Chromosomal imbalances in lung adenocarcinomas with or without mutations in the epidermal growth factor receptor gene.

BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas of Asian patients, implying a good response to treatment with the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. However, the distinct chromosomal imbalances between lung adenocarcinomas with and those without EGFR mutations have not been fully elucidated. METHODS: Seventy-seven patients of surgically resected lung adenocarcinoma were analysed for the EGFR exon 19 deletion and the L858R mutation, using mutant-enriched PCR, and for chromosomal imbalance alterations using comparative genomic hybridization. RESULTS: EGFR mutations were detected in 42 (54.5%) patients, including 22 with the exon 19 deletion and 20 with the L858R mutation. The mean number of chromosomal arms with imbalance alterations was significantly higher in tumours with EGFR mutations than in those lacking these two mutations. The minimal regions with gain on 1q23-q31, 6p12-p21.1 and 7q11.2, and loss on 3p21, 8p22-p23, 9q33, 10q25 and 13q13, differed significantly between lung adenocarcinomas with or without EGFR mutations. However, neither EGFR mutations, nor any of the common chromosomal imbalance alterations alone, exhibited significant associations with tumour stage or disease-specific survival of the patients. CONCLUSIONS: These results indicate that imbalance alterations at several chromosomal regions occur significantly more frequently in lung adenocarcinomas with EGFR mutations than in those without such mutations. Tumour growth-related genes in these chromosomal regions should be further investigated to improve our understanding of the common genetic alterations in lung adenocarcinomas with EGFR mutations.

Chronic lymphocytic leukemia with paraimmunoblastic transformation - with comparative genomic hybridization and review of the literature.

Richter's transformation (RT) is the development of a high-grade lymphoma in patients with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We report an extremely rare case with paraimmunoblastic transformation. A 78-year-old Taiwanese male had Rai stage 1 and Binet stage B CLL/SLL involving skin, peripheral blood (PB), and bone marrow (BM) with paraimmunoblastic transformation in the lymph node. Molecular/genomic studies showed the same clonal origin of tumor tissues at various locations with trisomy 12 and a deletion of chromosome 13q14. Interestingly, there seemed to be no additional chromosomal aberrations in the transformed nodal tissue, suggesting that the micro-environment rather than an additional genetic lesion contributed to the transformation. The patient received chemotherapy and was alive with disease after 33.5 months.

Methyl-CpG-binding PCR of bloodspots for confirmation of fragile X syndrome in males.

This study demonstrates that methyl-CpG-binding PCR (MB-PCR) is a rapid and simple method for detecting fragile X syndrome (FXS) in males, which is performed by verifying the methylation status of the FMR1 promoter in bloodspots. Proteins containing methyl-CpG-binding (MB) domains can be freeze-stored and used as stocks, and the entire test requires only a few hours. The minimum amount of DNA required for the test is 0.5 ng. At this amount, detection sensitivity is not hampered, even mixing with excess unmethylated alleles up to 320 folds. We examined bloodspots from 100 males, including 24 with FXS, in a blinded manner. The results revealed that the ability of MB-PCR to detect FMR1 promoter methylation was the same as that of Southern blot hybridization. Since individuals with 2 or more X chromosomes generally have methylated FMR1 alleles, MB-PCR cannot be used to detect FXS in females.

Deletions of chromosome 1p and 15q are associated with aggressiveness of gastrointestinal stromal tumors.

BACKGROUND/PURPOSE: Site-dependent profiles of chromosome imbalances (CIs) have been reported in gastrointestinal stromal tumors (GISTs). However, the role of specific CIs in association with metastasis is not clear. METHODS: Thirteen resected liver metastatic GISTs, including seven from the stomach and six from the small intestine, were analyzed using comparative genomic hybridization (CGH). The CIs associated with metastatic risk were assessed by comparing them with those identified in our previous study of 25 primary GISTs, including 14 from the stomach and 11 from the small intestine. RESULTS: Synchronous detection of liver metastasis was found more often in patients with intestinal than gastric GIST (5/6 vs. 2/7, p = 0.048). When compared with the primary tumors, the CI profile of liver metastases was similar in the intestinal group, but became more complex in the gastric group. Deletions of chromosomes 1p and 15q were very common (> 80%) in primary and metastatic tumors of the intestinal group, and exhibited a trend towards increase in the metastatic tumors of the gastric group. Both groups had a doubling in the frequency of 22q deletion in the liver metastases, which was not significantly different. Other CIs, including 9p deletion, increased significantly in the liver metastases of the gastric group, but not in the intestinal group. CONCLUSION: Our results, together with clinical findings, indicated a CGH profile associated with the intrinsic aggressiveness of the GISTs. Deletion of 1p and 15q play a critical role in the acquisition of aggressiveness during early GIST development.

Chromosomal gain of 3q and loss of 11q often associated with nodal metastasis in early stage cervical squamous cell carcinoma.

BACKGROUND/PURPOSE: Cervical cancer remains a health problem among women worldwide. Delineation of genetic changes is critical to understanding the molecular basis of tumor progression, as well as for identifying genetic markers for early identification of patients at high risk for a poor outcome. METHODS: To provide comparative genomic hybridization data for cervical squamous cell carcinoma in Taiwan, and to gain further insight into genetic markers associated with lymph node metastasis of this disease, we performed comparative genomic hybridization analysis of 30 consecutive cases of cervical squamous cell carcinoma (24 stage IB and 6 stage IIB). RESULTS: The results disclosed that higher staged tumors or those with lymph node metastasis had more chromosomal imbalances. The commonly recurrent chromosomal imbalances were gains of 3q (46.7%), 1q (36.7%) and 8q (20.0%) and losses of 11q (36.7%), 3p (33.3%), 6q (23.3%), and 2q (20.0%). The frequencies of these chromosomal imbalances in stage IB and IIB tumors did not differ significantly. However, when compared with tumors without lymph node metastasis, the loss of 11q14-q22 (5/9 vs. 3/21, p = 0.019) and gains of 3q11-q22 and 3q26-qter (6/9 vs. 5/21, p = 0.026) were significantly more prevalent in tumors with lymph node metastasis. CONCLUSION: The results suggest that certain tumor-associated genes residing on 3q and 11q warrant further investigation to elucidate their role in the progression of this disease.

Molecular cytogenetics of ovarian granulosa cell tumors by comparative genomic hybridization.

OBJECTIVE: Patients with stage I granulosa cell tumors (GCTs) may occasionally develop metastasis, which is hard to predict using pathologic criteria. It is interesting to elucidate whether certain chromosomal imbalances (CIs), detected by comparative genomic hybridization (CGH), could be useful prognostic markers. METHODS: CGH was used to identify CI(s) in 37 adult-type GCTs from 36 women. Nonrandom CIs were compared with clinical and pathological features to evaluate their significance as a prognostic marker. RESULTS: Twenty-two (61%) of the 36 primary tumors had CIs. One woman's tumor showed identical CIs to another tumor that occurred in contralateral ovary 2 years later, supporting a metastatic nature. The nonrandom CIs included losses of 22q (31%), 1p33-p36 (6%), 16p13.1 (6%), and 16q (6%) and gains of 14 (25%), 12 (14%), and 7p15-p21 (6%). No tumor exhibited high-level amplification. The associations between each CI and pathological features, including the growth pattern, tumor size, and mitotic activity, were not evident. The only CI repeatedly detected in tumors with metastasis was monosomy 22, which presented in 2 of the 4 cases with metastasis but also in 2 of the 5 cases without recurrence for more than 5 years. CONCLUSIONS: Monosomy 22 was the most common CI in GCTs, which often coexisted with trisomy 14 (in 55% cases). Deletion of 22q seems to be, albeit not very specific, associated with the risk of early metastases of stage I disease. The role of loss-of-function mutation(s) of certain putative tumor suppressor gene(s) on 22q is worthy of further investigations.

Biological significance of chromosomal imbalance aberrations in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Current criteria for the diagnosis of malignant GISTs do not always reliably predict patient outcomes. In order to search for genetic markers with prognostic potential, chromosomal imbalance aberrations (CIAs) were analyzed in 28 subjects with GIST using comparative genomic hybridization and correlated with clinicopathological features. Except for a small rectal tumor, CIAs were identified in all GISTs, including 14 from the stomach, 11 from the small intestine, 1 from the esophagus, and 1 from the rectum. Losses were more common than gains. The median number of CIAs in high-risk GISTs was significantly higher than that in low-risk GISTs (5.60 +/- 2.59 vs. 3.38 +/- 2.55; p < 0.05), especially for losses (4.60 +/- 1.84 vs. 2.63 +/- 2.13; p < 0.01). Loss of 14q was the most common CIA in both low-risk and high-risk GISTs, and can be regarded as an early event of GIST development. Losses of 1p and 15q were also very common, often coexisting, and were slightly more frequent in high-risk GISTs than in low-risk GISTs. Other recurrent CIAs, including losses of 10q, 13q, 15q, 18q, and 22q and gains of 5p, 12q, 17q, and 20q were relatively less common in this series. Among these CIAs, losses of 13q, 10q (with minimal overlapping on q11-q22), and 22q were most likely the chromosomal loci potentially harboring the tumor suppressor gene(s) which may be related to early recurrence and/or metastasis during malignant transformation of GISTs.

A rare synovial sarcoma of the kidney exhibiting translocation (X;18) and SYT-SSX2 fusion gene.

Malignant spindle cell neoplasms are often a diagnostic challenge in histopathology, especially those arising from unusual locations. The authors report a primary synovial sarcoma of the kidney in a 19-year-old female. Initially, the tumor was considered adult Wilms' tumor exhibiting predominantly blastemal component. It was then revised to monophasic synovial sarcoma due to discovery of the characteristic chromosomal translocation (X;18)(p11.2;q11.2). This is the tenth reported case of renal synovial sarcoma with genetic confirmation. In addition to emphasizing the usefulness of genetic study in diagnostic pathology, the clinical implication of SYT/SSX subtypes and other additional chromosomal changes were also discussed by reviewing literature.