Cytogenetic analysis of pancreatic carcinomas: Intratumor heterogeneity and nonrandom pattern of chromosome aberrations
Corresponding Author
Ludmila Gorunova
Department of Clinical Genetics, University Hospital, Lund, Sweden
Department of Clinical Genetics, University Hospital, S-221 85 Lund, SwedenSearch for more papers by this authorMattias Höglund
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorÅke Andrén-Sandberg
Department of Surgery, University Hospital, Lund, Sweden
Search for more papers by this authorSigmund Dawiskiba
Department of Pathology and Cytology, University Hospital, Lund, Sweden
Search for more papers by this authorYuesheng Jin
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorFelix Mitelman
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorBertil Johansson
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorCorresponding Author
Ludmila Gorunova
Department of Clinical Genetics, University Hospital, Lund, Sweden
Department of Clinical Genetics, University Hospital, S-221 85 Lund, SwedenSearch for more papers by this authorMattias Höglund
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorÅke Andrén-Sandberg
Department of Surgery, University Hospital, Lund, Sweden
Search for more papers by this authorSigmund Dawiskiba
Department of Pathology and Cytology, University Hospital, Lund, Sweden
Search for more papers by this authorYuesheng Jin
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorFelix Mitelman
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorBertil Johansson
Department of Clinical Genetics, University Hospital, Lund, Sweden
Search for more papers by this authorAbstract
Twenty-nine nonendocrine pancreatic carcinomas (20 primary tumors and nine metastases) were studied by chromosome banding after short-term culture. Acquired clonal aberrations were found in 25 tumors and a detailed analysis of these revealed extensive cytogenetic intratumor heterogeneity. Apart from six carcinomas with one clone only, 19 tumors displayed from two to 58 clones, bringing the total number of clones to 230. Karyotypically related clones, signifying evolutionary variation, were found in 16 tumors, whereas unrelated clones were present in nine, the latter finding probably reflecting a distinct pathogenetic mechanism. The cytogenetic profile of pancreatic carcinoma was characterized by multiple numerical and structural changes. In total, more than 500 abnormal chromosomes, including rings, markers, homogeneously stained regions, and double minutes, altogether displaying 608 breakpoints, were detected. This complexity and heterogeneity notwithstanding, a nonrandom karyotypic pattern can be discerned in pancreatic cancer. Chromosomes 1, 3, 6, 7, 8, 11, 12, 17, and 19 and bands 1q12, 1q21, 3q11, 6p21, 6q21, 7q11, 7q22, 7q32, 11q13, 13cen, 14cen, 17q11, 17q21, and 19q13 were most frequently involved in structural rearrangements. A total of 19 recurrent unbalanced structural changes were identified, 11 of which were not reported previously: del(1)(q11), del(3)(p11), i(3)(q10), del(4)(q25), del(11)(p13), dup(11)(q13q23), i(12)(p10), der(13;15)(q10;q10), del(18)(q12), del(18)(q21), and i(19)(q10). The main karyotypic imbalances were entire-copy losses of chromosomes 18, Y, and 21, gains of chromosomes 7, 2, and 20, partial or whole-arm losses of 1p, 3p, 6q, 8p, 9p, 15q, 17p, 18q, 19p, and 20p, and partial or whole-arm gains of 1q, 3q, 5p, 6p, 7q, 8q, 11q, 12p, 17q, 19q, and 20q. In general, the karyotypic pattern of pancreatic carcinoma fits the multistep carcinogenesis concept. The observed cytogenetic heterogeneity appears to reflect a multitude of interchangeable but oncogenetically equivalent events, and the nonrandomness of the chromosomal alterations underscores the preferential pathways involved in tumor initiation and progression. Genes Chromosomes Cancer 23:81–99, 1998. © 1998 Wiley-Liss, Inc.
References
- Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53: 549–554.
- Bardi G, Johansson B, Pandis N, Mandahl N, Bak-Jensen E, Andrén-Sandberg A, Mitelman F, Heim S (1993) Karyotypic abnormalities in tumours of the pancreas. Br J Cancer 67: 1106–1112.
- Bardi G, Åman P, Johansson B, Pandis N, Mandahl N, Bak-Jensen E, Björkman A, Sjögren HO, Andrén-Sandberg Å, Mitelman F, Heim S (1994) Cytogenetic characterization of a periampullary adenocarcinoma of the pancreas, its liver metastasis, and a cell line established from the metastasis in a patient with Gardner's syndrome. Cancer Genet Cytogenet 76: 29–32.
- Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA Jr, Goodfellow PJ (1995) Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. Genes Chromosomes Cancer 14: 189–195.
- Brat DJ, Hahn SA, Griffin CA, Yeo CJ, Kern SE, Hruban RH (1997) The structural basis of molecular genetic deletions. An integration of classical cytogenetic and molecular analyses in pancreatic carcinoma. Am J Pathol 150: 383–391.
- Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE (1994) Frequent somatic mutations and homozygous deletions of p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8: 27–32.
- Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR (1996) Amplification of AKT2 in human pancreatic cancer cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 93: 3636–3641.
- Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui L-C, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL, Attisano L (1996) MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86: 543–552.
- Fazeli A, Dickinson SL, Hermiston ML, Tighe RV, Steen RG, Small CG, Stoeckli E, Keino-Masu K, Masu M, Rayburn H, Simons J, Bronson RT, Gordon JI, Tessier-Lavigne M, Weinberg RA (1997) Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386: 796–804.
-
Fukushige S,
Waldman FM,
Kimura M,
Abe T,
Furukawa T,
Sunamura M,
Kobari M,
Horii A
(1997)
Frequent gain of copy number on the long arm of chromosome 20 in human pancreatic adenocarcinoma.
Genes Chromosomes Cancer
19:
161–169.
10.1002/(SICI)1098-2264(199707)19:3<161::AID-GCC5>3.0.CO;2-W CAS PubMed Web of Science® Google Scholar
- Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger H (1997) Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 57: 1634–1637.
- Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE (1996) Germline BRCA2 mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56: 5360–5364.
- Gorunova L, Johansson B, Dawiskiba S, Andrén-Sandberg Å, Jin Y, Mandahl N, Heim S, Mitelman F (1995) Massive cytogenetic heterogeneity in a pancreatic carcinoma: Fifty-four karyotypically unrelated clones. Genes Chromosomes Cancer 14: 259–266.
- Griffin CA, Hruban RH, Long PP, Morsberger LA, Douna-Issa F, Yeo CJ (1994) Chromosome abnormalities in pancreatic adenocarcinoma. Genes Chromosomes Cancer 9: 93–100.
- Griffin CA, Hruban RH, Morsberger LA, Ellingham T, Long PP, Jaffee EM, Hauda KM, Bohlander SK, Yeo CJ (1995) Consistent chromosome abnormalities in adenocarcinoma of the pancreas. Cancer Res 55: 2394–2399.
- Hahn SA, Seymour AB, Hoque ATMS, Schutte M, da Costa LT, Redston MS, Caldas C, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE (1995) Allelotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res 55: 4670–4675.
- Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271: 350–353.
- Heim S, Jin Y, Mandahl N, Biörklund A, Wennerberg J, Jonsson N, Mitelman F (1988) Multiple unrelated clonal chromosome abnormalities in an in situ squamous cell carcinoma of the skin. Cancer Genet Cytogenet 36: 149–153.
-
Höglund M,
Gorunova L,
Andrén-Sandberg Å,
Dawiskiba S,
Mitelman F,
Johansson B
(1998a)
Cytogenetic and fluorescence in situ hybridization analyses of chromosome 19 aberrations in pancreatic carcinomas: Frequent loss of 19p13.3 and gain of 19q13.1–13.2.
Genes Chromosomes Cancer
21:
8–16.
10.1002/(SICI)1098-2264(199801)21:1<8::AID-GCC3>3.0.CO;2-5 CAS PubMed Web of Science® Google Scholar
- Höglund M, Gorunova L, Jonson T, Dawiskiba S, Andrén-Sandberg Å, Stenman G, Johansson B (1998b) Cytogenetic and FISH analyses of pancreatic carcinoma reveal breaks in 18q10-11 with consistent loss of 18q12–ter and frequent gain of 18p. Br J Cancer 77: 1893–1899.
- Höhne MW, Halatsch M-E, Kahl GF, Weinel RJ (1992) Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res 52: 2616–2619.
- Hruban RH, van Mansfeld ADM, Offerhaus GJA, van Weering DHJ, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL (1993) K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143: 545–554.
- ISCN (1995) An International System for Human Cytogenetic Nomenclature. F Mitelman (ed). Basel: S. Karger.
- Jin Y, Mertens F, Mandahl N, Heim S, Olegård C, Wennerberg J, Biörklund A, Mitelman F (1993) Chromosome abnormalities in eighty-three head and neck squamous cell carcinomas: Influence of culture conditions on karyotypic pattern. Cancer Res 53: 2140–2146.
-
Johansson B,
Bardi G,
Heim S,
Mandahl N,
Mertens F,
Bak-Jensen E,
Andrén-Sandberg Å,
Mitelman F
(1992)
Nonrandom chromosomal rearrangements in pancreatic carcinomas.
Cancer
69:
1674–1681.
10.1002/1097-0142(19920401)69:7<1674::AID-CNCR2820690706>3.0.CO;2-L CAS PubMed Web of Science® Google Scholar
- Johansson B, Heim S, Mandahl N, Mertens F, Mitelman F (1993) Trisomy 7 in nonneoplastic cells. Genes Chromosomes Cancer 6: 199–205.
- Johansson B, Bardi G, Pandis N, Gorunova L, Bäckman PL, Mandahl N, Dawiskiba S, Andrén-Sandberg Å, Heim S, Mitelman F (1994) Karyotypic pattern of pancreatic adenocarcinomas correlates with survival and tumour grade. Int J Cancer 58: 8–13.
-
Kimura M,
Abe T,
Sunamura M,
Matsuno S,
Horii A
(1996)
Detailed deletion mapping on chromosome arm 12q in human pancreatic adenocarcinoma: Identification of a 1–cM region of common allelic loss.
Genes Chromosomes Cancer
17:
88–93.
10.1002/(SICI)1098-2264(199610)17:2<88::AID-GCC3>3.0.CO;2-X CAS PubMed Web of Science® Google Scholar
- Klöppel G, Maillet B (1989) Classification and staging of pancreatic nonendocrine tumors. Radiol Clin North Am 27: 105–119.
-
Mahlamäki EH,
Höglund M,
Gorunova L,
Karhu R,
Dawiskiba S,
Andrén-Sandberg Å,
Kallioniemi O-P,
Johansson B
(1997)
Comparative genomic hybridization reveals frequent gains of 20q, 8q, 11q, 12p, and 17q and losses of 18q, 9p, and 15q in pancreatic cancer.
Genes Chromosomes Cancer
20:
383–391.
10.1002/(SICI)1098-2264(199712)20:4<383::AID-GCC10>3.0.CO;2-O CAS PubMed Web of Science® Google Scholar
- Mitelman F (1998) Catalog of Chromosome Aberrations in Cancer, 6th ed. New York: Wiley-Liss.
- Mitelman F, Johansson B, Mandahl N, Mertens F (1997a) Clinical significance of cytogenetic findings in solid tumors. Cancer Genet Cytogenet 95: 1–8.
- Mitelman F, Mertens F, Johansson B (1997b) A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet 15: 417–474.
- Miwa W, Yasuda J, Murakami Y, Yashima K, Sugano K, Sekine T, Kono A, Egawa S, Yamaguchi K, Hayashizaki Y, Sekiya T (1996) Isolation of DNA sequences amplified at chromosome 19q13.1–q 13.2 including the AKT2 locus in human pancreatic cancer. Biochem Biophys Res Commun 225: 968–974.
- Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194: 23–28.
- Ohta M, Inoue H, Cotticelli MH, Kastury K, Baffa R, Palazzo J, Siprashivili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K (1996) The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587–597.
-
Panagopoulos I,
Thelin S,
Mertens F,
Mitelman F,
Åman P
(1997)
Variable FHIT transcripts in non-neoplastic tissues.
Genes Chromosomes Cancer
19:
215–219.
10.1002/(SICI)1098-2264(199708)19:4<215::AID-GCC2>3.0.CO;2-# CAS PubMed Web of Science® Google Scholar
- Pandis N, Jin Y, Gorunova L, Petersson C, Bardi G, Idvall I, Johansson B, Ingvar C, Mandahl N, Mitelman F, Heim S (1995) Chromosome analysis of 97 primary breast carcinomas: Identification of eight karyotypic subgroups. Genes Chromosomes Cancer 12: 173–185.
- Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JKV, Markowitz SD, Kinzler KW, Vogelstein B (1996) Mad-related genes in the human. Nat Genet 13: 347–349.
- Ruggeri B, Zhang S-Y, Caamano J, DiRado M, Flynn SD, Klein-Szanto AJP (1992) Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumor-suppressor genes. Oncogene 7: 1503–1511.
- Scarpa A, Capelli P, Mukai K, Zamboni G, Oda T, Iacono C, Hirohashi S (1993) Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol 142: 1534–1543.
- Schutte M, da Costa LT, Hahn SA, Moskaluk C, Hoque ATMS, Rozenblum E, Weinstein CL, Bittner M, Meltzer PS, Trent JM, Yeo CJ, Hruban RH, Kern SE (1995) Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci USA 92: 5950–5954.
- Schuuring E (1995) The involvement of the chromosome 11q13 region in human malignancies: Cyclin D1 and EMS1 are two new candidate oncogenes—A review. Gene 159: 83–96.
-
Schwab M,
Praml C,
Amler LC
(1996)
Genomic instability in 1p and human malignancies.
Genes Chromosomes Cancer
16:
211–229.
10.1002/(SICI)1098-2264(199608)16:4<211::AID-GCC1>3.0.CO;2-0 CAS PubMed Web of Science® Google Scholar
- Seymour AB, Hruban RH, Redston M, Caldas C, Powell SM, Kinzler KW, Yeo CJ, Kern SE (1994) Allelotype of pancreatic adenocarcinoma. Cancer Res 54: 2761–2764.
- Shridhar R, Shridhar V, Wang X, Paradee W, Dugan M, Sarkar F, Wilke C, Glover TW, Vaitkevicius VK, Smith DI (1996) Frequent breakpoints in the 3p14.2 fragile site, FRA3B, in pancreatic tumors. Cancer Res 56: 4347–4350.
- Solinas-Toldo S, Wallrapp C, Müller-Pillasch F, Bentz M, Gress T, Lichter P (1996) Mapping of chromosomal imbalances in pancreatic carcinoma by comparative genomic hybridization. Cancer Res 56: 3803–3807.
- Sporn MB (1996) The war on cancer. Lancet 347: 1377–1381.
- Uchida K, Nagatake M, Osada H, Yatabe Y, Kondo M, Mitsudomi T, Masuda A, Takahashi T, Takahashi T (1996) Somatic in vivo alterations of the JV18–1 gene at 18q21 in human lung cancers. Cancer Res 56: 5583–5585.
-
van den Berg A,
Draaijers TG,
Kok K,
Timmer T,
Van der Veen AY,
Veldhuis PMJF,
de Leij L,
Gerhartz CD,
Naylor SL,
Smith DI,
Buys CHCM
(1997)
Normal FHIT transcripts in renal cell cancer-and lung cancer-derived cell lines, including a cell line with a homozygous deletion in the FRA3B region.
Genes Chromosomes Cancer
19:
220–227.
10.1002/(SICI)1098-2264(199708)19:4<220::AID-GCC3>3.0.CO;2-Z CAS PubMed Web of Science® Google Scholar
- Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9: 138–141.
- Warshaw AL, Fernández-del Castillo C (1992) Pancreatic carcinoma. N Engl J Med 326: 455–465.
- Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK Jr, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Erlich GD (1996a) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14: 141–145.
- Whitcomb DC, Preston RA, Aston CE, Sossenheimer MJ, Barua PS, Zhang Y, Wong-Chong A, White GJ, Wood PG, Gates LK Jr, Ulrich CD, Martin SP, Post JC, Erlich GD (1996b) A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110: 1975–1980.
