Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1992 Oct;141(4):797–804.

The relationship of quantitative nuclear morphology to molecular genetic alterations in the adenoma-carcinoma sequence of the large bowel.

J W Mulder 1, G J Offerhaus 1, E P de Feyter 1, J J Floyd 1, S E Kern 1, B Vogelstein 1, S R Hamilton 1
PMCID: PMC1886650  PMID: 1357973

Abstract

The relationship of abnormal nuclear morphology to molecular genetic alterations that are important in colorectal tumorigenesis is unknown. Therefore, Feulgen-stained isolated nuclei from 22 adenomas and 42 carcinomas that had been analyzed for ras gene mutations and allelic deletions on chromosomes 5q, 18q, and 17p were characterized by computerized image analysis. Both nuclear area and the nuclear shape factor representing irregularity correlated with adenoma-carcinoma progression (r = 0.57 and r = 0.52, P < 0.0001), whereas standard nuclear texture, a parameter of chromatin homogeneity, was inversely correlated with progression (r = -0.80, P < 0.0001). The nuclear parameters were strongly interrelated (P < 0.0005). In multivariate analysis, the nuclear parameters were predominantly associated with adenoma-carcinoma progression (P < or = 0.0001) and were not influenced significantly by the individual molecular genetic alterations. Nuclear texture, however, was inversely correlated with fractional allelic loss, a global measure of genetic changes, in carcinomas (r = -0.39, P = 0.011). The findings indicate that nuclear morphology in colorectal neoplasms is strongly related to tumor progression. Nuclear morphology and biologic behavior appear to be influenced by accumulated alterations in cancer-associated genes.

Full text

PDF
797

Images in this article

799Figure 1
on p.799

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  2. Baker S. J., Preisinger A. C., Jessup J. M., Paraskeva C., Markowitz S., Willson J. K., Hamilton S., Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990 Dec 1;50(23):7717–7722. [PubMed] [Google Scholar]
  3. Bibbo M., Bartels P. H., Sychra J. J., Wied G. L. Chromatin appearance in intermediate cells from patients with uterine cancer. Acta Cytol. 1981 Jan-Feb;25(1):23–28. [PubMed] [Google Scholar]
  4. Boring C. C., Squires T. S., Tong T. Cancer statistics, 1991. CA Cancer J Clin. 1991 Jan-Feb;41(1):19–36. doi: 10.3322/canjclin.41.1.19. [DOI] [PubMed] [Google Scholar]
  5. Bos J. L., Fearon E. R., Hamilton S. R., Verlaan-de Vries M., van Boom J. H., van der Eb A. J., Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. 1987 May 28-Jun 3Nature. 327(6120):293–297. doi: 10.1038/327293a0. [DOI] [PubMed] [Google Scholar]
  6. Boyd J., Pienta K. J., Getzenberg R. H., Coffey D. S., Barrett J. C. Preneoplastic alterations in nuclear morphology that accompany loss of tumor suppressor phenotype. J Natl Cancer Inst. 1991 Jun 19;83(12):862–866. doi: 10.1093/jnci/83.12.862. [DOI] [PubMed] [Google Scholar]
  7. Broers J. L., Pahlplatz M. M., Katzko M. W., Oud P. S., Ramaekers F. C., Carney D. N., Vooijs G. P. Quantitative description of classic and variant small cell lung cancer cell lines by nuclear image cytometry. Cytometry. 1988 Sep;9(5):426–431. doi: 10.1002/cyto.990090504. [DOI] [PubMed] [Google Scholar]
  8. Collin F., Salmon I., Rahier I., Pasteels J. L., Heimann R., Kiss R. Quantitative nuclear cell image analyses of thyroid tumors from archival material. Hum Pathol. 1991 Feb;22(2):191–196. doi: 10.1016/0046-8177(91)90042-n. [DOI] [PubMed] [Google Scholar]
  9. Delattre O., Olschwang S., Law D. J., Melot T., Remvikos Y., Salmon R. J., Sastre X., Validire P., Feinberg A. P., Thomas G. Multiple genetic alterations in distal and proximal colorectal cancer. Lancet. 1989 Aug 12;2(8659):353–356. doi: 10.1016/s0140-6736(89)90537-0. [DOI] [PubMed] [Google Scholar]
  10. Diamond D. A., Berry S. J., Jewett H. J., Eggleston J. C., Coffey D. S. A new method to assess metastatic potential of human prostate cancer: relative nuclear roundness. J Urol. 1982 Oct;128(4):729–734. doi: 10.1016/s0022-5347(17)53158-4. [DOI] [PubMed] [Google Scholar]
  11. Diamond D. A., Berry S. J., Umbricht C., Jewett H. J., Coffey D. S. Computerized image analysis of nuclear shape as a prognostic factor for prostatic cancer. Prostate. 1982;3(4):321–332. doi: 10.1002/pros.2990030402. [DOI] [PubMed] [Google Scholar]
  12. Dvorak H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986 Dec 25;315(26):1650–1659. doi: 10.1056/NEJM198612253152606. [DOI] [PubMed] [Google Scholar]
  13. Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  14. Fearon E. R. Genetic alterations underlying colorectal tumorigenesis. Cancer Surv. 1992;12:119–136. [PubMed] [Google Scholar]
  15. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  16. Fey E. G., Penman S. Tumor promoters induce a specific morphological signature in the nuclear matrix-intermediate filament scaffold of Madin-Darby canine kidney (MDCK) cell colonies. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4409–4413. doi: 10.1073/pnas.81.14.4409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fidler I. J. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 1990 Oct 1;50(19):6130–6138. [PubMed] [Google Scholar]
  18. Folkman J., Moscona A. Role of cell shape in growth control. Nature. 1978 Jun 1;273(5661):345–349. doi: 10.1038/273345a0. [DOI] [PubMed] [Google Scholar]
  19. Getzenberg R. H., Pienta K. J., Coffey D. S. The tissue matrix: cell dynamics and hormone action. Endocr Rev. 1990 Aug;11(3):399–417. doi: 10.1210/edrv-11-3-399. [DOI] [PubMed] [Google Scholar]
  20. Hedley D. W., Friedlander M. L., Taylor I. W., Rugg C. A., Musgrove E. A. Method for analysis of cellular DNA content of paraffin-embedded pathological material using flow cytometry. J Histochem Cytochem. 1983 Nov;31(11):1333–1335. doi: 10.1177/31.11.6619538. [DOI] [PubMed] [Google Scholar]
  21. Kern S. E., Fearon E. R., Tersmette K. W., Enterline J. P., Leppert M., Nakamura Y., White R., Vogelstein B., Hamilton S. R. Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected]. JAMA. 1989 Jun 2;261(21):3099–3103. doi: 10.1001/jama.261.21.3099. [DOI] [PubMed] [Google Scholar]
  22. Kinzler K. W., Nilbert M. C., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hamilton S. R., Hedge P., Markham A. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991 Mar 15;251(4999):1366–1370. doi: 10.1126/science.1848370. [DOI] [PubMed] [Google Scholar]
  23. Lee T. K., Myers R. T., Bond M. G., Marshall R. B., Kardon B. The significance of nuclear diameter in the biologic behavior of thyroid carcinomas: a retrospective study of 127 cases. Hum Pathol. 1987 Dec;18(12):1252–1256. doi: 10.1016/s0046-8177(87)80409-4. [DOI] [PubMed] [Google Scholar]
  24. Martinez-Hernandez A. The extracellular matrix and neoplasia. Lab Invest. 1988 Jun;58(6):609–612. [PubMed] [Google Scholar]
  25. Mitmaker B., Begin L. R., Gordon P. H. Nuclear shape as a prognostic discriminant in colorectal carcinoma. Dis Colon Rectum. 1991 Mar;34(3):249–259. doi: 10.1007/BF02090165. [DOI] [PubMed] [Google Scholar]
  26. Nakayama H., Kondo Y., Saito N., Sarashina H., Okui K. Morphometric analysis of cytological atypia in colonic adenomas. Virchows Arch A Pathol Anat Histopathol. 1988;413(6):499–504. doi: 10.1007/BF00750390. [DOI] [PubMed] [Google Scholar]
  27. Nishisho I., Nakamura Y., Miyoshi Y., Miki Y., Ando H., Horii A., Koyama K., Utsunomiya J., Baba S., Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991 Aug 9;253(5020):665–669. doi: 10.1126/science.1651563. [DOI] [PubMed] [Google Scholar]
  28. Nowell P. C. Mechanisms of tumor progression. Cancer Res. 1986 May;46(5):2203–2207. [PubMed] [Google Scholar]
  29. Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
  30. Pienta K. J., Coffey D. S. Correlation of nuclear morphometry with progression of breast cancer. Cancer. 1991 Nov 1;68(9):2012–2016. doi: 10.1002/1097-0142(19911101)68:9<2012::aid-cncr2820680928>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  31. Pienta K. J., Murphy B. C., Getzenberg R. H., Coffey D. S. The effect of extracellular matrix interactions on morphologic transformation in vitro. Biochem Biophys Res Commun. 1991 Aug 30;179(1):333–339. doi: 10.1016/0006-291x(91)91374-l. [DOI] [PubMed] [Google Scholar]
  32. Pienta K. J., Partin A. W., Coffey D. S. Cancer as a disease of DNA organization and dynamic cell structure. Cancer Res. 1989 May 15;49(10):2525–2532. [PubMed] [Google Scholar]
  33. Staufenbiel M., Deppert W. Different structural systems of the nucleus are targets for SV40 large T antigen. Cell. 1983 May;33(1):173–181. doi: 10.1016/0092-8674(83)90346-x. [DOI] [PubMed] [Google Scholar]
  34. Verhest A., Kiss R., d'Olne D., Larsimont D., Salmon I., de Launoit Y., Fourneau C., Pasteels J. L., Pector J. C. Characterization of human colorectal mucosa, polyps, and cancers by means of computerized morphonuclear image analyses. Cancer. 1990 May 1;65(9):2047–2054. doi: 10.1002/1097-0142(19900501)65:9<2047::aid-cncr2820650926>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  35. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  36. Vogelstein B., Fearon E. R., Kern S. E., Hamilton S. R., Preisinger A. C., Nakamura Y., White R. Allelotype of colorectal carcinomas. Science. 1989 Apr 14;244(4901):207–211. doi: 10.1126/science.2565047. [DOI] [PubMed] [Google Scholar]
  37. Wied G. L., Bartels P. H., Bibbo M., Dytch H. E. Image analysis in quantitative cytopathology and histopathology. Hum Pathol. 1989 Jun;20(6):549–571. doi: 10.1016/0046-8177(89)90245-1. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES