of new therapeutic targets. The recent identification of BRCA1 or BRCA2 (BRCA1/2) mutations in some MCC raises the issue of the use of poly-(ADP-Ribose)-polymerase inhibitors in selected advanced cases. The main objective of our study is to determine the accurate frequency of BRCA1/2 pathogenic variants. We studied a series of 30 MCC and performed a meta-analysis of BRCA1/2 variants of published cases in the literature. In our series, we detected only one BRCA2 pathogenic variant. The low frequency of BRCA1/2 pathogenic variants in our series of MCC (3%) was confirmed by the meta-analysis of BRCA1/2 variants in the literature. Among the 915 MCC from 13 published series studied for molecular alterations of BRCA1/2, only 12 BRCA1/2 pathogenic mutations were identified (1-2% of MCC), whereas many other BRCA1/2 variants were variants of unknown significance or benign. BRCA1/2 pathogenic variants are uncommon in MCC. However, in BRCA-mutated MCC, poly-(ADP-Ribose)-polymerase inhibitors might be a valuable therapeutic option requiring validation by clinical trials.

Double minute chromosomes harboring MDM2 amplification in a pediatric atypical lipomatous tumor.

Adipocytic tumors are rare in children and are mostly benign. Less than 25 cases of pediatric well-differentiated liposarcoma (WDLPS), atypical lipomatous tumors (ALT), and dedifferentiated liposarcoma (DDLPS) have been reported. Among them, only three cases were genetically analyzed. We describe the genetic features of a rapidly growing adipose tumor that occurred in the thigh of a 7-year-old girl. Histologically, it was composed of mature adipocytic cells with a few atypia. Molecular analysis showed high-level amplification of the 12q13-21 region including MDM2 among 64 amplified genes. MDM2 amplification is a diagnostic hallmark of ALT/WDLPS/DDLPS. In adult cases, it is typically located in ring or giant marker chromosomes. In the present case, extra-copies of MDM2 were located on double minute chromosomes (dmin). This raised the hypothesis of dmin being precursors of adult's rings and giant markers and may provide indications for a better understanding of the mechanisms of adipose tumor oncogenesis.

Dismantling papillary renal cell carcinoma classification: The heterogeneity of genetic profiles suggests several independent diseases.

Papillary renal cell carcinoma (pRCC) is the second most frequent renal cell carcinoma (RCC) after clear cell RCC. In contrast to clear cell RCC, there is no consensual protocol using targeted therapy for metastatic pRCC. Moreover, diagnosis of some pRCC, especially pRCC of type 2 (pRCC2) may be challenging. Our aim was to identify molecular biomarkers that could be helpful for the diagnosis and treatment of pRCC. We studied the clinical, histological, immunohistological, and comprehensive genetic features of a series of 31 pRCC including 15 pRCC1 and 16 pRCC2. We aimed to determine whether pRCC represents a unique entity or several diseases. In addition, we compared the genetic features of pRCC2 to those of eight RCC showing various degrees of tubulo-papillary architecture, including three TFE-translocation RCC and five unclassified RCC. We demonstrate that pRCC is a heterogeneous group of tumors with distinct evolution. While most pRCC2 had genetic profiles similar to pRCC1, some shared genomic features, such as loss of 3p and loss of chromosome 14, with clear cell RCC, TFE-translocation RCC, and unclassified RCC. We identified variants of the MET gene in three pRCC1. A mutation in the BRAF gene was also identified in one pRCC1. In addition, using next-generation sequencing (NGS), we identified several variant genes. Genomic profiling completed by NGS allowed us to classify pRCC2 in several groups and to identify novel mutations. Our findings provide novel information on the pathogenesis of pRCC that allow insights for personalized treatment.

Immunohistological features in adenomatoid odontogenic tumor: review of the literature and first expression and mutational analysis of ß-catenin in this unusual lesion of the jaws.

