Alterations of chromosome 1 are among the most common chromosomal anomalies in human neoplasia. These abnormalities include translocations and other structural rearrangements involving chromosome 1 and various other chromosomes, as well as deletions or amplifications of specific regions. In general, regions on 1p seems to be more frequently lost, indicating the presence of tumor suppressor genes, whereas regions on 1q (or the entire long arm) are more often amplified. Recent work on the identification, cloning and characterization of possible target genes for common deletions and amplifications in various neoplasia was presented at this workshop. This report will concentrate on these results and reports published since the previous chromosome 1 workshop (Gregory et al., 1998).

Comparative genomic hybridization (CGH) studies of chromosome 1

During the last year a large number of studies using CGH to detect copy number changes in a variety of tumors have been published, the most recent of which are mentioned here. Gain of 1q has been observed in the following tumor types: acute lymphoblastic leukemia (partial gain of 1q31-p32) (Larramendy et al., 1998); adrenocortical tumors of childhood (Figueiredo et al., 1999); 47% of nasopharyngeal carcinomas (Chen et al., 1999a); 37% of bladder tumors (Richter et al., 1998); 54% of papillary superficial bladder tumors, where gains of 1q was most frequent in stage pT1 (Simon et al., 1998); breast carcinoma of various subtypes (see below); esophageal carcinoma in 41% of black and mixed race populations in South Africa (Du Plessis et al., 1999); fallopian tube carcinoma (Pere et al., 1998); 45% of invasive cervical carcinomas (Kirchhoff et al., 1998); sporadic gastric carcinomas from HNPCC patients, with a minimal overlapping region at 1q22-q31 (Larramendy et al., 1998); and Wilms tumor (Getman et al., 1998). Amplifications of 1q21-q22 were reported for malignant fibrous histiocytoma (Mairal et al., 1999), nasopharyngeal carcinoma (Chen et al., 1999a) and papillary superficial bladder carcinoma (Simon et al., 1998). Loss of 1q material is uncommon but has been reported for adenocarcinoma of the prostate (Verma et al., 1999).

Loss of 1p has been observed for the following malignancies: astrocytic tumors (Maruno et al., 1998); colorectal carcinoma (Du Plessis et al., 1999); esophageal squamous cell carcinoma, with a high percentage in tumors from black and mixed race populations in South Africa (Du Plessis et al., 1999; Pack et al., 1999); 50% of malignant meningiomas (Maruno et al., 1998); at 1p12-p22 in 42% of malignant mesotheliomas (Balsara et al., 1999); malignant peripheral nerve sheath tumors (Mechtersheimer et al., 1999); 31% of malignant follicular thyroid tumors (Hemmer et al., 1998); mantel cell lymphoma (Bea et al., 1999); nasopharyngeal carcinoma (Hui et al., 1999); oligodendral glioma (Jeuken et al., 1999); 24% of papillary renal cell carcinomas (Jiang et al., 1998); 40% of parathyroid tumors (Agarwal et al., 1998); 42% of plasmacytomas (Aalto et al., 1999); and Wilms tumor (Getman et al., 1998). Amplification of 1p material is rare but has been detected in cervical cancer (Aubele et al., 1998) and at 1p32 in bladder tumors (Koo et al., 1999).

1p deletions in solid tumors

Ragnarsson and colleagues recently published an extensive study of various solid tumors where loss of 1p was evaluated by microsatellite markers (Ragnarsson et al., 1999). Regions with high percentages of loss of heterozygosity (LOH) were 1p36.3, 1p36.1, 1p35-p34.3, 1p32 and 1p31, and LOH at each of these locations was detected in more than one tumor type. The general LOH percentages in the different tumor types were as follows: stomach (53%), colon and rectum (55%), lung (60%), breast (61%), endometrium (72%), ovary (55%), testis (37%), kidney (39%), thyroid (29%), and sarcomas (64%) (Ragnarsson et al., 1999).

Brain tumors

Allelic alterations of chromosome 1p and 19q are strong predictors of chemotherapeutic responses in oligodendrogliomas, and 1p deletions affecting 1p36 were detected in 73% of these tumors, but only in 18% of astrocytomas. A minimal deleted region has been defined between D1S468 and D1S1612 (Smith et al., 1999). Similarly, Bigner and colleagues found LOH of 1p in 74% and 83% of well-differentiated and anaplastic oligodendroglioma subtypes, respectively, but only in 38% of oligoastrocytomas (Bigner et al., 1999). In other studies, loss of 1p was detected in about 80% of oligodendral gliomas (Jeuken et al., 1999; Rasheed et al., 1999). Meningiomas also show frequent loss of 1p (34-36%), mostly in the more aggressive tumors (Leone et al., 1999; Sulman et al., 1998).

Breast and ovarian tumors

Distal alterations of 1p are common in breast cancer. Bieche and co-workers have found allelic imbalances of 1p32-pter in 58% of the tumors analyzed (Bieche et al., 1999). Consensus regions of LOH were identified at 1p32 and 1p36.3, but the PRDM2 gene was not involved. Additional deletions were located in 1p12 and 1p22 (Bieche et al., 1999). Another study reported loss of 1p36 (D1S160 and D1S243) in 33% and 1p32 (MYCL) in 51% of the tumors from families with early-onset bilateral breast cancer (Millikan et al., 1999). These frequencies were similar to those found for sporadic cases and largely rules out a susceptibility locus in 1p36.

Chromosomal gain of 1q has previously been reported as one of the most frequent abnormalities in breast cancer. Tsukamoto and colleagues recently reported that this aberration was much more common in non-invasive ductal and papillotubular histological subtypes than in solid-tubular or schirrhous types (Tsukamoto et al., 1999). Buerger and co-workers reported that 1q gains were more frequent in intermediately-differentiated than in well-differentiated ductal carcinomas (Buerger et al., 1999), whereas a separate study found gain of 1q and loss of 1p21-p22 associated with highly differentiated tumors (Schwendel et al., 1998). Gain of 1q was also the second most common aberration in lymph node-negative breast carcinoma (Hermsen et al., 1998), but 1q gain was not detected in lobular carcinoma in situ and atypical lobular hyperplasia (Lu et al., 1998). A recurrent der(1;16)(q10;p10), resulting in 1q gain and 16q loss, was frequently observed in lobular breast cancer (Flagiello et al., 1998).

Recently, the 1q44 locus AKT was found to produce much high enzymatic activity in estrogen receptor-deficient breast and androgen-independent prostate tumors, indicating a possible role in tumor progression (Nakatani et al., 1999).

A study of ovarian adenocarcinoma revealed a non-random occurrence of chromosome breakpoints affecting various regions of 1p and 1q (Taetle et al., 1999a). Tumor grade was significantly associated with the occurrence of specific breakpoints. Breakpoints clustered within 1p11-p13 were associated with independent, deleterious effects on survival (Taetle et al., 1999b). Loss of 1p and gain of 1q was common also in pediatric ovarian tumors (Bussey et al., 1999) and were reported as common aberrations in benign, borderline and malignant ovarian tumors (Zborovskaya et al., 1999).

Colorectal cancer (CRC)

Hereditary and spontaneous CRC frequently contain deletions of 1p. Combined analysis of SNPs and microsatellite markers show that some sporadic tumors have lost the entire telomeric part of 1p (down to about 30 cM from pter), and some hereditary tumors show LOH in the same region (Chadwick et al., this report). A more detailed analysis has identified three commonly deleted regions corresponding to 1p36.3, 1p35.1-1p36.3 and 1p34.2-1p35 (Matsuzaki et al., 1998). Deletion of 1p was also frequently observed (56%) in CRC liver metastases (Korn et al., 1999).

Germ cell tumors

Gain of 1q and chromosome 3 were the most frequent abnormalities found in a panel of pediatric germ cell tumors studied by Bussey and colleagues (Bussey et al., 1999). Also, testicular germ cell tumors show recurrent breakpoints in 1p36 and 1p13-qh (Smolarek et al., 1999). Chromosomal amplification at 1q31-q32 was detected only in cisplatin-resistant tumors, suggesting a possible role in chemotherapy resistance for genes in this region (Rao et al., 1998).

Hematological malignancies

Cytogenetic analyses of diffuse large B-cell lymphomas showed clustering in breakpoints at several recurring sites, including 1p36 and 1p22. Deletion breaks affecting 1p22 and translocations affecting 1q21 were among the particularly frequent and distinctive abnormalities for this subset of tumors (Cigudosa et al., 1999). Jerkeman and co-workers reported that breakpoints within 1q21-q23 were associated with shorter survival for patients with diffuse large B-cell lymphoma (Jerkeman et al., 1999).

In anaplastic large cell lymphoma, it was recently shown that t(1;2)(q25;p23) creates a fusion between the TPM3 and ALK genes (Lamant et al., 1999). A jumping translocation of 1q21-qter to other chromosomes has been reported as the sole anomaly in a case of follicular lymphoma (Rosenwald et al., 1999).

Mantel cell lymphomas show relatively frequent loss of 1p (24%), and overall, gains and losses are more frequent in the blastoid variants (Bea et al., 1999). Loss of 1p was also the most frequent aberration observed in plasmacytoma (42%), although gain and occasional amplification of 1q was also detected (Aalto et al., 1999). Deletion of 1p36 between D1S508 and D1S507 seems important in the evolution of chronic myelocytic leukemia from chronic phase to blast crisis (Mori et al., 1998).

Hepatocellular carcinoma (HCC)

Deletions involving 1p36 in HCC define a consensus region between D1S160 and D1S436, thus proximal to the neuroblastoma locus. A possible candidate suppressor gene, PRDM2, has been identified. The gene is expressed in normal tissue but shows decreased expression in HCC cell lines. Although no mutations were detected in tumors, forced PRDM2 expression suppressed HCC tumorigenicity in nude mice and loss of expression was linked to tumor formation (Fang et al., this report).

Gain of 1q material is one of the most frequent chromosomal alterations in HCC, as it has been detected in about 70-80% of analyzed tumors (Kusano et al., 1999; Wong et al., 1999b; Zimonjic et al., 1999). Minimal regions of overlap were detected at 1q24-q25 (Kusano et al., 1999), and a highly amplified region has been identified at 1q21-q25, with a core region in 1q21.1 as determined by FISH analyses (Wong et al., this report). This region coincides with the most frequently amplified region in sarcomas (Forus et al., 1998). Gains or losses of 1p were relatively rare in these tumor panels.

Neuroblastoma (NB)

Previous research has identified 1p35-p36 as one of the most commonly deleted regions in NB. The overall frequency of 1p deletions has been reported to be around 35% (Iolascon et al., 1998), and the association of 1p deletion with MYCN amplification and a poor prognosis is highly significant. Komuro and colleagues reported 1p36 deletions in 73% of MYCN-amplified tumors (Komuro et al., 1998). Spieker et al. (this report) has searched for possible 1p36.1 tumor suppressor genes associated with MYCN-amplified tumors by analyzing corresponding human and murine PACs for conserved sequences. A search for mutations in the candidate tumor suppressor AML2 yielded no mutations in a panel of tumors. Ejeskar and colleagues studied two possible target genes in 1p36.3, TP73 and CORT (Ejeskar et al., 1999). Expression of both genes was detected in several tumors with deletions, and no mutations were found at either locus (Martinsson et al., this report). Versteeg and colleagues (this report) have applied Serial Analysis of Gene Expression (SAGE) to obtain integral expression profiles from neuroblastoma. They constructed 5 SAGE libraries from neuroblastoma tumors and cell lines and are presently characterizing tags from 1p35-p36. So far, at least 40% of these tags represent genes expressed in neuroblastoma.

Horii and colleagues (this report) describe a strategy for cloning of the t(1;9)(p32.3; p21.2) breakpoint in a neuroblastoma patient. They also reported LOH around the D1S197 locus (1p32) in 38% of the examined cases.

Possible prognostic impact of 1p deletions in NB have been reported by several groups. MYCN amplification and 1p deletion were strongly associated with gain of 17q material; however, while and 1p deletions were indicative of an adverse outcome, they were a less powerful prognostic factor than 17q gain and grade 4 disease in this study (Bown et al., 1999). A separate report confirmed 1p deletion as an adverse prognostic factor (Gallego et al., 1999).

A recent study demonstrated that gain of 1q21-q25 is frequent in stage 4 NB (50% overall) and is strongly associated with a poor outcome (Hirai et al., 1999). Tumors with gain of this region showed resistance to chemotherapy, and a consensus region of 1p gain was defined at 1q23.

Pancreatic cancers (PCA)

Recently, deletion mapping has identified a region in 1p35 (between D1S233 and D1S247) as a major consensus region of deletion in pancreatic cancers. Overall, LOH on 1p was detected in 49% of the tumors analysed (Hilgers et al., 1999). A novel amplicon was detected at 1q31 in 11 of 14 (78%) PCA cell lines (Tirado et al., 1999).

Prostate cancer

Unlike most other malignancies, prostate tumors frequently contain allelic loss of the entire 1q arm (Verma et al., 1999). The locus for hereditary prostate cancer (HPC) has been mapped to 1q24.3-q31.3. A Swedish group has reported that the linkage of HPC1 to 1q24-q25 is restricted to a subset of families with early onset disease (Gronberg et al., 1999), whereas a British group concludes that allelic imbalances at HPC1 are low in both sporadic and familial cases (Dunsmuir et al., 1998). Studies of another putative prostate cancer susceptibility locus within 1q42.2-q43 detected no significant evidence for linkage in 152 families (Gibbs et al., 1999b), in contrast to a previous report (Berthon et al., 1998).

Sarcomas

High-level amplification of 1q21-q22 was first reported for sarcomas and is one of the most frequent alterations of these tumors. A highly amplified marker for the affected region has been identified (YAC clone 789f2) (Forus et al., 1998). Using this marker in direct cDNA selection, three novel candidate genes have been cloned (Meza-Zepeda et al., this report). All genes show overrepresentation and high expression levels in a subset of tumors, and two are novel members of known gene families.

Analyses of a panel of primary sarcomas and their pulmonary metastases revealed gain of 1q as the most frequent chromosomal abnormality, occurring within 1q21-q23 in 36% of primary cases and at 1q21 in 46% of metastatic cases, respectively (Tarkkanen et al., 1999a). The same investigators have reported that osteosarcoma patients with copy number increases at 1q21 showed a trend towards shorter survival (Tarkkanen et al., 1999b). In leiomyosarcomas, gains of 1q occur mainly in large tumors, with a minimal region of overlap defined within 1q23-q25 (El-Rifai et al., 1998). Frequent allelic loss or rearrangement of 1p was detected among leiomyosarcomas and malignant peripheral nerve sheath tumors (Fletcher et al., 1999), and was confirmed for the latter tumor by CGH (Mechtersheimer et al., 1999).

Supernumerary ring chromosomes in intra-muscular lipomas have been shown to carry amplifications of 1q21, as opposed to similar chromosomes detected in well-differentiated liposarcomas (Pedeutour et al., 1999).

Other tumors

A locus for the hyperparathyroidism-jaw tumor syndrome, HRPT2, characterized by the development of multiple adenomas and fibro-osseous tumors of the maxilla and mandible, has been localized to 1q25-q31, between the markers D1S2848 and D1S191 (Hobbs et al., 1999). Rearrangement of 1p11-p13 was reported as the most frequent aberration of tenosynovial giant cell tumors (Sciot et al., 1999), and head and neck carcinomas also show frequent breakpoints and deletions within this region (Jin et al., 1998).