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(American Journal of Pathology. 1999;155:683-694.)
© 1999 American Society for Investigative Pathology

Review

DNA Copy Number Losses in Human Neoplasms

Sakari Knuutila^*, Yan Aalto^*, Kirsi Autio^*, Anna-Maria Björkqvist^*, Wa'el El-Rifai^*, Samuli Hemmer^*, Tarja Huhta^*, Eeva Kettunen^*, Sonja Kiuru-Kuhlefelt^*, Marcelo L. Larramendy^*, Tamara Lushnikova^*, Outi Monni^*, Heini Pere^*, Johanna Tapper^*, Maija Tarkkanen^*, Asta Varis^*, Veli-Matti Wasenius^*, Maija Wolf^* and Ying Zhu^*

From the Department of Medical Genetics,^*
Haartman Institute and Helsinki University Central Hospital, University of Helsinki, and the Departments of Oncology
and Obstetrics and Gynecology,
Helsinki University Central Hospital, Helsinki, Finland

	Abstract

Top Abstract Introduction Comparative Genomic... Recurrent DNA Copy Number... Known and Putative Tumor... Conclusion References

 
This review summarizes reports of recurrent DNA sequence copy number losses in human neoplasms detected by comparative genomic hybridization. Recurrent losses that affect each of the chromosome arms in 73 tumor types are tabulated from 169 reports. The tables are available online at http://www.amjpathol.org and http://www.helsinki.fi/~lgl_www/CMG.html. The genes relevant to the lost regions are discussed for each of the chromosomes. The review is supplemented also by a list of known and putative tumor suppressor genes and DNA repair genes (see Table 1, online). Losses are found in all chromosome arms, but they seem to be relatively rare at 1q, 2p, 3q, 5p, 6p, 7p, 7q, 8q, 12p, and 20q. Losses and their minimal common overlapping areas that were present in a great proportion of the 73 tumor entities reported in Table 2 (see online) are (in descending order of frequency): 9p23-p24 (48%), 13q21 (47%), 6q16 (44%), 6q26-q27 (44%), 8p23 (37%), 18q22-q23 (37%), 17p12-p13 (34%), 1p36.1 (34%), 11q23 (33%), 1p22 (32%), 4q32-qter (31%), 14q22-q23 (25%), 10q23 (25%), 10q25-qter (25%),15q21 (23%), 16q22 (23%), 5q21 (23%), 3p12-p14 (22%), 22q12 (22%), Xp21 (21%), Xq21 (21%), and 10p12 (20%). The frequency of losses at chromosomes 7 and 20 was less than 10% in all tumors. The chromosomal regions in which the most frequent losses are found implicate locations of essential tumor suppressor genes and DNA repair genes that may be involved in the pathogenesis of several tumor types.

	Introduction

Top Abstract Introduction Comparative Genomic... Recurrent DNA Copy Number... Known and Putative Tumor... Conclusion References

As methodological problems in the cytogenetic analysis of solid tumors have restrained attempts to apply standard techniques to screening for deleted chromosomal areas, comparative genomic hybridization (CGH) has been proven to be a powerful genome-wide screening method. Since the CGH technique was introduced in 1992, studies using this method have been reported in about 200 papers that describe a great number of recurrent deleted chromosomal areas in a wide variety of human neoplasms.^3,4 The Peutz-Jeghers syndrome is the first example of how CGH suggested the chromosomal region to which the tumor suppressor gene STH11/LKB1 (serine/threonine kinase) was mapped.⁴ Here we summarize 170 reports of DNA sequence copy number losses detected by CGH in 73 tumor types. We aimed to cover all relevant papers published by the end of 1998.

	Comparative Genomic Hybridization Reveals DNA Copy Number Imbalances

Top Abstract Introduction Comparative Genomic... Recurrent DNA Copy Number... Known and Putative Tumor... Conclusion References

 
Comparative genomic hybridization allows DNA copy number losses and gains to be studied in one hybridization experiment.³ CGH methodology has been described and discussed in detail previously.^5,6

Comparative genomic hybridization is sensitive for detecting deletions that are 10 to 20 megabases in size.^7,8

The present paper and our previous review of DNA copy number amplifications can be accessed electronically at http://www.amjpathol.org and http://www.helsinki.fi/~lgl_www/CMG.html.

