Christina Enders

Site-independent prognostic value of chromosome 9q loss in primary gastrointestinal stromal tumours

Although the significance of tumour site for estimating malignant potential in gastrointestinal stromal tumours (GISTs) has recently been recognized, site‐specific genetic patterns have not to date been defined. This study examined 52 c‐kit‐positive primary GISTs (with a mean follow‐up of 42.3 months in 51 cases) from three different locations (35 gastric, 12 small intestinal, and five colorectal) using comparative genomic hybridization (CGH). In general, tumour site correlated with key prognostic factors, including tumour size, mitotic rate, proliferative activity, and probable malignant potential. Furthermore, several DNA copy number changes showed a site‐dependent pattern. These included losses at 14q (gastric 83%, intestinal 35%; p = 0.001), losses at 22q (gastric 46%, intestinal 82%; p = 0.02), losses at 1p (gastric 23%, intestinal 88%; p = 1 × 10−5), losses at 15q (gastric 14%, intestinal 59%; p = 0.002), losses at 9q (gastric 14%, intestinal 53%; p = 0.006), and gains at 5p (gastric 11%, intestinal 53%; p = 0.002). These data demonstrate strong site‐dependent genetic heterogeneity in GISTs that may form a basis for subclassification. Prognostic evaluation of DNA copy number changes identified losses at 9q as a site‐independent prognostic marker associated with shorter disease‐free survival (p = 0.03) and overall survival (p = 0.002). Furthermore, 9q loss also appeared to carry prognostic value in predicting overall survival for patients with advanced or progressive GISTs (p = 0.003). Copyright

Overrepresentation of 8q in Carcinosarcomas and Endometrial Adenocarcinomas

We report on genomic imbalances in 19 uterine and extrauterine carcinosarcomas and comparisons with findings in 7 endometrial adenocarcinomas using comparative genomic hybridization (CGH). In the carcinosarcomas, the number of imbalances ranged from 2 to 27. Overrepresentations predominated over losses (mean, 5.8 vs 4.3) and included gains or amplifications at 8q as the single most frequent change in 15 of 19 carcinosarcomas, followed by overrepresentations at 3q (9/19), 1q (7/19), 6p (7/19), and 12p (7/19). Losses were most common at 22q (9/19), 16q (8/19), 15q (7/19), 18q (7/19), Xp (6/19), and 9q (6/19). Among 3 carcinosarcomas in which carcinomatous and sarcomatous elements could be analyzed separately, gains of 8q were identified in both components of one tumor and in the sarcomatous component of another tumor. Additional CGH analyses of 7 endometrial adenocarcinomas revealed simpler copy number changes, including recurrent gains at 8q (4/7) and 1q (4/7), suggesting a central role of 8q gains in the pathogenesis of carcinosarcomas and endometrial adenocarcinomas.

Common molecular cytogenetic pathway in papillary tumors of the pineal region (PTPR).

Primary papillary tumors of the central nervous system and particularly the pineal region are rare. Papillary tumor of the pineal region (PTPR) is a recently described neoplasm that has been formally recognized in the 2007 World Health Organization Classification of Tumors of the Nervous System. Because of their rarity, further pheno‐ and genotypical observations as well as therapeutic experience are necessary to differentiate PTPR from other primary or secondary papillary tumors of this region. We herein present three cases of PTPR characterized by local recurrence in two of them. Primary and recurrent tumors were analyzed by immunohistochemistry and comparative genomic hybridization (CGH). From our results clonal chromosomal aberrations can be postulated which seem to be a feasible tool to differentiate PTPRs from other primary or secondary papillary tumors of this region.

Common Genomic Aberrations in Basaloid Squamous Cell Carcinoma and Carcinosarcoma of the Esophagus Detected by CGH and Array CGH

Basaloid squamous cell carcinoma (BSCC) and carcinosarcoma of the esophagus are rare entities, making up fewer than 2% of esophageal malignancies. Comparative genomic hybridization (CGH) in 1 case of BSCC and 2 cases of carcinosarcoma and subsequent array CGH in 1 case each of BSCC and carcinosarcoma revealed common chromosomal gains at 2p25.3-2p12, 7q21.3-7q22.3, and 11q13.2-11q13.4. Chromosomal losses at 13q31qter were observed in both carcinosarcomas. In addition, progression of genomic instability from in situ to invasive carcinosarcoma could be demonstrated by using array CGH. Our observations suggest a common genetic origin of BSCC and carcinosarcoma.

Etiologic influence on chromosomal aberrations in European hepatocellular carcinoma identified by CGH

Previous studies suggest different pathways in the molecular development of hepatocellular carcinoma (HCC). We investigated the pattern of chromosomal imbalances in HCC depending on the type of underlying liver disease as detected by comparative genomic hybridization in 67 cases of primary HCC occurring in non-cirrhotic livers (n=30), in liver cirrhosis (LC) related to alcohol intake (n=9), cryptogenic or metabolic changes (n=11), and chronic viral hepatitis B or C (n=17). HCC were treated by liver resection in 48 patients and transplantation in 19 patients. The 10-year disease-free and overall survival rates were 51% and 68%, respectively. The copy number changes occurring in more than 10% of cases were gains at 8q (55%), 1q (49%), 7q (15%), 7p (13%), 6p (12%), and 20q (12%), as well as losses at 8p (55%), 4q (33%), 6q (33%), 13q (25%), 14q (24%), 17p (22%), 16q (19%), 1p (18%), 18q (16%), 9p (13%), 10q (13%), 4p (12%), and 9q (12%). HCC arising in alcoholic LC showed a different pattern with significantly fewer net changes (p=0.008), particularly fewer chromosomal gains (p=0.008) and fewer breakpoints (p=0.003) compared to the other investigated HCC subgroups. Future clinical studies should evaluate the prognostic relevance of these findings.

High chromosomal instability in adenocarcinoma of the ileum arising from multifocal gastric heterotopia with gastritis cystica profunda.

Adenocarcinoma of the small intestine arising from heterotopic gastric mucosa is extremely rare. In this report, we present the case of a 68-year-old woman who complained of abdominal pain, weight loss and subileus. Gross examination of resected small bowel revealed multiple flat polypous lesions with cysts in the ileal submucosa, one of which containing an ulcerated, stenosing tumour. On microscopic examination, an adenocarcinoma of the ileum arising from multifocal gastric heterotopia with secondary gastritis cystica profunda was diagnosed. Comparative genomic hybridization of the adenocarcinoma revealed chromosomal gains at 1q, 3q, 5p, 8q, 11p, 12p, 13q and losses at Xp, 4q, 8p, 10p, 14q, 17p, 20p, compatible with a high degree of genomic instability.

Predictive chromosomal clusters of synchronous and metachronous brain metastases in clear cell renal cell carcinoma

Synchronous (early) and metachronous (late) brain metastasis (BM) events of sporadic clear cell renal cell carcinoma (ccRCC) (n = 148) were retrospectively analyzed using comparative genomic hybridization (CGH). Using oncogenetic tree models and cluster analyses, chromosomal imbalances related to recurrence-free survival until BM (RFS-BM) were analyzed. Losses at 9p and 9q appeared to be hallmarks of metachronous BM events, whereas an absence of detectable chromosomal changes at 3p was often associated with synchronous BM events. Correspondingly, k-means clustering showed that cluster 1 cases generally exhibited low copy number chromosomal changes that did not involve 3p. Cluster 2 cases had a high occurrence of -9p/-9q (94-98%) deletions, whereas cluster 3 cases had a higher frequency of copy number changes, including loss at chromosome 14 (80%). The higher number of synchronous cases in cluster 1 was also associated with a significantly shorter RFS-BM compared with clusters 2 and 3 (P = 0.02). Conversely, a significantly longer RFS-BM was observed for cluster 2 versus clusters 1 and 3 (P = 0.02). Taken together, these data suggest that metachronous BM events of ccRCC are characterized by loss of chromosome 9, whereas synchronous BM events may form independently of detectable genetic changes at chromosomes 9 and 3p.

1773 IS VEGF TARGETED THERAPY IN RENAL CELL CARCINOMA WITH LATE METASTASES TO THE PANCREAS AND THE THYROID GLAND REASONABLE? – A STUDY OF CHROMOSOMAL IMBALANCES

INTRODUCTION AND OBJECTIVES: Chromosomal imbalances in clear cell renal cell carcinoma (ccRCC) are common. The most relevant on chromosome 3p leads to a loss of the von HippelLindau gene. In solid tumors metastases to endocrine organs rarely occur. In ccRCC they are a characteristic feature in the late onset of metastatic disease, which then are often located in the thyroid or the pancreatic gland. Aim of the study was to compare chromosomal imbalances in ccRCC metastasis of the thyroid and pancreas with the corresponding primary tumor with regard to a possible VEGF targeted therapy. METHODS: A total of 63 tumor specimens with 24 metastases of the thyroid with 12 corresponding primary tumors and 19 metastasis of the pancreas with 8 corresponding primary ccRCC from 45 patients (23 men and 22 women, mean age at primary diagnosis, 57.8 years; range, 45.7 e 77.3 years, TNM 7th ed. T1 to T3b) were analysed by comparative genomic hybridization (CGH). Mean follow-up was 92.3 months, available in 33 patients (pt). RESULTS: Mean time to metastasis was 87.9 in pancreas and 83.4 months in thyroid. In all tumors the most frequently observed chromosomal imbalances included losses at 3p (84.1%), 8p (31.7%) and 14q (25.4%) and gains at 5q (36.5%). Most frequent chromosomal aberrations in primary ccRCC with metastases to pancreas were losses at 3p (62.5%) and gains at 5q (50%), which increased in pancreatic metastasis to 89.5% (losses at 3p) and 52.6% (gains at 5q). Most frequent chromosomal aberrations in primary ccRCC with metastases to thyroid included losses at chromosomes 3p (83.3%), 8p (33.3%), 14q (33.3%) and 8q (25%). Thyroid metastases most frequently displayed losses at 3p (87.5%), 8p (41.7%), gains at 5q (29.2%). The comparison of the mean number of changes per tumor revealed an increase in chromosomal imbalances in pancreatic metastasis (primary tumor: 2.13 changes vs. pancreatic metastases: 4.37, p 0.071), while the number of changes in primaries of thyroid metastasis did not differ with thyroid metastasis (4.25 vs. 4.38, p 0.497). CONCLUSIONS: The high frequency of 3p loss which was further increased in pancreatic metastatic tissue and in thyroid metastatic tissue when compared to the corresponding primary tumor underlines the importance of VHL / VEGF pathway alterations in ccRCC. This result supports the use of VEGF targeted therapy with a possible vulnerability of pancreas and thyroid metastasis to these agents.