Gain of 1q is associated with adverse outcome in favorable histology Wilms' tumors

Although several genes/genetic loci involved in the etiology of Wilms' tumor have been identified, little is known of the molecular changes associated with relapse. We therefore undertook an analysis by comparative genomic hybridization (CGH) of 58 tumor samples of favorable histology Wilms' tumor taken at initial diagnosis and/or relapse. Tumors with anaplastic histology were excluded as this is known to be associated with p53 mutation and a poor prognosis. A control group of 21 Wilms' tumors that did not relapse was also analyzed. The overall frequency of gains or losses of genetic material detected by CGH was similar in both groups (77% in relapsing tumors and 70% in the nonrelapse group) as was the median number of changes per tumor (relapse group: n = 4, range, 1 to 19; nonrelapse group: n = 3, range, 1 to 8). However, gain of 1q was significantly more frequent in the relapse series [27 of 46 (59%) versus 5 of 21 (24%), P: = 0.019]. In 12 matched tumor pairs, the CGH profiles, including 1q gain, were similar at diagnosis and relapse, with little evidence for further copy number changes being involved in clonal evolution. The results suggest that 1q gain at diagnosis could be used to identify patients with favorable histology Wilms' tumor at increased risk of relapse who might benefit from early treatment intensification.     

Allelic loss at chromosome band 6q14 correlates with favorable prognosis in hepatocellular carcinoma

Cytogenetic and molecular studies have frequently shown chromosome 6q deletions in non-Hodgkin lymphoma and several human cancers. There have been few studies concerning chromosome 6q deletion in hepatocellular carcinoma (HCC), and most of these studies have focused on region 6q26-27. We previously described frequent allelic loss at 6q14 in HCC. As a step toward narrowing the scope of search for tumor suppressor genes, we used a series of yeast artificial chromosome clones that map to the long arm of chromosome 6 (6q14-6q22) by fluorescence in situ hybridization (FISH) to define the minimal common region of allelic loss in 25 cases of HCC. Altogether, 12 tumors had allelic loss on 6q (48%). Eleven of the 12 tumors had polysomy of chromosome 6 with evident intratumor cytogenetic heterogeneity. The minimal common region of allelic loss lies within a 2-cM region at 6q14, flanked by D6S458 (849_d_8) and D6S275 (911_a_3). Clinicopathologic correlation between the 12 patients with allelic loss at 6q and the 13 patients without allelic loss showed no significant differences in any basic characteristics except survival. Patients with allelic loss at 6q had a much longer median survival time than those without allelic loss (50 months vs. 11 months, P = 0.0019). Only 5 of the 25 HCC patients were still alive at the time of this study, and all of them had allelic loss at 6q, which is also statistically significant (P = 0.037, alive vs. dead). The association of allelic loss at 6q with polysomy implies that this may be a progression-associated event in HCC. The correlation of allelic loss at 6q with long survival suggests a complex mechanism of tumorigenesis in HCC and is worthy of further investigation.     

BRAF mutations are associated with some histological types of papillary thyroid carcinoma

Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot-spot mutation BRAF(V599E) is frequently detected in PTC (36-69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities-hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAF(V599E) mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAF(V599E) was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAF(V599E) mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAF(V599E) was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular-papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAF(V599E) in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular-papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC.     

Chromosomal losses of regions on 5q and lack of high-level amplifications at 8q24 are associated with favorable prognosis for ovarian serous carcinoma

In this study, we describe characteristic chromosomal alterations in a consecutive series of 96 serous ovarian tumors by comparative genomic hybridization. We analyze their association with different pathways of progression, histological grade, and clinical outcome. The most striking difference between low-grade and high-grade serous carcinomas was seen in a higher incidence of chromosomal gains at 3q and 20q and losses of 13q in the high-grade carcinomas. In addition, high-level amplifications were significantly more frequent in high-grade carcinomas, specifically involving regions on 3q and 8q. Chromosomal amplifications of 19p and 19q and losses of 4q and 5q were among the most frequent changes found in both low-grade and high-grade carcinomas, distinguishing them from borderline tumors, which had very few recurrent alterations. The most significant impact on survival of patients with invasive carcinomas Stage II-IV was observed for high-level amplifications of regions on 8q (mean overall survival (OS) 69 versus 27 months, P = 0.0006). Interestingly, low-level gains on 8q do not show any impact compared to cases with no alteration. Surprisingly, chromosomal losses on 5q had a protective impact (mean OS 36 versus 76 months, P = 0.0007). Combination of both parameters resulted in two risk groups. Low risk: loss on 5q, no amplification on 8q (mean OS 84 months); high risk: no loss on 5q, amplification on 8q (mean OS 26 months). This difference is even more pronounced, if only cases with residual tumor of less than 2 cm are included, resulting in a 5-year survival of 100% and 0% (P = 0.0005).     

Focal features of papillary carcinoma of the thyroid in fine-needle aspiration material are strongly associated with papillary carcinoma at resection

The cytologic features of papillary carcinoma of the thyroid in fine-needle aspiration material have been well described. The significance of finding these features in only a small population of cells is not well characterized. I reviewed the results of 28 thyroid fine-needle aspirates processed as direct smears and cell blocks in which only a small population (<20 cells) showed features of papillary carcinoma. Papillary carcinoma was considered in 142 (8.98%) of 1,581 aspirates, and in 28 cases (1.77%), 20 cells or fewer showed features of papillary carcinoma and follow-up was available. Papillary carcinomas greater than 1 cm were identified in 11 cases (39%; 3 follicular variants), papillary carcinomas less than 1 cm were identified in 4 cases (14%), and benign lesions in the remaining 13 cases (46%). The background material (either scant or abundant benign epithelium) did not correlate significantly with the result of resection. Identifying features of papillary carcinoma in a small population of cells in either a scant or an abundant thyroid aspirate are associated with a high rate of papillary carcinomas at resection, only a minority of which represent either the follicular variant or incidental tumors.     

S100A4及CEACAM-1蛋白与甲状腺乳头状癌淋巴结转移的相关性

目的探讨S100A4及CEACAM-1蛋白在甲状腺乳头状癌中的表达及其与淋巴结转移的关系。方法收集整理102例手术切除的甲状腺乳头状癌病例标本,分析其相关临床病理因素并应用免疫组织化学EnVision及Histofine Simple Stain MAX两步法检测癌组织中S100A4、CEACAM-1、cyclinD1及p27Kip1蛋白的表达,运用单因素及多因素分析研究上述因素与甲状腺乳头状癌淋巴结转移的相关性。结果 S100A4及CEACAM-1蛋白在甲状腺乳头状癌标本中的阳性率分别为79.4%(81/102)和51.0%(52/102);通过单因素分析,发现年龄45岁、肿物直径1cm、S100A4阳性表达及CEACAM-1阴性表达与甲状腺乳头状癌淋巴结转移相关。性别、纤维化、肿物包膜完整、组织学亚型(滤泡型或其他亚型)、伴发桥本甲状腺炎、多灶、侵及甲状腺包膜外(镜下),cyclinD1及p27Kip1的阳性表达与淋巴结转移无关。进一步的多因素分析发现:年龄45岁、S100A4阳性表达及CEACAM-1阴性表达为甲状腺乳头状癌淋巴结转移的独立性危险因素。结论 S100A4的阳性表达及CEACAM-1的阴性表达与甲状腺乳头状癌淋巴结转移相关,可作为甲状腺乳头状癌淋巴结转移的预测因素。     

Definition of a 1-Mb homozygous deletion at 9q32-q33 in a human bladder-cancer cell line

We performed detailed molecular analyses of a suspected homozygous deletion on chromosome 9q32-q33 in a bladder-cancer cell line (KYBTDS) derived from a superficial papillary transitional cell carcinoma (TCC). We examined 13 sequence-tagged site (STS) markers mapped along 9q32-q33 by polymerase chain reaction (PCR), and used 13 bacterial artificial chromosome (BAC)/bacteriophage P1-derived artificial chromosome (PAC) genomic clone probes representing these STS markers as probes for dual-color fluorescence in situ hybridization (FISH) analyses to define the deleted region cytogenetically and at the molecular level. Southern blotting confirmed the findings. This combination of techniques revealed that the homozygous deletion in the KYBTDS cell line involved less than 1 megabase of DNA, flanked by markers A003P42 and SGC33380. This interval overlaps part of a common region of deletion observed in a number of primary bladder cancers; moreover, the DNA sequence within the 1-Mb segment corresponds to part of a YAC genomic clone that encompasses a putative tumor suppressor gene, DBCCR1. Received: January 29, 2001 / Accepted: March 26, 2001     

Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis

To better understand the role of beta-catenin mutation in hepatocellular carcinoma (HCC), we correlated the gene mutation with hepatitis virus B (HBV) and hepatitis virus C (HCV) status and the clinicopathological features in 366 patients with resected primary unifocal HCC. beta-Catenin mutations were also analyzed in 55 patients with multifocal HCC (68 tumors). Of the whole series, 57 (13.1%) of 434 tumors examined had beta-catenin mutations, 34 occurred at the serine/threonine residues of the GSK-3beta region of beta-catenin. Outside the GSK-3beta phosphorylation site, codons 32 and 34 were two mutational hot spots (17 tumors). The non-HBV-related HCC that was predominantly HCV related had a higher frequency of mutation (P: < 0.00001) and more frequent mutations at codon 45 than HBV-related HCC. HBV-related HCC had a younger mean age (P: < 0.00001), and higher male-to-female ratio (P: < 0.003) and positive familial history of HCC (P: < 0.014). Among 366 unifocal HCCs selected for clinicopathological analysis, beta-catenin mutations were associated with grade I (P: = 0.005) and stage I and II HCC (P: < 0.0001), and a better 5-year survival rate (P: = 0. 00003). These findings suggest mechanisms for beta-catenin mutations differ between HBV-related and non-HBV-related HCCs, and that beta-catenin mutation is a favorable prognostic factor related to low stage. beta-Catenin mutation was associated with nuclear expression of the protein (P: < 0.00001), but we failed to detect point or large fragment deletion mutation in 39 HCCs with nuclear beta-catenin expression, presumably wild-type protein. HCCs expressing mutant nuclear beta-catenin had a better 5-year survival rate (P: < 0.007), suggesting that mutant and wild-type nuclear beta-catenin proteins are not functionally equivalent and deserve more studies for further clarification.     

Postmenopause is associated with recurrence of differentiated papillary thyroid carcinoma

Differentiated papillary thyroid carcinoma (D-PTC) is the most common malignancy arising in the thyroid gland. There are gender differences in the incidence of PTC being mainly observed in females. Low-risk groups consisted of men younger than 40-year-old and women younger than 50-year-old, whereas the high-risk group are older patients. We believe that age is not enough to explain the clinical course of this neoplasm and hypothesize that aggressive behavior of D-PTC may be correlated with hormonal status. Studies that support this idea showed that the follicular neoplastic cells had higher estrogen receptor-alpha in premenopausal (28.1+/-4.5) than in postmenopausal women (14.2+/-2.9). According to author's prior observations, there are evidences correlating recurrence of D-PTC with postmenopause in women. Postmenopause status is characterized by estrogen decrease and FSH increases both associated with EGFR activation. Previous observations identified EGFR over-expression in D-PTC of postmenopause when compared with premenopausal ladies. Conclusions: Postmenopause is an adverse factor for tumor evolution in women with D-PTC and is associated with EGFR expression. It's introduction in thyroid tumor stratification could be a fine tuning in predicting papillary thyroid carcinoma behavior.     

