Skip to main content
NCBI home page
Gut logoLink to Gut
. 1998 May;42(5):680–684. doi: 10.1136/gut.42.5.680

Infrequent K-ras codon 12 mutation in serrated adenomas of human colorectum

Y Ajioka 1, H Watanabe 1, J Jass 1, Y Yokota 1, M Kobayashi 1, K Nishikura 1
PMCID: PMC1727113  PMID: 9659164

Abstract

Background—Serrated adenoma is a new morphological subtype of colorectal adenoma. The lesion provides a distinct morphological route to carcinoma, but the underlying genetic changes have not yet been investigated. 
Aims—To determine the frequency of K-ras mutation in serrated adenoma. 
Methods—The frequency of K-ras codon 12 point mutation in 20 serrated adenomas, five atypical hyperplastic polyps, and 58sporadic polypoid adenomas was investigated by nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. 
Results—Although most of the serrated adenomas were large (average size 11.4 mm) and polypoid, K-ras codon 12 point mutation was detected in only one of the 20 (5%), which is a significantly lower frequency than that in sporadic polypoid adenomas (18/60; 30%) (p = 0.017). No mutation was detected in the atypical hyperplastic polyps. Three of 20 (15%) serrated adenomas contained a focus of carcinoma in situ, indicating their malignant potential and the existence of a serrated adenoma-carcinoma sequence, but no mutation was detected in the foci of carcinoma in situ. 
Conclusions—K-ras mutation is uncommon in serrated adenomas, indicating a different spectrum of genetic alterations in these lesions from those in typical polypoid sporadic adenomas. This subtype of colorectal adenoma represents a new genetic pathway in the histogenesis of colorectal carcinoma. 



Keywords: serrated adenoma; colorectal adenoma; K-ras mutation; PCR-RFLP

Full Text

The Full Text of this article is available as a PDF (207.7 KB).

Figure 1 .

Figure 1

Open in a new tab

Nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of K-ras codon 12 mutations in serrated adenomas and sporadic traditional polypoid adenomas. The wild type and mutant fragments were detected at 86 and 106 bp respectively. M, ΦX174/HaeIII DNA size marker; lane C1, positive mutant control (AsPcl1) homozygous for mutant K-ras at codon 12 showing uncleaved mutant band (106 bp) only; lane C2, normal control (normal human placental DNA) showing cleaved wild type band (86 bp) only; lanes A1 to A4, DNA samples from polypoid adenomas showing both mutant and wild type bands (heterozygous); lanes S1 to S4, DNA samples from serrated adenoma with wild type band only; lane N1, DNA sample from normal colorectal tissue with wild type band only. No negative control is shown. 


Figure 2 .

Figure 2

Open in a new tab

(A) Whole mount view of serrated adenoma that was almost pure histologically, measuring 9 mm in size with subpedunculated configuration (original magnification × 2.5). (B) The serrated glandular architecture is reminiscent of a hyperplastic polyp but its cytology (pseudostratified enlarged and/or spindle shaped nuclei with loss of goblet cells) and lack of surface maturation indicate its neoplastic nature (original magnification × 50). 


Figure 3 .

Figure 3

Open in a new tab

(A) Whole mount view of serrated adenoma accompanied by hyperplastic polyps and focus of severe atypia, equivalent to carcinoma in situ, measuring 12 mm in size with pedunculated configuration (original magnification × 2.5). (B) Serrated adenoma with enlarged nuclei with prominent nucleoli (original magnification × 40). (C) Hyperplastic polyp accompanied by serrated adenoma located at the periphery of the lesion (indicated by the small arrows in (A)) (original magnification × 25). (D) Focus of carcinoma in situ located at the centre of the lesion (indicated by the large arrows in (A)) (original magnification × 50).


Figure 4 .

Figure 4

Open in a new tab

Serrated adenoma adjoining hyperplastic polyp, measuring 8 mm with sessile configuration (original magnification × 13.2). Area of serrated adenoma (left half of the lesion) measuring 5 mm, showing slight but definite luminal serration. K-ras mutation was detected only in the area of serrated adenoma. 


Figure 5 .

Figure 5

Open in a new tab

Atypical hyperplastic polyp showing irregular glandular structure, numerous dystrophic goblet cells, and a slight degree of surface maturation (original magnification × 25). 