PURPOSE: To investigate for the first time the immunohistochemical and mutational status of ß-catenin in a mandibular case of adenomatoid odontogenic tumor (AOT) and to review the immunohistochemical expression data of various markers (cytokeratins, metalloproteinases, etc) in such a lesion. MATERIALS AND METHODS: A case of follicular-type AOT in a young male patient was analyzed in regard to the immunohistochemical expression of ß-catenin and mutations of the ß-catenin gene (CTNNB1). Its expression is altered in some odontogenic tumors. RESULTS: We found a strong cytoplasmic expression of ß-catenin, but no molecular anomaly within the exon 3 of CTNNB1. ß-catenin is considered to play a role in cell differentiation processes. CONCLUSION: Our results were consistent with previous findings in ameloblastoma and malignant odontogenic tumors. However, ß-catenin alterations had not been explored in AOT so far. Further studies are necessary to understand the specific regulation of ß-catenin in the AOT pathogenesis.

Renal cell carcinoma and a constitutional t(11;22)(q23;q11.2): case report and review of the potential link between the constitutional t(11;22) and cancer.

We observed a t(11;22)(q23-24;q11.2-12) and monosomy 3 in renal tumor cells from a 72-year-old man. The hypothesis of a primitive peripheral neuroectodermal tumor (PPNET) located in the kidney was promptly excluded: Histologically, the tumor was a clear cell renal cell carcinoma (RCC) and we did not observe an EWSR1 gene rearrangement. The constitutional origin of this alteration was established. We report on the second case of RCC in a patient with a constitutional t(11;22). The t(11;22)(q23;q11.2) is the main recurrent germline translocation in humans. Unbalanced translocation can be transmitted to the progeny and can cause Emanuel syndrome. Our observation alerts cancer cytogeneticists to the fortuitous discovery of the constitutional t(11;22) in tumor cells. This translocation appears grossly similar to the t(11;22)(q24;q12) of PPNET and should be evoked if present in all cells of a tumor other than PPNET. This is important when providing appropriate genetic counseling. Moreover, the potential oncogenic role of the t(11;22) and its predisposing risk of cancer are under debate. The family history of the patient revealed a disabled brother who died at an early age from colon cancer and a sister with breast cancer. This observation reopens the issue of a link between the constitutional t(11;22) and cancer, and the utility of cancer prevention workups for t(11;22) carriers.

Plexiform fibrohistiocytic tumor with molecular and cytogenetic analysis.

A child with plexiform fibrohistiocytic tumor is presented, in whom a superficial biopsy was misdiagnosed as an inflammatory granuloma. Cytogenetic analysis revealed a 46,X,del(X)(q13)[3]/46,XX[23] karyotype. However, fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (CGH) analysis failed to detect any numerical or quantitative genomic anomaly. Because of lack of specific chromosomal hallmarks, a molecular diagnosis of plexiform fibrohistiocytic tumor with the currently available tools is not reliable.

A novel case of t(X;1)(p11.2;p34) in a renal cell carcinoma with TFE3 rearrangement and favorable outcome in a 57-year-old patient.

Renal cell carcinoma (RCC) with translocation involving Xp11.2 (Xp11.2-RCC) is a rare neoplasm that usually occurs in children and young adults. This incidence is underestimated in adults because its morphological similarities with clear-cell RCC or papillary RCC2,3, as well as immunohistochemical and cytogenetic analyses are not carried out systematically in adults. We present a novel case of Xp11.2-RCC in a 57-year-old woman. The histologic features were those of a clear-cell RCC. Molecular cytogenetic analysis showed an uncommon t(X;1)(p11.2;p34) with TFE3 rearrangement and no alteration of chromosome 3. The immunohistochemical analysis showed expression of the TFE3 protein. Only nine cases of (X;1)(p11.2;p34) have been published, most of them occurring in children or young adults. To our knowledge, this is the second report of such a translocation in a patient older than 55 years. After a follow-up period of 13 months, the patient showed no evidence of disease. The clinical outcome was favorable, indicating that this particular translocation might be associated with a good prognosis. This observation confirms that Xp11.2-RCC are very likely to be underestimated in adults older than 40 years, and it highlights the importance of performing immunohistochemical and cytogenetic analyses in RCC for accurate diagnosis.

Strength of molecular cytogenetic analyses for adjusting the diagnosis of renal cell carcinomas with both clear cells and papillary features: a study of three cases.