Gain of 1q is a marker of poor prognosis in Wilms' tumors

Wilms' tumor (WT) trials aim to better tailor treatment intensity to the risk of relapse and death. Currently, stage, histology, age (< or > 24 months), and combined loss of heterozygosity at 1p and 16q in chemotherapy‐naïve WTs are the only risk factors used for treatment stratification. However, they predict only less than one‐third of all relapsing patients, implying that other factors are involved in treatment failure. Previous studies have associated 1q gain with adverse outcome. Therefore, in this study, the role of 1q gain and other common cytogenetic aberrations (CAs) in WTs was investigated and related to follow‐up data from patients with WT treated in the United Kingdom; 19% (64/331) had 1q gain. Gain of 1q was significantly associated with 16q loss (P < 0.001) and 1p loss (P < 0.001). In multivariate analysis taking account of age, tumor stage, anaplasia, and common CA (e.g., 1p loss and 16q loss), 1q gain was independently associated with adverse event‐free survival [EFS; hazard ratio (HR) = 2.45, P = 0.02] and overall survival (HR = 4.28, P = 0.004). Loss of 14q was independently associated with an adverse EFS (HR = 4.0, P = 0.04). Gain of 1q is a marker of poor prognosis in WTs, independent of high tumor stage and anaplasia which remain the overarching adverse prognostic factors. Confirmation in other studies is necessary before future therapeutic studies can incorporate 1q gain into new risk stratification schema. © 2013 Wiley Periodicals, Inc.     

Surgically treated incidentally discovered low-grade gliomas are mostly IDH mutated and 1p19q co-deleted with favorable prognosis

Objective: LGGs (low-grade gliomas) are sometimes encountered by chance during radiological examinations. These incidentally discovered LGGs (IDLGGs) were relatively under-studied in the literature. The purpose of current study is to review a cohort of patients with IDLGGs surgically treated in our institution for their clinical and histological aspects and determine their IDH1 and 1p19q status. Methods: All patients with hemispheric LGGs receiving operation in our institution between 2001 and 2004 were reviewed. Clinical, radiological and treatment data of the patients were collected and IDLGGs were retrieved and compared with symptomatic LGGs. Histological review was carried out and formalin-fixed paraffin embedded (FFPE) tissues of IDLGGs were examined for IDH1/IDH2 mutation and 1p/19q codeletion. Results: Twenty three IDLGGs (10.4%) were identified while 196 patients had symptomatic LGGs. The reasons for patients with IDLGGs having radiological examination included trauma (47.8%), dizziness (26.1%), unrelated headache (21.7%), and health checkup (4.4%). Clinically, patients with IDLGGs had higher preoperative KPS (P < 0.001), smaller tumor volume (P = 0.014), lower frequency of eloquent areas involvement (P < 0.001) and higher rate of complete resection (P = 0.037) comparing to those with symptomatic LGGs. Histologically, there is a preponderance of oligodendroglial differentiation with 6 oligodendrogliomas and 11 oligoastrocytomas but there were also 6 astrocytomas. IDH1 mutation and 1p/19q co-deletion were detected in 95.7% (22/23) and 69.6% (16/23) of IDLGGs, respectively. The latter encompassed all but one of the cases of oligodendroglial tumors. Patients with IDLGGs had longer overall survival than those with symptomatic LGGs (P = 0.027). Conclusions: We conclude that the majority of IDLGGs are IDH1 mutated and are predominantly oligodendroglial tumors. With a median follow-up of 9.3 years to our series, we conclude that patients with IDLGGs had better prognosis than those with symptomatic LGGs. The favorable prognosis of IDLGGs may be accounted by the higher practicability of extensive resection, non-eloquent tumor location and smaller tumor volume. Frequent IDH1 mutation and 1p/19q co-deletion in IDLGGs may also contribute to the favorable prognosis of this subgroup of patients.     

