Lynch syndrome

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Background

Lynch syndrome (LS), previously called hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant condition caused by germline mutations in any one of the mismatch repair genes (MSH2, MLH1, MSH6, PMS2) ) or a deletion of the last few exons of the gene EPCAM that results in epigenetic silencing of MSH2. It is associated with a high risk of early onset colorectal cancer, particularly in the proximal colon. The lifetime risk of some extracolonic cancers is also elevated and is estimated to be 33% for endometrial cancer, 9% for ovarian cancer, 6% for gastric cancer and < 3% for urothelial and small intestinal cancer.[1]

LS is relatively common and is thought to account for approximately 2–3% of all colorectal cancers.[2][3] The risk estimates for colorectal cancer by age 70 years are 31–47% for MLH1 and MSH2 mutation carriers.[4] The risk of colorectal cancer is less in carriers of other mutations and risk estimates range from 10 to 22% for MSH6 mutation carriers and 15 to 20% for PMS2 mutation carriers.[1]

The incidence of adenomas is not high but those that do arise have a high risk of rapidly progressing to malignancy due to loss of the remaining wild type allele of the mutated mismatch repair gene. The cancers thus have mismatch repair deficiency leading to characteristic microsatellite instability (MSI) in the DNA of the cancer cells. The mutated protein degrades and shows loss of expression of one or more of the mismatch repair protein on immunohistochemistry (IHC). The case of MSH2 protein expression loss is usually associated with the loss of expression of the binding partner MSH6 protein as the unbound protein degrades. Similarly, MLH1 protein expression loss usually leads to loss of expression of the PMS2 protein. Isolated loss of MSH6 or PMS2 protein expression suggests the defect is in the affected gene.

Results of IHC and MSI testing need to be interpreted with the knowledge that MLH1 can be silenced by somatic methylation in the MLH1 promoter region in sporadic colorectal cancers. These cancers show high levels of MSI and loss of MLH1 and PMS2 expression on IHC. They typically occur in the proximal colon of older females without a family history of colorectal cancer. They commonly have a V600E mutation of the BRAF oncogene whereas BRAF mutation is rare in LS cancers.

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Identification of Lynch Syndrome

Identification of LS has traditionally relied on multiple factors, including recognition of typical features and appropriate testing and/or referral to a genetics provider. Although there are some histological features within individual tumours that can indicate a likelihood of MMR deficit, and other clues, such as location of the tumour (e.g. proximal colon cancer), Lynch syndrome-associated colon cancers are not necessarily distinguishable from sporadic colon cancers.[5] Systematic collection and assessment of family history are highly variable among health care providers, and rarely is this information readily available to pathologists who may recognize histological features of LS. Given these limitations and compelling reasons to identify these individuals and their at-risk family members, universal screening has been proposed as a way to adequately identify individuals with LS.[6][7]

It should be noted that evidence to support the cost-effectiveness of universal testing of colorectal cancers in Australia is not yet available, but that this is an area of ongoing active research.[6]

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Universal testing of colorectal cancers

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

There is no recommendation whether universal testing should be done by IHC or MSI testing as the sensitivity and specificity of the tests are very similar. IHC is more widely available and has the advantage of indicating which gene is abnormal. However, appropriate training and experience of pathologists is required for accurate results.[8]

Implementation of universal testing requires an effective multidisciplinary programme with sufficient resources to follow-up positive results.[3] Most cancers demonstrating MSI or loss of MLH1 and PMS2 on IHC, will be sporadic cancers with somatic methylation and silencing of MLH1. It is recommended that cancers with loss of MLH1 be tested for BRAF mutation or MLH1 promoter hypermethylation before considering germline mutation testing.[9][2][3][8] This makes testing more cost effective and reduces unnecessary anxiety amongst affected individuals. However, neither test is completely sensitive or specific and the result of methylation testing can depend on the technique used. A recent study reported MLH1 hypermethylation in 16% of patients with LS and 92% of patients with BRAF mutant cancer presumed to be sporadic. [2]

IHC in adenomas is of limited benefit to identify LS as a normal IHC result does not exclude LS. However, where adenomas are the only neoplastic tissue available (especially if >1cm in size) within a family for mismatch repair expression testing, such testing should be done. An informative test is helpful, though a negative test is not.

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Use of risk prediction models

In individuals without a personal history of colorectal cancer but with a family history suggestive of LS, it is recommended that a risk prediction model be used to guide referral for further assessment. [9][2][3][8] Currently available appropriate risk prediction models are PREMM or MMRpro. A simpler algorithm but with less evidence of validity is the Management for Lynch Syndrome protocol on EviQ. The initial approach to further assessment would to perform IHC or MSI testing on the cancer of an affected relative if this is possible to arrange.

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Management

A systematic review of aspirin in the prevention of colorectal cancer, including Lynch syndrome-associated cancers, was undertaken in the preparation of this guideline. The results are summarised in Primary prevention (Part 2): Chemopreventive candidate agents.

No systematic reviews on testing or surgical management of LS were undertaken in the development of this section. The guidance on LS is based on recent international guidelines.[1][9][2][3][4][8][10]

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Genetic testing

IHC of cancer tissue from an affected family member can be used to guide germline genetic testing of mismatch repair genes. The probability of identifying a pathogenic germline mutation is shown in Table 6.2.[1]

Genetic Testing for Hereditary Mutations in the Mismatch Repair Genes (MMR-genes) protocol on eviQ includes the following flow chart

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Table 6.2 Probability of identifying a pathogenic germline mutation

Finding Probability
Loss of MSH2 and MSH6 MSH2 67%
Loss of MLH1 and PMS2 with no BRAF mutation and/or no MLH1 hypermethylation MLH1 33%
Loss of MSH6 only MSH6 24%
Loss of PMS2 only PMS2 62%
Source: eviQ Cancer Genetics Referral Guidelines for ColorectalReferring to the large bowel, comprising the colon and rectum. Cancer or Polyposis Risk Assessment and Consideration of Genetic Testing (2016).[1]

If no germline mutation or a variant of unknown significance is found, LS cannot be excluded.[3] These cases, characterized by mismatch repair deficiency with loss of expression of the MMR proteins, are sometimes referred to as Lynch-like syndrome. Some may be due to biallelic somatic mutations and in future these may be identified on tumour testing and used to exclude LS.[11] However others, particularly those with a suggestive family history, are most likely due to germline mutations not yet detectable by currently available techniques. These families should be managed clinically according to LS guidelines and re-investigated as genetic techniques advance.

Finding a pathogenic germline mutation confirms the diagnosis and allows relatives to be tested with a very high degree of accuracy.

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Surveillance

Surveillance colonoscopy every 1 to 2 years is recommended for individuals carrying a germline mutation or clinically at risk of carrying a mutation but in whom definitive testing is not possible.[1][9][2][3][8] It should commence at age 25 or 5 years younger than the youngest affected family member if < 30 years.[1] Annual surveillance is preferred in known mutation carriers.[3] The risk of colorectal cancer is lower and the age of diagnosis is later in carriers of MSH6 or PMS2 mutations and surveillance starting at age 30 years could be considered,[1][3] although there are no data to directly guide this.[2][8]

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Surgical management

In patients with colorectal cancer and known LS the choice of procedure should be individualised according to the site and number of tumour(s), age at diagnosis, risk of surgical morbidity, patient comorbidities and their wishes. If a segmental (partial) colectomy is performed there is a high (16–19%) 10-year cumulative risk of metachronous colorectal cancer, even with colonoscopic surveillance.[3][10] This risk is substantially reduced by performing an extended resection (either a subtotal colectomy with an ileosigmoid anastomosis or a total colectomy with an ileorectal anastomosis) and is generally favoured.[3][10] Functional outcome is however better after segmental colectomy and this procedure can still be considered in older patients.[3][10] Annual surveillance is required for the residual colorectum.

For patients with LS and rectal cancer, either a proctectomy and coloanal anastomosis or a total proctocolectomy and IPAA can be performed. A restorative proctocolectomy and IPAA will reduce the risk of metachronous cancer however is associated with more functional problems.[3][10] Ongoing surveillance of the pouch-anal anastomosis is required.

In order to plan best surgical management it is important to perform IHC on pre-operative biopsy specimens from patients likely to have LS. [3]

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ChemopreventionThe use of drugs or natural substances to prevent or delay the development of cancer.

Systematic review evidence on the effectiveness of aspirin in the prevention of colorectal cancer in people with LS is summarised in Primary prevention (Part 2): Chemopreventive candidate agents.

The considerations in making the LS recommendation, and health system implications, are described in Primary prevention (Part 2): Chemopreventive candidate agents.

Regular colonoscopy must continue for patients taking aspirin.

Next section: Peutz-Jeghers syndrome

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References

  1. 1.01.11.21.31.41.51.61.7 Cancer Institute NSW. eviQ Cancer Genetics Referral Guidelines for Colorectal Cancer or Polyposis Risk Assessment and Consideration of Genetic Testing. [homepage on the internet] Sydney; 2016 [cited 2016 Sep 6]. Available from: https://www.eviq.org.au/Category/tabid/65/categoryid/6/Default.aspx.
  2. 2.02.12.22.32.42.52.6 Ladabaum U, Ford JM, Martel M, Barkun AN. American Gastroenterological Association Technical Review on the Diagnosis and Management of Lynch Syndrome. Gastroenterology 2015 Sep;149(3):783-813.e20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26226576.
  3. 3.003.013.023.033.043.053.063.073.083.093.103.113.123.13 Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Dis ColonThe main part of the large bowel, which absorbs water and electrolytes from undigested food (solid waste). Its four parts are the ascending colon, transverse colon, descending colon and sigmoid colon. RectumThe final section of the large bowel, ending at the anus. 2014 Aug;57(8):1025-48 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25003300.
  4. 4.04.1 Jenkins MA, Dowty JG, Ait Ouakrim D, Mathews JD, Hopper JL, Drouet Y et al. Short-term risk of colorectal cancer in individuals with lynch syndrome: a meta-analysis. Journal of Clinical Oncology 2015;; 33: 326-31. Abstract available at http://jco.ascopubs.org/content/early/2014/12/22/JCO.2014.55.8536.short.
  5. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008 Dec 10;26(35):5783-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18809606.
  6. 6.06.1 National Institute for Health and Care Excellence (NICE). Molecular testing strategies for Lynch syndrome in people with colorectal cancer. UK: NICE; 2017 Feb 22 Available from: https://www.nice.org.uk/guidance/dg27.
  7. The Canadian Agency for Drugs and Technologies in Health (CADTH). DNA mismatch repair deficiency tumour testing for patients with colorectal cancer: recommendations. (CADTH optimal use report; vol.5, no.3d). Ottawa: CADTH; 2016.
  8. 8.08.18.28.38.48.5 Rubenstein JH, Enns R, Heidelbaugh J, Barkun A, Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. Gastroenterology 2015 Sep;149(3):777-82; quiz e16-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26226577.
  9. 9.09.19.29.3 Robays J, Poppe B. Oncogenetic testing for Lynch syndrome and familial adenomatous polyposis. Brussels: Belgian Health Care Knowledge Centre (KCE); 2014.
  10. 10.010.110.210.310.4 Rodriguez-Bigas MA, Möeslein G. Surgical treatment of hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome). Fam Cancer 2013 Jun;12(2):295-300 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23508345.
  11. Haraldsdottir S, Hampel H, Tomsic J, Frankel WL, Pearlman R, de la Chapelle A, et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 2014 Dec;147(6):1308-1316.e1 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25194673.
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