Histological features are usually sufficient for providing an accurate diagnosis of renal cell carcinomas (RCC). However, the morphological appearance might sometimes be misleading. For instance, RCC with papillary areas and extensive clear cell changes may be difficult to classify either as clear cell renal carcinoma or as papillary renal cell carcinoma (pRCC). We used the combination of immunohistochemistry, conventional cytogenetics, fluorescence in situ hybridization (FISH), bacterial artificial chromosomes comparative genomic hybridization arrays and high-density single nucleotides polymorphism arrays (SNP arrays) to characterize three cases of RCC showing a predominant cytology of cells with clear cytoplasm and variable amounts of papillary areas. In accordance with the 2004 World Health Organization (WHO) classification, we initially assessed the diagnosis of clear cell RCC for one of the cases and unclassified RCC for the two remaining cases. However, because of a strong immunohistochemical labeling for alpha-methylacyl-CoA racemase, as well as the presence of a gain of chromosomes 7 and 17, we concluded that two of these tumors were actually pRCC. As for the third case, because of the presence of both pCCR and ccCCR molecular cytogenetic aberrations, including gains of chromosomes 7 and 17, loss of chromosome Y and whole chromosome 3 loss of heterozyosity (isodisomy), the final diagnosis was hybrid tumor cc-pRCC, so-called "unclassified RCC" according to the WHO classification. Our observations demonstrate the necessity to use immunohistochemical and cytogenetic tools in all cases of RCC showing unusual features. The combination of FISH and SNP arrays is prevailing for characterizing cases with hybrid features.

KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: biological and clinical implications.

BACKGROUND: KRAS and BRAF mutations in primary colorectal tumors (PT) are predictive of nonresponse to anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). The question of primary resistance to anti-EGFR treatment as a result of the presence of KRAS or BRAF mutations only in metastases has been raised but not resolved. METHODS: We analyzed the mutational status of KRAS and BRAF in 64 new patients with mCRC and performed a systematic review of published data from 285 patients. RESULTS: A total of 285 and 95 matched PT/metastases were available for the analysis of the KRAS and the BRAF status, respectively. An identical mutational pattern of KRAS in PT and the matching metastases were reported in all the cases but 14 (5%). In six cases (2%), KRAS was mutated in the PT and wild type in the metastatic site, whereas in eight cases (3%), KRAS was wild type in the PT and mutated in the metastatic site. An identical mutational pattern of BRAF in PT and the matching metastases was reported in all but two cases (3%). In one case (1.5%), BRAF was mutated in the PT and wild type in the metastatic site, whereas in one case (1.5%), BRAF was wild type in the PT and mutated in the metastatic site. CONCLUSIONS: The acquisition by metastases of a KRAS or a BRAF mutation that was not present in the PT is a rare event, occurring in 5% of cases of mCRC. This is not a frequent mechanism of primary resistance to anti-EGFR treatments in mCRC.

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: implications for anti-EGFR treatment of a rare lung malignancy.

Sarcomatoid carcinomas (SC) of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous cell components and characterized by a more aggressive outcome than other histological subtypes of nonsmall cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR)-targeted therapies have emerged as a promising therapeutic approach in patients with advanced typical NSCLC such as adenocarcinoma, the potential clinical activity of these drugs in lung SC is still unknown. To investigate this point, we have analyzed the status of 4 EGFR pathways biomarkers in a series of lung SC. EGFR protein expression, EGFR gene copy number, EGFR mutational status and KRAS mutational status were assessed in a series of 22 consecutive cases of primary lung SC. EGFR protein overexpression was observed in all the cases. High level of polysomy (>or=4 copies of the gene in >40% of cells) was detected in 5 cases (23%). No EGFR mutation was detected. KRAS mutations were found in 8 patients (38%; Gly12Cys in 6 cases and Gly12Val in 2 cases). The consistent EGFR protein overexpression and the high rate of KRAS mutation may contribute to the poorer outcome of lung SC in comparison with typical NSCLC. The rare incidence of increased EGFR gene copy number, the lack of EGFR mutation and the high rate of KRAS mutation observed in our series also suggest that most patients with lung SC are not likely to benefit from anti-EGFR therapies.