CCY '13: Screening for Lynch Syndrome (hereditary bowel cancer) using antibodies alone

Screening for Lynch Syndrome (hereditary bowel cancer) using antibodies alone

Project Lead: Prof Nicholas Hawkins, School of Medical Sciences, UNSW Australia.


  • A/Prof Elizabeth Salisbury, South Eastern Area Laboratory Services (SEALS), Randwick, NSW.
  • A/Prof Adrienne Morey, SydPath, Darlinghurst, NSW.
  • Dr Veli Marjoneimi, SEALS, Kogarah, NSW
  • Dr Leon Vonthethoff, SEALS, Kogarah, NSW
  • Prof Robyn Ward, Prince of Wales Hospital, Randwick, NSW
  • Dr Robyn Levingston, DHM Pathology, Ryde.


Many cases of colorectal cancer are sporadic, arising in one person, with no increase in likelihood of cancer for close relatives of that person. Some cases, however, are hereditary. These cases are classed as Lynch Syndrome. Identifying patients with Lynch Syndrome is essential in reducing risks associated with cancer through  preventative strategies for patients and close relatives who also have Lynch Syndrome.

Until recently, the process for identifying patients lacked an effective, affordable tool for screening for Lynch Syndrome. A new antibody can detect a mutant molecule, BRAF V600E, associated with sporadic colorectal cancer. This antibody has been used to create a valuable tool to screen for Lynch Syndrome, and thus prevent unnecessary stress and testing in patients who are unlikely to have Lynch Syndrome.

Mismatch repair (MMR) enzymes are proteins produced by dividing cells that are essential for maintenance of the integrity of the genome. A number of MMR proteins occur in humans, including MLH1, PMS2, MSH2 and MSH6. Immunohistochemical analysis of these MMR proteins has proven very effective in identifying cells that are unable to express these proteins. Such cells are defective in MMR function (MMRD), and can give rise to cancers at various sites in the body, most notably in the large bowel. In fact, it is now known that ~15% of bowel cancers are defective for these enzymes.

Of all the MMRD bowel cancers seen in clinical practice, about one in ten occur because the patient has an hereditary predisposition to bowel cancer. Such individuals are born with mutation or loss of one allele of a relevant MMR gene (most commonly MLH1, MSH2 or MSH6), and then lose the other allele at some point during life within cells of the gut, endometrium or other sites. Because of this, such individuals are predisposed to the development of cancer, and have a syndrome previously known as hereditary non-polyposis colorectal cancer (HNPCC), but now more commonly as Lynch Syndrome. People with Lynch Syndrome are at increased risk of cancer, often at an early age, and this risk is shared with their first degree relatives in an autosomal dominant fashion.

Identifying cases of Lynch Syndrome is an important clinical task, which ultimately relies on the demonstration of pathogenic germline mutations in relevant MMR genes, in the setting of the family cancer clinic. Accurate diagnosis of Lynch Syndrome is important because patients can utilise effective preventative strategies shown to decrease morbidity and mortality from the common cancers in this syndrome, including bowel and endometrial cancer. Importantly, the finding a proband with Lynch Syndrome means that this benefit is potentially applicable to half of their first degree relatives, and so finding one case can result in benefit to many.

However, the large majority (90%) of cases of bowel cancer showing MMRD arise not because of Lynch Syndrome, but to entirely somatic changes occurring in bowel epithelium during life. These somatic changes, most notably epigenetic silencing of the MLH1 gene by promoter hypermethylation, result in MMRD and hence the development of cancer. 

Thus, it is important to be able to effectively identify the relatively small number of cases of Lynch Syndrome from the larger grouping of MMRD colorectal cancers. Currently, the accurate identification of Lynch Syndrome cases from somatic causes of MMRD requires specialised genetic tests for mutation of BRAF. This is because the gene BRAF is commonly mutated in cases of somatic MLH1 loss, but never in cases where MLH1 is lost as part of the Lynch Syndrome. There is a clear need to have more effective ways of doing this that let the pathologist rapidly determine BRAF status using the same methods they use to detect MMRD (immunohistochemistry).

Project Aims:

  1. Develop immunohistochemical protocols for the robust assessment of BRAF status in selected colorectal cancer cases.
  2. Determine the sensitivity and specificity of this assay in identifying cases of Lynch syndrome from a population-based cohort of MMRD colorectal cancers that show MLH1 loss by immunohistochemistry and with known germline MLH1 gene status.
  3. Determine the reproductivity of assay results across at least four independent pathology laboratories related to the TCRN, and identify factors that may be responsible for inter-laboratory or inter-assay variation. 

Project Updates:

– February 2015: Final Project Update; Cancer Challenge of the Year Project Sheds New Light on Lynch Syndrome 

– August 2014: Cancer Challenge of the Year Research Results in Improvements in Lynch Syndrome Screening

– May 2014:  CCY 2013 Lynch Syndrome update

– February 2014: Cancer Challenge of the Year Project Sheds New Light on Lynch Syndrome