Selected References

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

  1. Adachi M., Muto T., Morioka Y., Ikenaga T., Hara M. Flat adenoma and flat mucosal carcinoma (IIb type)--a new precursor of colorectal carcinoma? Report of two cases. Dis Colon Rectum. 1988 Mar;31(3):236–243. doi: 10.1007/BF02552553. [DOI] [PubMed] [Google Scholar]
  2. Aoki T., Takeda S., Yanagisawa A., Kato Y., Ajioka Y., Watanabe H., Kudo S., Nakamura Y. APC and p53 mutations in de novo colorectal adenocarcinomas. Hum Mutat. 1994;3(4):342–346. doi: 10.1002/humu.1380030403. [DOI] [PubMed] [Google Scholar]
  3. Berrozpe G., Schaeffer J., Peinado M. A., Real F. X., Perucho M. Comparative analysis of mutations in the p53 and K-ras genes in pancreatic cancer. Int J Cancer. 1994 Jul 15;58(2):185–191. doi: 10.1002/ijc.2910580207. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Bos J. L. The ras gene family and human carcinogenesis. Mutat Res. 1988 May;195(3):255–271. doi: 10.1016/0165-1110(88)90004-8. [DOI] [PubMed] [Google Scholar]
  6. Boughdady I. S., Kinsella A. R., Haboubi N. Y., Schofield P. F. K-ras gene mutations in adenomas and carcinomas of the colon. Surg Oncol. 1992 Aug;1(4):275–282. doi: 10.1016/0960-7404(92)90088-3. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Forrester K., Almoguera C., Han K., Grizzle W. E., Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. 1987 May 28-Jun 3Nature. 327(6120):298–303. doi: 10.1038/327298a0. [DOI] [PubMed] [Google Scholar]
  9. Fujimori T., Satonaka K., Yamamura-Idei Y., Nagasako K., Maeda S. Non-involvement of ras mutations in flat colorectal adenomas and carcinomas. Int J Cancer. 1994 Apr 1;57(1):51–55. doi: 10.1002/ijc.2910570110. [DOI] [PubMed] [Google Scholar]
  10. Hasegawa H., Ueda M., Watanabe M., Teramoto T., Mukai M., Kitajima M. K-ras gene mutations in early colorectal cancer ... flat elevated vs polyp-forming cancer.... Oncogene. 1995 Apr 6;10(7):1413–1416. [PubMed] [Google Scholar]
  11. Ilyas M., Tomlinson I. P. Genetic pathways in colorectal cancer. Histopathology. 1996 May;28(5):389–399. doi: 10.1046/j.1365-2559.1996.339381.x. [DOI] [PubMed] [Google Scholar]
  12. Itoi T., Watanabe H., Ajioka Y., Oohashi Y., Takel K., Nishikura K., Nakamura Y., Horil A., Saito T. APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis. Pathol Int. 1996 May;46(5):333–340. doi: 10.1111/j.1440-1827.1996.tb03618.x. [DOI] [PubMed] [Google Scholar]
  13. Jass J. R., Smith M. Sialic acid and epithelial differentiation in colorectal polyps and cancer--a morphological, mucin and lectin histochemical study. Pathology. 1992 Oct;24(4):233–242. doi: 10.3109/00313029209068874. [DOI] [PubMed] [Google Scholar]
  14. Jeevaratnam P., Cottier D. S., Browett P. J., Van De Water N. S., Pokos V., Jass J. R. Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol. 1996 May;179(1):20–25. doi: 10.1002/(SICI)1096-9896(199605)179:1<20::AID-PATH538>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  15. Kobayashi M., Watanabe H., Ajioka Y., Honma T., Asakura H. Effect of K-ras mutation on morphogenesis of colorectal adenomas and early cancers: relationship to distribution of proliferating cells. Hum Pathol. 1996 Oct;27(10):1042–1049. doi: 10.1016/s0046-8177(96)90281-6. [DOI] [PubMed] [Google Scholar]
  16. Kuramoto S., Oohara T. Minute cancers arising de novo in the human large intestine. Cancer. 1988 Feb 15;61(4):829–834. doi: 10.1002/1097-0142(19880215)61:4<829::aid-cncr2820610431>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  17. Longacre T. A., Fenoglio-Preiser C. M. Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol. 1990 Jun;14(6):524–537. doi: 10.1097/00000478-199006000-00003. [DOI] [PubMed] [Google Scholar]
  18. McLellan E. A., Owen R. A., Stepniewska K. A., Sheffield J. P., Lemoine N. R. High frequency of K-ras mutations in sporadic colorectal adenomas. Gut. 1993 Mar;34(3):392–396. doi: 10.1136/gut.34.3.392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Muto T., Bussey H. J., Morson B. C. The evolution of cancer of the colon and rectum. Cancer. 1975 Dec;36(6):2251–2270. doi: 10.1002/cncr.2820360944. [DOI] [PubMed] [Google Scholar]
  20. Muto T., Kamiya J., Sawada T., Konishi F., Sugihara K., Kubota Y., Adachi M., Agawa S., Saito Y., Morioka Y. Small "flat adenoma" of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum. 1985 Nov;28(11):847–851. doi: 10.1007/BF02555490. [DOI] [PubMed] [Google Scholar]
  21. Ohshima S., Shimizu Y., Takahama M. Detection of c-Ki-ras gene mutation in paraffin sections of adenocarcinoma and atypical bronchioloalveolar cell hyperplasia of human lung. Virchows Arch. 1994;424(2):129–134. doi: 10.1007/BF00193491. [DOI] [PubMed] [Google Scholar]
  22. Powell S. M., Zilz N., Beazer-Barclay Y., Bryan T. M., Hamilton S. R., Thibodeau S. N., Vogelstein B., Kinzler K. W. APC mutations occur early during colorectal tumorigenesis. Nature. 1992 Sep 17;359(6392):235–237. doi: 10.1038/359235a0. [DOI] [PubMed] [Google Scholar]
  23. Riddell R. H., Goldman H., Ransohoff D. F., Appelman H. D., Fenoglio C. M., Haggitt R. C., Ahren C., Correa P., Hamilton S. R., Morson B. C. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol. 1983 Nov;14(11):931–968. doi: 10.1016/s0046-8177(83)80175-0. [DOI] [PubMed] [Google Scholar]
  24. Shimoda T., Ikegami M., Fujisaki J., Matsui T., Aizawa S., Ishikawa E. Early colorectal carcinoma with special reference to its development de novo. Cancer. 1989 Sep 1;64(5):1138–1146. doi: 10.1002/1097-0142(19890901)64:5<1138::aid-cncr2820640529>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  25. Torlakovic E., Snover D. C. Serrated adenomatous polyposis in humans. Gastroenterology. 1996 Mar;110(3):748–755. doi: 10.1053/gast.1996.v110.pm8608884. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Yamagata S., Muto T., Uchida Y., Masaki T., Sawada T., Tsuno N., Hirooka T. Lower incidence of K-ras codon 12 mutation in flat colorectal adenomas than in polypoid adenomas. Jpn J Cancer Res. 1994 Feb;85(2):147–151. doi: 10.1111/j.1349-7006.1994.tb02075.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES