KRAS or BRAF—that is the question

July 07, 2015 By: Bjorn Rembacken

KRAS or BRAF—that is the question

What's causing the altered bowel habits in this elderly patient?

The photograph shows a lesion that was found in the ascending colon of a 75-year-old man who was undergoing colonoscopy because of a change in bowel habit.

WHAT IS YOUR ENDOSCOPIC DIAGNOSIS?

a) Hyperplastic polyp

b) Sessile serrated polyp

c) Traditional serrated adenoma

d) Mixed hyperplastic polyp

e) Tubulovillous adenoma

 

 

 

Discussion

Of course, this lesion could simply be an unusually large hyperplastic polyp. In fact, histology confirmed that it was a sessile serrated polyp (SSP) harbouring high-grade dysplasia. In the presence of dysplasia a purist might insist that the lesion be more correctly called a sessile serrated adenoma (SSA).

Traditional serrated adenomas (TSAs) are usually found in the left-sided colon and look more like small balls of spaghetti. Mixed hyperplastic/adenomatous polyps should have a mixed appearance, whereby part of the polyp is covered with the typical large crypt openings of a hyperplastic polyp and part covered with a different crypt pattern, small slits or gyrate crypts, for example. Tubulovillous adenomas (TVAs) appear to be covered by branched or ‘brain-like’ crypt openings and the lesion in this patient is obviously not a TVA.

When I trained in colonoscopy, hyperplastic polyps were considered to be distinct lesions with little malignant potential. TSAs (then simply called serrated adenomas) were recognised as a distinct entity, but more closely related to villous adenomas than to hyperplastic polyps. There were dissenting voices though, and some 20 years ago the histopathologist Jeremy Jass began talking about hyperplastic polyps being linked to ‘microsatellite unstable’ cancers (microsatellite instability being a measurement of DNA instability).1 In 2003, Torlakovic et al.2 looked more deeply into the issue of hyperplastic polyps and reclassified them as hyperplastic polyps, TSAs and SSAs.

It seems to be the SSAs that are most closely associated with a risk of proximal microsatellite instability-high (MSI-H) cancers.3,4 For example, SSAs are usually found in the right-sided colon and have a high frequency of BRAF mutations.5 BRAF is a human gene that encodes the B-raf protein, which is involved in the regulation of cell division and differentiation. ‘Activating’ BRAF mutations have been found in lots of cancers such as non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, adenocarcinoma of the lung and hairy cell leukaemia.

In addition SSAs are associated with the CpG island hypermethylation phenotype (CIMP). If I understand the concept correctly, CIMP is the insertion of a methyl group into the promoter region of the DNA of the mismatch repair genes hMLH1 and/or hMSH2.6 Methylation of a gene promoter region is the way our bodies are able to silence the expression of genes. This is a novel concept. In medical school I was taught that we are born with genes and they inevitably get transcribed into proteins. However, it turns out that we have lots of genes that can be switched off, presumably if the environment is not conducive to their expression. Why our bodies would decide to switch off a fundamental defence against cancer seems odd though? Is this nature’s way of stopping us from growing too old?

Anyway, as a result of silencing a mismatch repair gene, cells begin to accumulate a high number of DNA errors and those cellular clones that accumulate particularly unfortunate mutations turn cancerous with a high degree of microsatellite instability. The accumulation of cells with bizarre DNA fragments, presumably resulting in the expression of some very odd protein fragments, generates an intense lymphocytic reaction by the immune system. Presumably it is the intense immune response that explains why these cancers have an unexpectedly good prognosis. If you would like to read more about the serrated pathway, I recommend Snover’s overview.7

It is unlikely that we can blame all right-sided cancers on SSAs. Hyperplastic polyps are common, but SSAs have been found in only 1–3% of patients undergoing colonoscopy.8,9 Ordinary hyperplastic polyps have KRAS mutations, but never BRAF mutations and only occasionally exhibit CIMP.10 By the way, it seems that KRAS mutations give rise to hyperplastic polyps unless the KRAS mutation happens to occur AFTER a previous APC mutation, in which case there is a far greater risk that the cell will develop into cancer.11

After the removal of a serrated lesion, what surveillance should be recommended? It seems that three findings are important when deciding how to proceed. First is a lesion size of 10mm or larger. Second is the presence of dysplasia within the lesion. Third is a location proximal to the sigmoid colon. These three findings have been linked with an increased risk of subsequent cancer.12 If your country does not have explicit guidelines for serrated lesions, I would propose that serrated polyps with any of the above high-risk features be regarded as an adenomatous lesion of equivalent size when the appropriate surveillance interval is calculated.

 

References

  1. Jass JR, Whitehall VL, Young J, et al. Emerging concepts in colorectal neoplasia. Gastroenterology 2002; 123: 862–876. 
  2. Torlakovic E, Skovlund E, Snover DC, et al. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 2003; 27: 65–81. 
  3. Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology 2007; 50: 131–150.
  4. Spring KJ, Zhao ZZ, Karamatic R, et al. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 2006; 131: 1400–1407. 
  5. Minoo P, Moyer MP and Jass JR. Role of BRAF-V600E in the serrated pathway of colorectal tumourigenesis. J Pathol 2007; 212: 124–133. 
  6. Wynter CV, Walsh MD, Higuchi T, et al. Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer. Gut 2004; 53: 573–580. 
  7. Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol 2011; 42: 1–10. 
  8. Hiraoka S, Kato J,Fujiki S, Kaji E, Morikawa T et al. The Presence of Large Serrated Polyps Increases Risk for Colorectal Cancer. Gastroenterology 2010; 139: 1503-1510. 
  9. Li D, Jin C, McCulloch C, et al. Association of large serrated polyps with synchronous advanced colorectal neoplasia. Am J Gastroenterol 2009; 104: 695–702. 
  10. O’Brien MJ, Yang S, Mack C, et al. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol 2006; 30: 1491–1501. 
  11. Vogelstein B and Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10: 789–799. 
  12. Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for  colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2012; 143: 844–857. 

 

 

 

 

 

 

 

 

 

 

Answer

Correct answer: b.

About the author

Bjorn Rembacken is at Leeds Teaching Hospitals NHS Trust, Leeds, UK. He was born in Sweden and qualified from Leicester University in 1987. He undertook his postgraduate education in Leicester and in Leeds. His MD was dedicated to inflammatory bowel disease. Dr Rembacken was appointed Consultant Gastroenterologist, Honorary Lecturer at Leeds University and Endoscopy Training Lead in 2005. Follow Bjorn on Twitter @Bjorn_Rembacken

 

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