	Recurrent DNA Copy Number Losses

Top Abstract Introduction Comparative Genomic... Recurrent DNA Copy Number... Known and Putative Tumor... Conclusion References

 
Recurrent losses in different tumor types are shown in Table 2¹⁹⁷ (online). We define a loss to be recurrent when its frequency in a certain tumor type is at least 10% and the number of aberrant cases is at least three. If a particular loss is observed in at least 30% of the cases and the loss has been reported in at least two publications, it is considered to be an established loss and indicated in bold type in Table 2. An asterisk in Table 2 indicates that the loss was located within the area but did not necessarily affect the whole area in all cases. As a whole, the description should be considered a flexible way to summarize critical areas of recurrent DNA copy number changes in each tumor type. A description without an asterisk indicates minimal overlapping areas. Figure 1 is a compilation of the recurrent losses in 73 tumor entities presented in Table 2. The most common losses (Figure 1) were 9p, 13q, and 6q, found in 35, 34, and 32 of the 73 tumor entities (48%, 47%, and 44%). The corresponding minimal overlapping regions were 9p23-p24, 13q21, 6q16, and 6q26-q27. Other frequent losses involved 8p (37%), 18q (37%), 17p (34%), 1p (34%), 11q (33%), and 4q (31%), with minimal overlapping regions at 8p23, 18q22-q23, 17p12-p13, 1p36.1, 11q23, 1p22, and 4q32-qter. Other recurrent losses involved 2q (16%), 3p (22%), 4p (21%), 5q (23%), 10p (21%), 10q (25%), 11p (19%), 12q (13%), 14q (25%), 15q (23%), 19p (13%), 21q (10%), 22q (22%), X (22%), and Y (12%), with minimal overlapping regions at 2q36-qter, 3p12-p14, 4p16, 5q21, 10p12, 10q23, 10q25-q26, 11p14, 12q21, 14q22-q23, 15q21, 19p13.1-pter, 21q21, 22q12, Xp21, Xq21, Yp, and Yq11-q12. The frequency of recurrent losses at chromosomes 7 and 20 was less than 10% in all tumors.

View larger version (33K): [in this window] [in a new window]   Figure 1. Summary of losses in 73 tumor entities reported in Table 2. Each line by a chromosome arm represents a tumor entity. Red and black lines indicate that the loss was found in at least 30% of the cases in that particular tumor type (numbers refer to numbering in Table 2 online). A red line signifies that two different publications reported the loss, and a black line shows that the loss was published in one report only. A blue line indicates that the loss was involved in 10 to 29% of the cases. A bold line shows the smallest common overlapping area of the losses.

	Known and Putative Tumor Suppressor Genes and DNA Repair Genes in Chromosomal Regions with Recurrent Losses

Top Abstract Introduction Comparative Genomic... Recurrent DNA Copy Number... Known and Putative Tumor... Conclusion References

Chromosome 1

The most relevant candidates may be MTS1/SA1/TFS1 (1pter-p22.1; malignant transformation suppression-1), ID3 (1p36.13-p36.12; inhibitor of DNA binding 3), NB/NBS (1p36.13-p36.11; neuroblastoma suppressor), TNFR2 (1p36.3-p36.2; tumor necrosis factor receptor 2), DAN (1p36.13-p36.11; differential-screening-selected gene aberrant in neuroblastoma), CDC2L1 (1p36; cell division cycle 2-like 1), MOM1/PLASG2 (1p35; phospholipase A2), and BRCD2 (1p36; breast cancer suppressor-2). Recently the P73 gene was mapped to 1p36 and its protein is known to share considerable homology with the tumor suppressor p53. 1p36 is a frequently deleted region in neuroblastoma and other tumors. Disregulation of P73 may therefore contribute to their tumorigenesis.^9,10 However, no clear evidence supporting the importance of the loss of any of these genes has been published.

Chromosome 2

The mismatch repair genes MSH2, MSH6/GTBP, and PMS1 have been assigned to 2p22-p21, 2p16, and 2q32, respectively.¹¹

Chromosome 3

Losses of DNA sequences at chromosome 3 mostly involve the short arm. Using standard cytogenetic and loss of heterozygosity (LOH) methods, four regions at 3p, which have been implicated to encompass putative tumor suppressor genes, have been recognized. They span bands p12, p14.2, p21.3, and p25 (reviewed by Le Beau et al).¹² The tumor suppressor gene VHL (von Hippel-Lindau) locates at 3p25-p26. Germline mutations of this gene are found in patients with the von Hippel-Lindau disease, a familial cancer syndrome with susceptibility to the development of several neoplasms, such as renal cell carcinoma.¹³ Mutations in VHL have also been reported to occur in sporadic renal cell carcinoma tumors (30 to 60%), with most of them displaying homozygous loss (reviewed by Decker et al),¹⁴ as well as in other tumor types.¹³ Another important gene in 3p is the FHIT (fragile histidine triad) gene that spans the fragile site FRA3B at 3p14.2. Several tumor types, including lung, pancreatic, and head and neck squamous cell carcinomas as well as gastrointestinal cancers, have been reported to display alterations of the FHIT gene.^15-18 However, because some analyses have shown similar alterations of FHIT in both malignant and nonmalignant tissues^19,20 and because studies using a non-nested polymerase chain reaction technique^20,21 show some discrepancies with the first reports, the role of FHIT as a possible tumor suppressor gene needs to be further clarified (reviewed by Le Beau et al).¹² A recent paper reports progress in the search of putative tumor suppressor gene(s) at 3p21.3 by the identification of a homozygous deletion in a breast cancer cell line and its corresponding tumor.²² DNA mismatch repair gene MLH1 resides at 3p21.3-p23 and DNA repair gene XPC, which was found mutated in xeroderma pigmentosum syndrome type C, is located at 3p25.²³

Chromosome 4

In breast cancer, loss of chromosome 4 was significantly more common in hypodiploid tumors.²⁴ So far no tumor suppressor gene has been identified on chromosome 4, but some CGH and LOH results clearly indicate regions in chromosome 4 to which a yet unidentified tumor suppressor gene will be assigned.^24-28 In esophageal adenocarcinoma, high frequency of LOH has been observed in regions 4q21–25, 4q21-qter, and 4q33-q35.²⁵ One of the critical areas in testicular cancer is 4cen-q13. Three candidate genes located in or close to this area have been suggested, AFP (-fetoprotein gene), ALB (embryonal protein gene), and KIT (tyrosine kinase receptor gene).²⁶

Chromosome 5

A myeloid tumor suppressor locus was recently mapped to 5q31.1,^29,30 which is consistently lost in myeloid neoplasms with 5q aberrations.³⁰ Two tumor suppressor genes, APC (adenomatosis polyposis coli) and MCC (mutated in colorectal cancer), which have been mapped to 5q21-q22, are mainly involved in colorectal cancer. Somatic mutations in APC have been identified in colorectal tumors as well as in some cancers of stomach, pancreas, thyroid, and ovary.³¹ DNA mismatch repair gene MSH3 is located at 5q11-q12.

Chromosome 6

p21/WAF/CDKN1A (6p21.2; cyclin-dependent kinase inhibitor 1A) is considered to be a putative tumor suppressor gene. So far no tumor suppressor gene has been identified at 6q. However, microsatellite marker analyses on different malignancies, such as breast and ovarian carcinoma, NHL, and malignant mesothelioma have revealed several regions at 6q showing allelic imbalance suggesting the existence of one or more tumor suppressor genes.^32-37 Moreover, chromosome 6 transfer experiments have implicated the chromosomal regions 6q23-q25 and 6q24-q25 as the locations for putative tumor suppressor genes involved in breast and ovarian cancer, respectively.^33,38 One candidate tumor suppressor gene is LOT-1/hZAC (lost on transformation 1) at 6q24-q25.^39,40

Chromosome 7

Cytogenetic data indicate that complete and interstitial deletions of chromosome 7 are among the most common solely occurring cytogenetic aberrations in myeloid neoplasms.⁴¹ Both 7p and 7q have been suggested to be locations of putative tumor suppressor genes. However, no tumor suppressor gene has so far been identified, but at least two distinct critical areas, 7q22 and q31, have been suggested in different solid tumors.^42-45 Involvement of more than one critical region in 7q has been shown in myeloid disorders as well,^46,47 and correlation between poor prognosis and a factor located at 7q31 has been reported.⁴⁸ DNA mismatch repair gene PMS2 is located at 7p22.

Chromosome 8

In bladder carcinomas loss of 8p has been associated with invasive tumor growth.^49,50 In breast, prostate, and small-cell lung carcinomas loss of 8p is often detected in association with gain at 8q, suggesting isochromosome 8q formation. LOH studies on different tumor types have often shown two or three independent regions of deletion at 8p, which may indicate that more than one tumor suppressor gene is located on this chromosome arm.^51-54 The 8p region has been suggested to harbor several candidate tumor suppressor genes. Recently, a gene frequently deleted in human liver cancer (DLC1, dynein light-chain gene 1) was isolated and localized at 8p21.3-p22.⁵⁵ Located at the same band is PRLTS (PDGF-receptor ß-like tumor suppressor), which has been found to be altered in a few cases of hepatocellular, colorectal, and non-small-cell lung carcinomas.⁵⁶ A third breast cancer susceptibility gene has been suggested to reside at 8p12-p22,⁵⁷ and recently a third EXT-like gene [EXTL3, exostoses (multiple)-like 3] has been identified in the same region.⁵⁸ EXT1, a putative tumor suppressor gene, is located at 8q24.1.

Chromosome 9

Band 9p21 contains a tumor suppressor gene, CDKN2A (cyclin-dependent kinase inhibitor 2A), which encodes a cell-cycle inhibitor, p16.^59,60 Deletions at the locus often encompass and inactivate a gene nearby, CDKN2B (p15), which has similar functions as CDKN2A.⁶¹ High frequency of CDKN2A alterations has been observed in many primary malignancies. Small homozygous deletions represent a major mechanism of the inactivation of the gene.^61-74 Germline alterations of CDKN2A are frequent in kindreds with familial melanoma, and CDKN2A has been suggested to be a familial melanoma gene.^66,75-77 In some reports of acute lymphoblastic leukemia, CDKN2A deletions have been associated with adverse prognostic factors^71-73 and also with poor rate of event-free survival.^74,78

LOH studies of transitional cell carcinoma of the bladder have revealed at least three common regions of deletion at 9q: 9q13-q31, 9q32-q33, and 9q34.^79-81

The locus for the nevoid basal cell carcinoma syndrome, an autosomal dominant disorder that predisposes to basal cell carcinomas, ovarian fibroma, and medulloblastoma, has been mapped to the 9q22.3-q31 region by linkage analysis.^82-85

In bladder cancer (9q32–33; DBCCR1, deleted in bladder cancer chromosome region candidate 1) and in ovarian carcinoma (9q31 and 9q32-q34) three candidate tumor suppressor genes/areas have been suggested,^68,86 and in lung carcinoma Suzuki et al⁸⁷ suggested tuberous sclerosis complex 1 (TSC1)-associated region at 9q34 as a candidate locus for a tumor suppressor gene.

DNA repair gene XPA, which was found mutated in xeroderma pigmentosum syndrome type A, is located at 9q22.3-q31.⁸⁸ Nearby, at 9q22.3 resides PTCH, a candidate gene for basal cell nevus syndrome characterized by postnatal cell carcinomas and developmental abnormalities.⁸⁹

Chromosome 10

Although no tumor suppressor gene has been mapped to 10p, both functional studies and direct analysis of human tumors strongly support the idea that at least one, and possibly two, tumor suppressor genes for prostate cancer and human gliomas are present on 10p.^90,91

Recent studies of the 10q23 region have led to the isolation of a candidate tumor suppressor gene, PTEN (phosphatase and tensin homolog), that appears to be mutated at a considerably high frequency in human cancers, eg, in breast cancer and thyroid cancer. In preliminary screenings, mutations of PTEN have been detected in glioblastoma, prostate cancer, breast cancer, and endometrial carcinoma.^92-94 Moreover, the 10q region is known to contain the MXI1 gene assigned to 10q24-q25. The MXI1 (MAX-interacting protein 1) gene may negatively regulate CMYC oncogene (V-MYC avian myelocytomatosis viral oncogene homolog) activity and have a tumor suppressing function. Altered MXI1 function as such might contribute to tumorigenesis.^95,96

Chromosome 11

The short arm of chromosome 11 harbors a number of known tumor suppressor genes, eg, WT1 (Wilms' tumor 1) at 11p13 and WT2 (Wilms' tumor 2) and a cyclin-dependent kinase inhibitor (CDKN1C) at 11p15.5, a tumor susceptibility gene 101 (TSG101) at 11p15.1–p15.2, a metastasis suppressor gene for prostate cancer KAI1 (Kangai 1) at 11p11.2, and a putative tumor suppressor gene EXT2 at 11p11-p12. Furthermore, a liver tumor suppressor gene has been localized at 11p11.2-p12.⁹⁷ It is not known whether these genes are lost in the above-mentioned tumor types, but the involvement of the known tumor suppressor genes or novel genes deserves further study.

In breast cancer, CGH studies have shown that the entire 11q or the region at 11q14-qter are most commonly affected. In several tumors, the minimal common region of 11q deletion has been mapped to 11q22-q23 by LOH studies.^98-107

11q is a very gene-rich area but contains only a few identified tumor suppressor genes. The ATM (11q22.3, ataxia telangiectasia mutated) gene, altered in some forms of leukemia, has a role in cell cycle check point control, genome surveillance, and cellular defense against oxidative stress, and has been considered to function as a tumor suppressor gene.¹⁰⁸ Recently PPP2R1B [protein phosphatase 2 (formerly ZA at 11q22-q24), regulatory subunit A(PR6) ß isoform], a gene which encodes a subunit for serine/threonine protein phosphatase, was identified as a putative tumor suppressor gene in lung and colon cancer.¹⁰⁹ In most cases the mutation in one allele was accompanied by the deletion of the other allele. MEN1, a gene located at 11q13, is defective in multiple endocrine neoplasia type 1 which is characterized by the occurrence of tumors of the parathyroid glands, the pancreas, and the pituitary gland.

Chromosome 12

The 12p13 region contains the TEL [for translocation, E Twenty-six Specific (ETS), leukemia] (ETV6) gene, which encodes a member of the ETS-like family of transcription factors.¹¹⁰ In the cryptic translocation t(12;21) (p13;q22) of childhood acute lymphoblastic leukemia (ALL), TEL is fused to the AML1 gene.^111,112 AML1 encodes a DNA-binding subunit of the AML1/CBFB transcription factor complex.¹¹³ This translocation is the most common molecular genetic aberration of childhood ALL, occurring in approximately 25% of the patients, and it is associated with a favorable outcome.^114-118 The nontranslocated allele of TEL is frequently deleted in connection with the translocation.^119,120 Raynaud et al¹²¹ showed this deletion to be a secondary event that occurred after the translocation. Cavé et al¹²⁰ reported deletion of TEL in 34 of 44 patients with t(12;21) (77%). In contrast, homozygous deletion of TEL is a rare event in childhood ALL.¹¹⁹ 12q13 harbors also a cyclin-dependent kinase inhibitor, CDKN1B, that using a mouse model has been shown to have a role in cell proliferation control. So far, little is known of putative candidate genes located at 12q.

