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Deletion (5q) in a desmoid tumor of a patient with Gardner's syndrome
Deletion (5q) in a Desmoid Tumor of a Patient with Gardner's Syndrome Astrid Dangel, Aurelia M. Meloni, Henry T. Lynch, and Avery A. Sandberg
ABSTRACT: Desmoid tumors are associated with as many as 20% of cases of familial adenomatous polyposis (FAP) and Gardner's syndrome. In the present study, four specimens from different regions of a massive intraabdominal desmoid tumor from a 23-year-old white male with Gardner's syndrome were analyzed cytogenetically. Two different clonal abnormalities were observed. Two of the four specimens analyzed showed a del(5)(q14q31), which involves the region q21-'22 where the familial adenomatous polyposis gene is localized. In the two other specimens, a balanced translocation involving chromosomes 3 and 4 and an inv(4) was detected. Ourfindings confirm previous reports about the importance of chromosome defects on 5q in development of desmoid tumors, particularly in patients with Gardner's syndrome.
INTRODUCTION Desmoid tumors, also known as aggressive fibromatoses, are primarily derived from mesenchymal cells, e.g., fascial sheaths and musculoaponeurotic structures. Despite a destructive growth pattern including infilt3"ation of the surrounding tissue, desmoid tumors are generally considered benign fibrous tissue tumors that do not metastasize [1]. The pathogenesis of these tumors remains uncertain: trauma, genetic, and endocrine factors have been implicated to play an important role [2, 3]. Desmoid tumors occur predominantly in the abdominal region, but may also occur at other sites throughout the body. They occur in approximately 8-20% of cases diagnosed with familial adenomatous polyposis (FAP) and Gardner's syndrome and commonly occur after colectomy, predominantly in small bowel mesentery and/or abdominal wall [4]. Gardner's syndrome manifests itself as FAP combined with extracolonic lesions, including osteomas, epidermoid cysts, fibromas, and lipomas inherited as an autosomal dominant trait [5]. Separating these two syndromes has become increasingly difficult, however, because extraintestinal manifestations of Gardner's syndrome may vary and extracolonic lesions in FAP are now diagnosed more frequently, possibly suggesting that both syndromes are variable expressions of a single disease process caused by the same genetic defect. In both syndromes, numerous adenomatous colonic polyps
From The Cancer Center, Southwest Biomedical Research Institute, Scottsdale, Arizona (A. D., A. M. M., A. A. S.), and Creighton University, School of Medicine, Omaha, Nebraska (H. T. L.). Address reprint requests to: A. A. Sandberg, M.D., The Cancer Center, Southwest Biomedical Research Institute. 6401 E. Thomas Road, Scottsdale, AZ 85251. Received March 11. 1994: accepted May 18. 1994.
94 Cancer Genet Cytogenet78:94-98 (1994) 0165-4608/94/$07.00
arise in early adolescence, associated with a high risk of undergoing malignant transformation that is progressive with age and, if left untreated, reaches almost 100% [6]. Recently, the gene coding for FAP and Gardner's syndrome (FAP locus) was mapped to the long arm of chromosome 5 (5q21-'22) [7-9]. We cytogenetically analyzed four different specimens of an intraabdominal desmoid tumor to investigate the presence of chromosome abnormalities possibly involving the FAP locus in extracolonic lesions associated with Gardner's syndrome. Our results are discussed in relation to previously published cytogenetic results in the same type of tumor.
Case Report A 23-year-old white male was diagnosed with Gardner's syndrome and an intraabdominal desmoid tumor at age 14 years. Prophylactic subtotal colectomy disclosed multiple adenomatous colonic polyps, all of which proved benign. Family history showed the patient's mother and maternal grandmother to be affected with Gardner's syndrome. His mother underwent a prophylactic colectomy, yet developed an adenocarcinoma years later that led to her death. At age 20 years, the patient developed a large desmoid tumor in the rectus sheath. Tumor resection was followed by radiation treatment and chemotherapy. Three years later, he had multiple bacteremias and septicemias secondary to small bowel fistulas. Laparotomy for surgical resection of these fistulas showed a massive intraabdominal desmoid tumor encasing the bowel. Surgical resection was determined to be futile at that time. He was placed on a chemotherapy regimen including doxorubicin (90 mg/m 2) and dacarbazine (900 mg/m z) in divided doses for 4 days of continuous infusion repeated every 28 days for six cycles. He showed complete response to the chemotherapy [10]. Tumor samples ob-
© 1994Elsevier S(:ience Inc. 655 Avenueof the Americas. New York. NY 10010
Del(5q) in a Desmoid T u m o r
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Representative histologic appearance of the intraabdominal desmoid tumor. H&E x 200.
tained for pathologic evaluation confirmed the diagnosis of a d e s m o i d tumor with typical histologic appearance (Fig. 1); specimens from four different regions of the tumor were used for chromosome studies. MATERIALS
. . . . ....:.: ~ . : .
METHODS
Four samples of different regions of the massive intraabdominal d e s m o i d tumor were collected aseptically during surgery and transported in sterile m e d i u m . The diagnosis of a desmoid tumor was confirmed histologically. The specimens were processed according to previously described methods
[11]. Tumor samples were disaggregated overnight in collagenase (200 U/ml), and the resulting suspension was seeded in flasks and on coverslips. Cells were cultured in RPMI m e d i u m s u p p l e m e n t e d with 17% fetal bovine serum and 1% L-glutamine with 2 % antibiotics (penicillin 100 U/ml, streptomycin 100 ~g/ml) and incubated in a h u m i d i f i e d atmosphere at 37°C and 5% CO2. Harvesting was performed after 4-10 days in culture with Colcemid exposure, hypotonic shock, and fixation with methanol:acetic acid (3:1). Airdried chromosome preparations were G-banded with trypsin. The karyotypes were expressed according to the International System for Human Cytogenetic Nomenclature [12].
A. Dangel et al.
96
Table I
Sample
Consistent structural chromosome changes intraabdominal desmoid tumor in a patient Days in
No. of cells
culture
analyzed
1 2
10 10
7 13
3
4-10
15
4
10
20
in four different with Gardner’s
samples syndrome
of an
Karyotypes 7: 2: 10: 1: 11: 4: 18:
46,XY,de1(5)(q14q31) 46,XY 46,XY,de1(5)[q14q31)
45,XY,idem,del(7)(pl4),rea(4q) 46,XY 46,XY,der(3)t(3;4)(pll;pl6],der(4)t(3;4)(pll;pl6)inv(4)(pl2pl4) 46,XY
2: 46~XY,der(3)t(3;4)(pll;p16),der(4)t(3;4)(pl~;p~6)inv[4)(p~2p~4)
Figure 2
G-banded partial karyotypes showing chromosome
mal chromosomes
rearrangements
in the four samples analyzed. Abnor-
are at right.
Chromosome 5
sample 2
Sounple 3
Chrolnosome3
Chzamosome4
Del(5q) in a Desmoid T u m o r
97
RESULTS Seven to 20 metaphases were scored in each sample. Clonal structural abnormalities were observed in cells of all four samples of the desmoid tumor (Table 1). Two samples showed a del(5}lq14q31) as a consistent change in at least seven ceils (Fig. 2). The other two samples showed a balanced translocation involving chromosomes 3 and 4 as clonal change, i.e., t{3;4)(pll;p16). The der(4} involved in this translocation also showed an inversion of the short arm (Fig. 2).
DISCUSSION Desmoid tumors are fibroblastic lesions that grow locally; though they may be infiltrative, they usually do not metastasize. Because the tumors are believed to occur mainly as a reactive process secondary to traumatic or hormonal factors [21, some investigators do not consider them to be true neoplasms. Three reports on desmoid tumors published to date [13-15] have described clonal changes involving several chromosomes, suggesting that they may be a true neoplasm in which trauma and hormonal stimulation may play a p r e d i s p o s i n g role. Cytogenetic analysis of 29 d e s m o i d tumors has been reported in the literature; nine of them showed clonal structural and/or numerical chromosome abnormalities. In two separate studies, four desmoid tumors in patients diagnosed with Gardner's syndrome were i n c l u d e d (Table 2) [14, 15]. Gardner's syndrome is inherited as an autosomal dominant trait, and the genetic defect has been localized to the long arm of chromosome 5, most probably 5(q21"-*'22) [7-9]. Loss of heterozygosity (IX)H) on chromosome Nt has been reported in adenomatous p o l y p s a n d colon carcinomas from patients with and without FAP [16-20]. In the sequence of conversion from benign colon adenomas to malignant carcinomas, I.OH has been well demonstrated, in particular on chromosomes 5q, 17p, and 18q [17, 21]. Involvement of 5q as the only clonal c h r o m o s o m e change was also reported in two previously p u b l i s h e d cases of d e s m o i d tumors in Gardner's syndrome [14, 15]. In our study, two of four samples of the intraabdominal desmoid tumor showed a del(Sq) involving the FAP gene locus. This abnormality was not present in the two other tumor samples, which instead showed a balanced tram-
Table 2
Karyotypes of desmoid tumors from patients with Gardner's s y n d r o m e published in the literature Karyotypes
Reference
1: 46,XX,15p + c 5: 42-46,XX,15p + c,del(5}(q21q31), random changes 4: 45-47,X, - X,15p + c,del(5)(q21q31), random changes 20: 48,XX,del(5)Iq14q21) 8: 46,XY 12: 45,XY, + 8, random changes 11: 46,XY 3: 46,XY,del(11)(q22q24), random changes
[13]
[14] [14] [14]
location involving chromosomes 3 and 4 and an inv(4). These findings demonstrate that two different clonal chromosome abnormalities existed as primary changes in one d e s m o i d tumor, highlighting the possible importance of regional heterogeneity of these neoplasms. The normal FAP gene has been suggested to he a dominant negative regulator of growth of mesenchymal as well as epithelial ceils, and homozygous inactivation of this gone, either by mutation or deletion, may lead to development of desmoid tumors [22]. Bridge et al. [15] described del(5q) in two patients with nonhereditary desmoid tumors, but one of the deletions did not involve the FAP locus, which leads to the assumption that mutation or deletion of the FAP gone causes development of desmoid tumors in patients with and without Gardner's syndrome. Somatic mutations in mesenchymal cells involving the FAP locus may give rise to desmoid tumors in the absence of the FAP or Gardner's syndrome phenotype. Sen-Gupta et al. [22] reported a frameshift mutation of the FAP gene in a desmoid t u m o r of a patient with FAP, hypothetically leading to a truncated gene product. The possibility of such mutations of the FAP gene at the molecular level without cytogenetically detectable abnormality in the 5q region, as in two of the tumor regions we examined, cannot be excluded. Twenty of 29 previously reported desmoid tumors showed only normal and/or random structural/numerical changes. Further investigations of these tumors will be necessary to evaluate the importance of abnormalities involving chromosomes other than 5q. This study was supported by Grant No. Ca 41183 from the National Cancer Institute. The authors thank Dr. Julia Bridge for expertise in photographing a histologic section of the tumor and James Kowitz for photographing the chromosomes. REFERENCES
1. Chang AE, Rosenberg SA, Glatstein EJ, Antman KH 11989): Desmold tumors. In: Cancer Principles and Practice of Oncology, 3rd ed., VT De Vita, S Hellman, SA Rosenberg, eds. J.B. Lippincott, Philadelphia, pp. 1353-1354. 2. Hayry P, Reitamo JJ, Totterman S, Hopfner-Hallikainen D, Sivula A (1982): The desmoid tumor If: Analysis of factors possibly contributing to the etiology and growth behavior. Am J Clin Pathol 77:674-680. 3. Hayry P, Reitamo JJ, Vihko R, Janne O, Scheinin TM, Totterman S, Ahonen J, Norio R, Alanko A (1982): The desmoid tumor HI: A biochemical and genetic analysis. Am J Clin Patho177:681-685. 4. Jagelman 13(; (1967}:Extracolonic manifestations of familial polyposis coll. Cancer Genet Cytogenet 27:319-325. 5. Gardner EJ, Richards RC (1953): Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 5:139-14Z 6. Boland CR, Itzkowitz SH, Kim YS (1989): Colonic polyps and the gastrointestinal polyposis syndromes. In: Gastrointestinal Disease. 4th ed., MH Sleisenger, IS Fordtran, eds. W.B. Saunders, Philadelphia, pp. 1483-1518. 7. Bodmer WF, Bailey CJ, Bodmer J, Bussey HIR, Ellis A, German P, Lucibello FC, Murday VA, Rider SH, Scambler P, Sheer D, Solomon E, Spurt NK (1987): Localization of the gone for familial adenomatous polyposis on chromosome 5. Nature 328:614-616. 8. Leppert M, Dobbs M, Scambler P, O'Connell P, Nakamum Y, Stauffer D, Woodward S, Burr R, Hughes l, Gardner E, Lathrop
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15.
A. Dangel et al. M, Wasmuth J, Lalouel J-M, White R (1987): The gene tor familial polyposis colt maps to the long arm of chromosome 5. Science 238:1411-1413. Kinzler WK, Nilbert MC, Su L-K, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, Finniear R, Markham A, Groffen J, Boguski MS, Altschul SF, Horii A, Ando H, Miyoshi Y, Miki Y, Nishisho I, Nakamura Y (1991): Identification of FAP locus genes from chromosome 5q21. Science 253:661-665. Lynch HT, Fitzgibbons R Jr, Chong S, Cavalieri J, Lynch J, Wallace F (1994): Use of doxorubicin and dacarbazine for the management of unresectable intm-abdominal desmoid tumors in Gardner's syndrome. Dis Colon Rectum (in press). Limon J, Dal Cin P, Sandberg AA (1986): Application of long term collagenase disaggregation for cytogenetic analysis of human solid tumors. Cancer Genet Cytogenet 23:305-313. ISCN (1991): Guidelines for Cancer Cytogenetics: Supplement to An International System for Human Cytogenetic Nomenclature, F Mitelman, ed. S. Karger, Basel. Karlsson I, Mandahl N, Helm S, Rydholm A, Willen H, Mitelman F (1988): Complex chromosome rearrangements in an extraabdominal desmoid tumor. Cancer Genet Cytogenet 34: 241-245. Yoshida MA, Ikeuchi T, lwama T, Miyaki M, Mort T, Ushijima Y, Ham A, Miyakita M, Tonomura A (1991): Chromosome changes in desmoid tumors developed in patients with familial adenomatous polyposis. Jpn J Cancer Res 82:916-921. Bridge JA, Sreekantaiah C, Mouron B, Neff JR, Sandberg AA, Wolman SR (1992): Clonal chromosomal abnormalities in des-
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mold tumors. Implications for histopathogenesis. Cancer 69: 430-436. Miyaki M, Seki M, Okamoto M, Yamanaka A, Maeda Y, Tanaka K, Kikuchi R, Iwama T, Ikeuchi T, Tonomura A, Nakamum Y, White R, Miki Y, Utsunomiya J, Koike M (1990): Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis. Cancer Res 50:7166-7173. Sasaki M, Okamoto M, Sato C, Sugio K, Soejima J, lwama T, lkeuchi T, Tonomura A, Miyaki M, Sasazuki T (1989): Loss of constitutional heterozygosity in colorectal tumors from patients with familial polyposis colt and those with nonpolyposis colorectal carcinoma. Cancer Res 49:4402-4406. Miki Y, Nishisho I, Miyoshi Y, Utsunomiya J, Nakamura Y (1992): Interstitial loss of the same region of 5q in multiple adenomas and a carcinoma derived from an adenomatous polyposis colt (APC) patient. Genes Chromosomes Cancer 4:81-83. Okamoto M, Sasaki M, Sugio K, Sato C, lwama T, lkeuchi T, Tonomura A, Sasazuki T, Miyaki M (1988): Loss of constitutional heterozygosity in colon carcinoma from patients with familial polypsosis colt. Nature 331:273-277. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AMM, Bos JL (1988): Genetic alterations during colorectal-tumor development. N Engl J Med 319:525-532. Fearon ER, Vogelstein B (1990): A genetic model for colorectal tumorigenesis. Cell 61:759-767. Sen-Gupta S, van der Luijt RB, Bowles LV, Meera Khan P, Delhanty JDA (1993): Somatic mutation of APC gene in desmoid tumour in familial adenomatous polyposis. Lancet 342:552-553.
ABSTRACT: Desmoid tumors are associated with as many as 20% of cases of familial adenomatous polyposis (FAP) and Gardner's syndrome. In the present study, four specimens from different regions of a massive intraabdominal desmoid tumor from a 23-year-old white male with Gardner's syndrome were analyzed cytogenetically. Two different clonal abnormalities were observed. Two of the four specimens analyzed showed a del(5)(q14q31), which involves the region q21-'22 where the familial adenomatous polyposis gene is localized. In the two other specimens, a balanced translocation involving chromosomes 3 and 4 and an inv(4) was detected. Ourfindings confirm previous reports about the importance of chromosome defects on 5q in development of desmoid tumors, particularly in patients with Gardner's syndrome.
INTRODUCTION Desmoid tumors, also known as aggressive fibromatoses, are primarily derived from mesenchymal cells, e.g., fascial sheaths and musculoaponeurotic structures. Despite a destructive growth pattern including infilt3"ation of the surrounding tissue, desmoid tumors are generally considered benign fibrous tissue tumors that do not metastasize [1]. The pathogenesis of these tumors remains uncertain: trauma, genetic, and endocrine factors have been implicated to play an important role [2, 3]. Desmoid tumors occur predominantly in the abdominal region, but may also occur at other sites throughout the body. They occur in approximately 8-20% of cases diagnosed with familial adenomatous polyposis (FAP) and Gardner's syndrome and commonly occur after colectomy, predominantly in small bowel mesentery and/or abdominal wall [4]. Gardner's syndrome manifests itself as FAP combined with extracolonic lesions, including osteomas, epidermoid cysts, fibromas, and lipomas inherited as an autosomal dominant trait [5]. Separating these two syndromes has become increasingly difficult, however, because extraintestinal manifestations of Gardner's syndrome may vary and extracolonic lesions in FAP are now diagnosed more frequently, possibly suggesting that both syndromes are variable expressions of a single disease process caused by the same genetic defect. In both syndromes, numerous adenomatous colonic polyps
From The Cancer Center, Southwest Biomedical Research Institute, Scottsdale, Arizona (A. D., A. M. M., A. A. S.), and Creighton University, School of Medicine, Omaha, Nebraska (H. T. L.). Address reprint requests to: A. A. Sandberg, M.D., The Cancer Center, Southwest Biomedical Research Institute. 6401 E. Thomas Road, Scottsdale, AZ 85251. Received March 11. 1994: accepted May 18. 1994.
94 Cancer Genet Cytogenet78:94-98 (1994) 0165-4608/94/$07.00
arise in early adolescence, associated with a high risk of undergoing malignant transformation that is progressive with age and, if left untreated, reaches almost 100% [6]. Recently, the gene coding for FAP and Gardner's syndrome (FAP locus) was mapped to the long arm of chromosome 5 (5q21-'22) [7-9]. We cytogenetically analyzed four different specimens of an intraabdominal desmoid tumor to investigate the presence of chromosome abnormalities possibly involving the FAP locus in extracolonic lesions associated with Gardner's syndrome. Our results are discussed in relation to previously published cytogenetic results in the same type of tumor.
Case Report A 23-year-old white male was diagnosed with Gardner's syndrome and an intraabdominal desmoid tumor at age 14 years. Prophylactic subtotal colectomy disclosed multiple adenomatous colonic polyps, all of which proved benign. Family history showed the patient's mother and maternal grandmother to be affected with Gardner's syndrome. His mother underwent a prophylactic colectomy, yet developed an adenocarcinoma years later that led to her death. At age 20 years, the patient developed a large desmoid tumor in the rectus sheath. Tumor resection was followed by radiation treatment and chemotherapy. Three years later, he had multiple bacteremias and septicemias secondary to small bowel fistulas. Laparotomy for surgical resection of these fistulas showed a massive intraabdominal desmoid tumor encasing the bowel. Surgical resection was determined to be futile at that time. He was placed on a chemotherapy regimen including doxorubicin (90 mg/m 2) and dacarbazine (900 mg/m z) in divided doses for 4 days of continuous infusion repeated every 28 days for six cycles. He showed complete response to the chemotherapy [10]. Tumor samples ob-
© 1994Elsevier S(:ience Inc. 655 Avenueof the Americas. New York. NY 10010
Del(5q) in a Desmoid T u m o r
95
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Figure
1
"~
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AND
,,,...
Representative histologic appearance of the intraabdominal desmoid tumor. H&E x 200.
tained for pathologic evaluation confirmed the diagnosis of a d e s m o i d tumor with typical histologic appearance (Fig. 1); specimens from four different regions of the tumor were used for chromosome studies. MATERIALS
. . . . ....:.: ~ . : .
METHODS
Four samples of different regions of the massive intraabdominal d e s m o i d tumor were collected aseptically during surgery and transported in sterile m e d i u m . The diagnosis of a desmoid tumor was confirmed histologically. The specimens were processed according to previously described methods
[11]. Tumor samples were disaggregated overnight in collagenase (200 U/ml), and the resulting suspension was seeded in flasks and on coverslips. Cells were cultured in RPMI m e d i u m s u p p l e m e n t e d with 17% fetal bovine serum and 1% L-glutamine with 2 % antibiotics (penicillin 100 U/ml, streptomycin 100 ~g/ml) and incubated in a h u m i d i f i e d atmosphere at 37°C and 5% CO2. Harvesting was performed after 4-10 days in culture with Colcemid exposure, hypotonic shock, and fixation with methanol:acetic acid (3:1). Airdried chromosome preparations were G-banded with trypsin. The karyotypes were expressed according to the International System for Human Cytogenetic Nomenclature [12].
A. Dangel et al.
96
Table I
Sample
Consistent structural chromosome changes intraabdominal desmoid tumor in a patient Days in
No. of cells
culture
analyzed
1 2
10 10
7 13
3
4-10
15
4
10
20
in four different with Gardner’s
samples syndrome
of an
Karyotypes 7: 2: 10: 1: 11: 4: 18:
46,XY,de1(5)(q14q31) 46,XY 46,XY,de1(5)[q14q31)
45,XY,idem,del(7)(pl4),rea(4q) 46,XY 46,XY,der(3)t(3;4)(pll;pl6],der(4)t(3;4)(pll;pl6)inv(4)(pl2pl4) 46,XY
2: 46~XY,der(3)t(3;4)(pll;p16),der(4)t(3;4)(pl~;p~6)inv[4)(p~2p~4)
Figure 2
G-banded partial karyotypes showing chromosome
mal chromosomes
rearrangements
in the four samples analyzed. Abnor-
are at right.
Chromosome 5
sample 2
Sounple 3
Chrolnosome3
Chzamosome4
Del(5q) in a Desmoid T u m o r
97
RESULTS Seven to 20 metaphases were scored in each sample. Clonal structural abnormalities were observed in cells of all four samples of the desmoid tumor (Table 1). Two samples showed a del(5}lq14q31) as a consistent change in at least seven ceils (Fig. 2). The other two samples showed a balanced translocation involving chromosomes 3 and 4 as clonal change, i.e., t{3;4)(pll;p16). The der(4} involved in this translocation also showed an inversion of the short arm (Fig. 2).
DISCUSSION Desmoid tumors are fibroblastic lesions that grow locally; though they may be infiltrative, they usually do not metastasize. Because the tumors are believed to occur mainly as a reactive process secondary to traumatic or hormonal factors [21, some investigators do not consider them to be true neoplasms. Three reports on desmoid tumors published to date [13-15] have described clonal changes involving several chromosomes, suggesting that they may be a true neoplasm in which trauma and hormonal stimulation may play a p r e d i s p o s i n g role. Cytogenetic analysis of 29 d e s m o i d tumors has been reported in the literature; nine of them showed clonal structural and/or numerical chromosome abnormalities. In two separate studies, four desmoid tumors in patients diagnosed with Gardner's syndrome were i n c l u d e d (Table 2) [14, 15]. Gardner's syndrome is inherited as an autosomal dominant trait, and the genetic defect has been localized to the long arm of chromosome 5, most probably 5(q21"-*'22) [7-9]. Loss of heterozygosity (IX)H) on chromosome Nt has been reported in adenomatous p o l y p s a n d colon carcinomas from patients with and without FAP [16-20]. In the sequence of conversion from benign colon adenomas to malignant carcinomas, I.OH has been well demonstrated, in particular on chromosomes 5q, 17p, and 18q [17, 21]. Involvement of 5q as the only clonal c h r o m o s o m e change was also reported in two previously p u b l i s h e d cases of d e s m o i d tumors in Gardner's syndrome [14, 15]. In our study, two of four samples of the intraabdominal desmoid tumor showed a del(Sq) involving the FAP gene locus. This abnormality was not present in the two other tumor samples, which instead showed a balanced tram-
Table 2
Karyotypes of desmoid tumors from patients with Gardner's s y n d r o m e published in the literature Karyotypes
Reference
1: 46,XX,15p + c 5: 42-46,XX,15p + c,del(5}(q21q31), random changes 4: 45-47,X, - X,15p + c,del(5)(q21q31), random changes 20: 48,XX,del(5)Iq14q21) 8: 46,XY 12: 45,XY, + 8, random changes 11: 46,XY 3: 46,XY,del(11)(q22q24), random changes
[13]
[14] [14] [14]
location involving chromosomes 3 and 4 and an inv(4). These findings demonstrate that two different clonal chromosome abnormalities existed as primary changes in one d e s m o i d tumor, highlighting the possible importance of regional heterogeneity of these neoplasms. The normal FAP gene has been suggested to he a dominant negative regulator of growth of mesenchymal as well as epithelial ceils, and homozygous inactivation of this gone, either by mutation or deletion, may lead to development of desmoid tumors [22]. Bridge et al. [15] described del(5q) in two patients with nonhereditary desmoid tumors, but one of the deletions did not involve the FAP locus, which leads to the assumption that mutation or deletion of the FAP gone causes development of desmoid tumors in patients with and without Gardner's syndrome. Somatic mutations in mesenchymal cells involving the FAP locus may give rise to desmoid tumors in the absence of the FAP or Gardner's syndrome phenotype. Sen-Gupta et al. [22] reported a frameshift mutation of the FAP gene in a desmoid t u m o r of a patient with FAP, hypothetically leading to a truncated gene product. The possibility of such mutations of the FAP gene at the molecular level without cytogenetically detectable abnormality in the 5q region, as in two of the tumor regions we examined, cannot be excluded. Twenty of 29 previously reported desmoid tumors showed only normal and/or random structural/numerical changes. Further investigations of these tumors will be necessary to evaluate the importance of abnormalities involving chromosomes other than 5q. This study was supported by Grant No. Ca 41183 from the National Cancer Institute. The authors thank Dr. Julia Bridge for expertise in photographing a histologic section of the tumor and James Kowitz for photographing the chromosomes. REFERENCES
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