Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 1 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age-and sex-matched controls (OR 3.3; p < 0.0001). A truncating mutation (IVS2 1 1G>A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR 5 5.7; p 5 0.006), than was the missense mutation I157T (OR 5 2.8; p 5 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p 5 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR 5 10; p 5 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid.Thyroid cancer is one of the most common cancers in young women. 1 The most common type of thyroid cancer is papillary thyroid cancer, which comprises 80% of all thyroid tumors. 2 Approximately 5% of cases of papillary thyroid cancer are familial. 3 Epidemiologic data suggests that inherited factors contribute to papillary thyroid cancer. 4 A familial association between thyroid and breast cancer has been suggested; a prior history of thyroid cancer is a risk factor for breast cancer and vice versa (relative risks in the range of 1.7-12.4). 5-11 However, outside of a rare inherited syndrome of cancer susceptibility called Cowden syndrome (caused by PTEN mutations) in which both breast and thyroid cancer risks are increased, the genetic basis for the association between these two cancers has not been established. 12 Cell cycle checkpoint kinase 2 (CHEK2) is a key component of the DNA damage pathway. [13][14][15][16] Four founder alleles of CHEK2 are present in Poland, three of these result in a truncated CHEK2 protein (c.1100delC, c.444 1 1G>A, del5395) and the fourth (c.470T>C) is a missense substitution of an isoleucine for a threonine in exon 3. 17 All these alleles were associated with multi-organ cancer susceptibility, including cancers of the breast and thyroid. [18][19][20] In the current study, we wished to better characterize the association between CHEK2 mutations and thyroid cancer. We genotyped 468 unselected patients with papillary thyroid cancer and 468 matched cancer-free controls for four founder mutations of CHEK2. We also ...

Preferentially expressed antigen in melanoma (PRAME) is considered a useful marker in the differential diagnosis between malignant melanoma and its melanocytic mimics. Recently PRAME expression was documented in nonmelanocytic tumors, but much of the data are based on mRNA studies. This investigation evaluated PRAME expression in the spectrum of normal tissues and > 5800 human tumors using immunohistochemistry and EP461 monoclonal antibody. In normal tissues, PRAME was expressed in the testis and proliferative endometrium. In tumors, PRAME was variably expressed in malignancies of different lineages. Among epithelial tumors, > 50% of PRAME-positive lesions were found among endometrial carcinomas (82%), uterine serous carcinomas (82%), uterine carcinosarcomas (60%), ovarian clear cell carcinomas (90%), ovarian serous carcinomas (63%), adenoid cystic carcinomas (81%), seminomas (78%), thymic carcinomas (75%), and basal cell carcinomas (62%). In mesenchymal and neuroectodermal malignancies, PRAME was frequently expressed in synovial sarcoma (71%), myxoid liposarcoma (76%), neuroblastoma (61%) and metastatic melanoma (87%). Also, PRAME was consistently expressed in 4 melanomas that lacked all melanoma markers including S100 protein and SOX10 but harbored typical for melanoma BRAF or NRAS driver mutations. However, strong and diffuse PRAME immunoreactivity was seen in many types of nonmelanocytic poorly differentiated carcinomas and sarcomas. Based on this study, PRAME is a relatively unspecific immunohistochemical marker, which limits its use in diagnostic surgical pathology. However, immunohistochemistry is a reliable and unexpensive method useful in detecting PRAME-positive malignancies for potential immunotherapy.

The prevalence of the BRAF(V600E)mutation increased significantly in PTCs diagnosed in the authors' institution. Improved detection and several causative factors, most likely environmental and changes in iodine intake, may contribute to the increasing occurrence of TC.

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Signet ring stromal cell tumor (SRSCT) of the ovary is a very rare benign ovarian neoplasm. To date, no underlying genetic mechanism has been identified. In this study, 50 oncogenes and tumor suppressor genes were evaluated for mutations in a typical SRSCT using the next-generation DNA sequencing approach. An in-frame deletion of 30 nucleotides in the glycogen serine kinase-3 beta phosphorylation region of the β-catenin gene (CTNNB1) was identified, and the finding was confirmed by Sanger sequencing. This deletion (c.68_97del) at the protein level would lead to a p.Ser23_Ser33delinsThr oncogenic-type mutation. Subsequent immunohistochemistry showed prominent nuclear accumulation of β-catenin and cyclin D1 in tumor cells. Thus, mutational activation of the Wnt/β-catenin pathway could be a crucial event in the molecular pathogenesis of SRSCT of the ovary. These findings may also assist in the diagnosis of this rare tumor.