Chromosome 13

RB1 (retinoblastoma 1) at 13q14.3 is one of the best studied tumor suppressor genes.^122-124 Hereditary retinoblastoma is caused by a germline mutation of RB1.^125,126 This finding gave support to the two-hit hypothesis proposed by Knudson in 1971.¹ RB1 is defective in several cancers, eg, osteosarcoma, soft tissue sarcoma, small-cell lung carcinoma, breast, and bladder cancer.¹²²

13q14 contains the recently reported genes LEU1 (leukemia associated gene 1) and LEU2 (leukemia associated gene 2) which are strong candidates as tumor suppressor genes relevant to chronic lymphocytic leukemia.¹²⁷ 13q14 losses in this region have been detected by CGH in 11 to 12% of chronic lymphocytic leukemia.^128,129

Germline mutations in BRCA2 (13q12.3; breast cancer 2) confer an increased risk for breast cancer.^130,131 Germline mutations predispose the carriers also to ovarian cancer, prostate cancer, and male breast cancer. A CGH study of breast cancers from mutation carriers revealed a loss at the BRCA2 locus at a high frequency (73%), indicating the loss of the wild-type allele.¹³²

ING1 (inhibitor of growth 1), a candidate tumor suppressor gene, was recently cloned and mapped to 13q34.^133,134 This region is known to contain alterations in squamous cell carcinomas of the head and neck.¹³⁵ By CGH, losses in this region have been detected in 50% of squamous cell carcinoma of the head and neck.¹³⁶

Chromosome 14

There is no known tumor suppressor gene at 14q. Several LOH studies at 14q have been performed on different tumors. Analyses on ovarian and bladder carcinomas have shown similar results revealing two regions, one at 14q12-q13 and another at 14q32, to be the most frequent areas to show LOH.^137,138 14q32.1-q32.2 was also found to exhibit LOH in renal oncocytomas.¹³⁹ 14q23-q24.3 and 14q24.2-qter were implicated as regions for frequent deletions in renal oncocytomas and nonpapillary renal cell carcinomas, respectively.^139,140 These data implicate the possibility of several tumor suppressor genes at 14q, which could be important in many different types of tumor.

Chromosome 15

It has been suggested that a putative tumor suppressor gene, which may play a role in the later stages of carcinogenesis and be associated with metastasis in breast cancer, is located at 15q14.¹⁴¹

Chromosome 16

The level of RB2/p130 (16q12.2, retinoblastoma-like 2) expression is inversely related to histological grade and the development of metastases in lung cancer,¹⁴² and a decreased level of pRb2/p130 is associated with increased risk of recurrence and death in endometrial cancer.¹⁴³ Expression of CMAR (16q24.3; cell matrix adhesion regulator) mRNA is frequently diminished in colorectal cancer¹⁴⁴ and in hepatocellular carcinoma.¹⁴⁵ Recently a putative tumor suppressor gene CTCF (CCCTC-binding factor) has been localized to 16q22.1 and it is a candidate for breast cancer tumorigenesis.¹⁴⁶ Mutations including large deletions in TSC2 (tuberous sclerosis 2), located at 16p13.3, are found in patients with tuberous sclerosis, indicating its role to act as a tumor suppressor.¹⁴⁷ E-cadherin, the CDH1 gene (16q22.1, cadherin 1) has been suggested to act as a tumor/invasion suppressor for sporadic infiltrative lobular breast carcinomas.¹⁴⁸ H-cadherin, the CDH13 gene (16q24.2-q23, cadherin 13), has been reported to be inactivated due to deletions and hypermethylations in lung cancer.¹⁴⁹

Chromosome 17

One of the best known tumor suppressor genes, TP53, is located at 17p13.¹⁵⁰ It codes for a protein, p53, that acts as a transcription factor and prevents damaged DNA from replicating.^151,152 Losses or other inactivating mutations in TP53 are possibly the most common genetic changes in cancer.^153,154 Other well known tumor suppressor genes located at chromosome 17 are BRCA1 (breast cancer 1) (17q21) and NF1 (neurofibromatosis 1) (17q11.2). BRCA1 codes for a component of the RNA polymerase II holoenzyme.¹⁵⁵ Mutations in BRCA1 are thought to be responsible for 52% of inherited breast cancer and 81% of inherited breast and ovarian cancer.¹⁵⁶ NF1 codes for neurofibromin, which stimulates the GTPase activity of ras.¹⁵⁷ Mutations in neurofibromin are associated with type 1 neurofibromatosis.

Chromosome 18

The band q21 includes two known tumor suppressor genes, DPC4 (deleted in pancreatic carcinoma 4) (SMAD4) and DCC (deleted in colorectal cancer). DPC4, a member of the MAD gene family, is involved in signal transduction of serine threonine kinase receptors.¹⁵⁸ Its inactivation occurs in almost half of pancreatic carcinomas¹⁵⁸ but is uncommon in other tumor types.^159-161 However, studies in colorectal cancer cells and DPC4 mutated mice have suggested that DPC4 has a role in the progression of colorectal tumors.^162,163 The DCC gene (deleted in colorectal cancer) encodes a netrin receptor.¹⁶⁴ Recently, DCC has been found to induce apoptosis in the absence of ligand binding.¹⁶⁵ Originally, deletions and mutations of DCC have been found in colorectal carcinomas.¹⁶⁶ Moreover, inactivation of DCC has been found in breast, prostate, pancreatic, and gastric cancer, in glioma and osteosarcoma, and in some hematological malignancies.^167-173 The 18q21 region harbors also another member of the MAD gene family, MADR2 (MAD-related protein 2) (SMAD2), which has been proposed to be a tumor suppressor gene.¹⁷⁴ No currently known tumor suppressor gene has been assigned to 18p.

Chromosome 19

A serine/threonine kinase STK11/LKB1 (19p13.3), found to be responsible for the Peutz-Jeghers syndrome, has been cloned recently.⁴ STK11/LKB1 is the first example of cloning in which the role of CGH was essential in indicating the chromosomal location.¹⁷⁵ Another candidate gene in 19 is EXT3 [exostoses (multiple) 3]. By using linkage analysis, one of the loci of hereditary multiple exostoses, EXT3, has been assigned to 19p.¹⁷⁶ It has been suggested that EXT3 has tumor suppressing functions. Cyclin-dependent kinase inhibitor 2D (19p13; CDKN2D) belongs to the INK4 family. One member of the INK4 family, CDKN2A, has been shown to function as a tumor suppressor in a variety of cancers (Table 1).

The BAX (BCL2-associated X protein) gene (19q13.3) is a primary-response gene for p53, involved in a p53-regulated pathway for induction of apoptosis.¹⁷⁷ BAX forms heterodimers with BCL2 and reduces the death-repressing activity of BCL2.¹⁷⁸ The gene coding for ZIP kinase is also located in 19q13.3. ZIP kinase induces morphological changes in apoptosis in mammalian cells when overexpressed, suggesting that it plays an important role in the induction of apoptosis.¹⁷⁹ Three functionally related genes, XRCC1 (X-ray-repair complementing defective in Chinese hamster 1),¹⁸⁰ ERCC1 (excision repair complementing defective repair in Chinese hamster 1),¹⁸¹ and ERCC2 (excision repair complementing defective repair in Chinese hamster 2),¹⁸² are located close to 19q13.2-q13.3. Several different lines of evidence have shown that these gene products play an important role in both UV cross-link repair and nucleotide excision repair.

Chromosome 20

Chromosome banding analysis has revealed recurrent deletions at 20q in myeloproliferative diseases and myeloid leukemias.² No CGH study of a large series of patients with these diseases has been reported so far.

No known tumor suppressor genes have been found in chromosome 20. Several candidate genes and novel ESTs (expressed sequence tags) have been identified in studies of deletions of chromosome 20q in myeloid disorders. The common deleted region (CDR) in cells of myeloid leukemia patients was narrowed down to 8 megabases at 20q12 by Wang et al¹⁸³ and a YAC contig was constructed on the CDR.¹⁸⁴ The plausible candidate genes in the CDR include PLCG1 (phospholipase C, 1), HNF4 (hepatocyte nuclear factor 4), TOP1 (topoisomerase 1), MYBB (myeloblastosis viral oncogene homolog-like 2), ADA (adenosine deaminase), and CD40.^183-186

Chromosome 21

No known tumor suppressor genes have been found on chromosome 21. Furthermore, evidence of any candidate gene for tumor suppression in this chromosome appears to be very scarce.

Chromosome 22

The long arm of chromosome 22 contains the tumor suppressor gene neurofibromatosis type 2 (NF2) at 22q12,¹⁸⁷ but there is also evidence for the presence of another putative tumor suppressor gene distal to NF2.¹⁸⁸

Chromosome X

No currently known tumor suppressor gene has been located to chromosome X. LOH studies of chromosome X on ovarian, endometrial, cervical, and breast cancer and on renal oncocytomas,^97,189-196 however, suggest that the chromosomal regions Xp11-p22, Xq12, X25-q26, and Xq28 could harbor tumor suppressor genes.

Chromosome Y

The genes involved with loss of Y have not yet been identified.

	Conclusion

Top Abstract Introduction Comparative Genomic... Recurrent DNA Copy Number... Known and Putative Tumor... Conclusion References

 
Our review (Table 2) shows that CGH has provided an enormous amount of data on DNA sequence copy number losses. Because the number of cases studied for many tumor types is less than 20, it is hardly possible to draw reliable conclusions based on the frequencies of losses. At this stage we can, however, conclude the following. Losses are found in all chromosome arms, but they seem to be relatively rare at 1q, 2p, 3q, 5p, 6p, 7p, 7q, 8q, 12p, and 20q (Figure 1) . Losses and their minimal common overlapping areas that were present in a great proportion of the 73 tumor entities reported in Table 2 are (in descending order of frequency): 9p23-p24 (48%), 13q21 (47%), 6q16 (44%), 6q26-q27 (44%), 8p23 (37%), 18q22-q23 (37%), 17p12-p13 (34%), 1p36.1 (34%), 11q23 (33%), 1p22 (32%), 4q32-qter (31%), 14q22-q23 (25%), 10q23 (25%), 10q25-qter (25%),15q21 (23%), 16q22 (23%), 5q21 (23%), 3p12-p14 (22%), 22q12 (22%), Xp21 (21%), Xq21 (21%), and 10p12 (20%).

The minimal overlapping areas presented above are merely approximations derived from the large number of original results. The reader should also take into consideration that in many original papers the results from subtelomeric and subcentromeric areas as well as from the problematic chromosomal regions at 1p, 16p, 17p, 19, 22, and Y have been interpreted with great caution. Despite the inaccuracy, the common losses are chromosomal areas in which essential (known and putative) tumor suppressor genes most probably reside. Relevant cancer genes or candidate genes have been discussed above in connection with each of the chromosomes under the heading Recurrent DNA Copy Number Losses.

Even when the above-mentioned common losses are seen in a wide variety of tumor entities, there seem to be tumor types that do not contain these losses or the frequency of these losses is very low. For example, in hematological neoplasms the loss at 11q23 seems to be restricted to mantle cell lymphoma and chronic lymphocytic leukemia. Losses at 7 and 20q are usually rare, but according to karyotype analysis these losses are recurrent in myeloid neoplasias. Excluding these examples, it is too early to draw conclusions about tumor-specific losses. Before the clinical significance of recurrent losses can be interpreted, more data need to be analyzed.

	Acknowledgements

 
We thank Pirjo Pennanen for essential help in preparing the manuscript.

	Footnotes

 
Address reprint requests to Sakari Knuutila, Ph.D., Department of Medical Genetics, Helsinki University Central Hospital, P.O.Box 404 (Haartmaninkatu 3, 4th floor), FIN-00029 HUCH, Helsinki, Finland. E-mail: sakari.knuutila{at}helsinki.fi

Supported by grants from the Finnish Cancer Society, Nordic Cancer Union, Helsinki University Hospital Research Fund, Leiras Research Foundation, Duodecim, and Sigrid Jusélius Foundation.

Accepted for publication May 22, 1999.

	References

Top Abstract Introduction Comparative Genomic... Recurrent DNA Copy Number... Known and Putative Tumor... Conclusion References

 

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