甲状腺乳头状癌形态学变型与预后的关系

目的研究和分析甲状腺乳头状癌(papillary thyroid carcinoma,PTC)变型的形态学及临床病理特征,并探讨与预后的关系。方法收集155例PTC,对石蜡包埋组织切片HE染色后进行形态学观察分型,并探讨与临床病理特征的关系。结果 (1)根据WHO甲状腺肿瘤分类标准,155例PTC可归到8个变型中,典型PTC(47.7%,74/155)最常见。在典型PTC中年龄≥45岁的病例占77%(57/74),明显高于滤泡型PTC(28.6%,2/7)和嗜酸细胞型PTC(33.3%,3/9,P0.05)。乳头状微癌的淋巴结转移率(27.5%,11/40)明显低于其他变型(P0.005)。弥漫硬化型PTC的局灶浸润率(4/8,50%)明显高于典型PTC(10/74,13.5%);实体型PTC(2/7,28.6%)的远处转移率明显高于典型PTC(2/74,2.7%);(2)45例(29%)PTC伴淋巴细胞性甲状腺炎(lymphocytic thyroiditis,LT),局部浸润发生率在伴有LT的PTC(4.4%,2/45)中明显低于不伴LT的PTC(16.4%,18/110,P0.05)。(3)对42例PTC随访8～12年,5年生存率为100%(42/42),10年生存率为96.6%(28/29)。结论 (1)典型PTC最常见,与之相比,滤泡型PTC、嗜酸细胞型PTC预后可能较好,而弥漫硬化型、高细胞型和实体型PTC预后较差。(2)伴淋巴细胞性甲状腺炎的PTC局灶浸润率低,提示预后较好;(3)随访资料表明,PTC的总体生存率高,预后好。     

Common variants on 14q32 and 13q12 are associated with DLBCL susceptibility

Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive cancers of B-lymphocytes. To investigate genetic susceptibility factors for DLBCL, we performed single-nucleotide polymorphism based genome-wide association study (GWAS) in a total of 399 DLBCL cases and 4243 controls of Japanese population. By following two-stage GWAS approach and an independent replication study, we identified disease susceptibility locus within intron 3 of the CDC42BPB gene on 14q32 (rs751837; P=3.30 × 10(-7) and odds ratio (OR) of 3.5), a region of frequent chromosomal translocations in lymphoma, and variant on 13q12 (rs7097; P=6.57 × 10(-6) and OR of 1.43) which harbors the notch signaling mediator, LNX2 gene. Our findings would contribute to the understanding of DLBCL risk and also may lead to the elucidation of its molecular pathogenesis.     

Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.     

Hybrid thyroid carcinoma with a coarse chromatin pattern and nuclear features of papillary thyroid carcinoma

Hybrid follicular carcinoma (FC) and papillary thyroid carcinoma (PTC) have not been previously well described. Consecutive cases of 29 FC, 12 Hurthle cell carcinomas (HC), 247 PTC and 13 Hurthle cell PTC (HPTC) were reviewed with special attention to the coarse (CC) and fine chromatin patterns (FIC), as well as to the presence of nuclear grooves, pseudoinclusions or optically clear appearance. Limited nuclear features of PTC (LNF-PTC) are defined as areas of tumor with FIC in addition to some other nuclear features, but insufficient for the diagnosis of PTC. Tumors with nuclei showing an admixture of CC and PTC or LNFPTC were submitted for immunostaining for cytokeratin 19, HBME and Ret/PTC. FC and HC contained areas of LNFPTC in 25 tumors and focal PTC in 3 tumors. None of these cases was associated with lymph node metastasis. Areas with CC were found in 54 PTC and 3 HPTC. The rates of vascular invasion and distant metastasis tended to be higher for PTC with areas of coarse chromatin pattern than for PTC without such areas; however, the difference was not statistically significant. Immunoreactivity for cytokeratin 19 and HBME was moderate to strong for PTC and focal areas of PTC or LNFPTC in FC without Hurthle cell changes. Ret/PTC immunostaining was positive in areas of LNFPTC or focal PTC in three FC. Focal PTC or areas of LNFPTC are frequently seen in FC. Likewise, areas of CC are often present in PTC. The presence of these focal areas does not appear to change the clinical behavior of the tumor and therefore does not warrant a change of nomenclature.