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A dedicated service for the Management of Hereditary Colorectal Cancer Improves Adherence with Molecular Testing for Lynch Syndrome


UEGW Amsterdam 2012

Leon Sergot, Sophie Stevens Poster, Fiona Turkes, Jason Smith, Kevin J. Monahan

The Family History of Bowel Cancer Clinic, West Middlesex University Hospital, London, United Kingdom


Lynch Syndrome (LS) is responsible for 2-3% of colorectal cancer (CRC) which equates to ~1000 cases of CRC in the United Kingdom annually. Previous studies have demonstrated that in current practise less than 10% of these cases are identified as LS due to lack of appropriate testing. The international Bethesda guidelines were devised in 2002 to help identify such cases for tumour testing for the molecular features of LS, such as immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 expression, or DNA microsatellite instability analysis (MSI). These criteria include all individuals diagnosed


We identified all new cases of CRC over 1 year before and after the establishment of a dedicated ‘Family History of Bowel Cancer Service’ in our hospital in March 2011. Adherence to the Bethesda guidelines was determined by examination of medical records and UK National Bowel Cancer Audit Programme (NBOCAP) data. Pathology reports were studied in patients aged 50-59 years at diagnosis for features consistent with MSI-type histology.


In total, 198 cases of CRC were discussed at the CRC multidisciplinary meeting over a 2 year period. 12 individuals were diagnosed under the age of 50 years (~6%) consistent with Office of National Statistics (ONS) data. 31 patients were diagnosed between 50-59 years, of which 4 patients had MSI-type histology. A further 25 patients had a significant family history of CRC or a LS-related cancer diagnosed under 50 years. Therefore in total 41 patients fulfilled Bethesda criteria (20.7%). Between March 2010-March 2011 there were 18 such cases with only 1 patient’s tumour tested for the molecular features of LS (5.6%) compared to 19/23 cases tested in the subsequent year (82.6%), p value = 9.7e-7 (Chi=23.9956).  Six out of 20 (30%) cases tested demonstrated these molecular features with MSI and abnormal IHC, and are undergoing germline genetic testing.


The establishment of a dedicated family history of bowel cancer service resulted in a significant improvement in testing individuals diagnosed with CRC with a possible diagnosis of LS. We recommend that this service be applied to identify such families throughout the United Kingdom to improve clinical pathways for these patients.

via Abstract View.

Lynch Syndrome and other non-polyposis inherited cancer syndromes

Lynch Syndrome / Hereditary non-polyposis colorectal cancer (HNPCC) and related syndromes

Lynch Syndrome (OMIM 120435)) is a familial cancer syndrome which accounts for approximately 2.2-4% of all colorectal cancer in the USA (Hampel et al. 2005) and 2-3% of the total in the UK.  It was also known as Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), however the phenotype is more complex with multiple extracolonic tumours, for example, so this term has now been largely abandoned.

An Irish family tree with Lynch Syndrome caused by an inherited mutation in MSH2.  Members of this family are affected predominantly with colorectal cancer (CRC), but also small bowel cancer (SBCa), Gastric, Pancreatic, Uterine and other cancers, as well as conditions not linked to Lynch Syndrome such as Crohn’s disease.

LS is an autosomally dominant inherited condition commonly caused by germline mutation in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2, involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single nucleotide mismatches or insertions and deletion loops. Mutations in four of the MMR genes can cause Lynch syndrome [Peltomaki 2003]. The functions of the mismatch repair genes can be disrupted by missense mutations, truncating mutations, splice site mutations, large deletions, or genomic rearrangements. In addition, germline deletion within EPCAM, which is not an MMR gene, can disrupt the MMR pathway. EPCAM deletions result in inactivating the adjacent MMR gene MSH2, even though MSH2 itself has not been mutated.

Identification of LS Families

A minority of Lynch Syndrome families may be identified because they have multiple affected members diagnosed at an early age.   The Amsterdam Criteria I and II (Vasen et al. 1993; Vasen et al. 1999)(see below) identify patients for colonoscopic and other screening.  Approximately 40-80% of patients meet these criteria, with 50% of the remainder meeting the modified criteria which include extracolonic cancers.  The revised Bethesda criteria (Umar et al. 2004) are used to identify patients for molecular screening of HNPCC, i.e. microsatellite instability ± immunohistochemistry studies.  Approximately 80% of patients are identified using the Bethesda criteria, although the specificity is low.

Immunohistochemistry and microsatellite instability analysis for Lynch Syndrome

Amsterdam I Criteria

  • ≥3 1st degree relatives with colorectal cancer (CRC)
  • ≥2 generations affected
  • One family member below age 50 years of age
  • Exclude familial adenomatous polyposis

Amsterdam II Criteria

  • As for Amsterdam I except that CRC may be substituted by cancer of endometrium, small bowel, or pelviureter.

Most families with LS, however, do not fulfil the Amsterdam criteria. The Revised Bethesda criteria are another set of diagnostic criteria designed to increase the diagnostic yield of testing for LS [7]. For example, all individuals diagnosed under the age of 50 years should be tested for the molecular features of LS in their tumours.  If molecular testing is diagnostic of LS, it can subsequently determine which families should undergo colonoscopic and other investigations, and to screen other high risk family members. The Revised Bethesda guidelines are designed to streamline the clinical diagnostic pathways used to identify mutation carriers in patients with colorectal cancer who might or might not fulfil the Amsterdam criteria, thus increasing diagnostic yield screening for LS.

The identification of such families with Lynch syndrome involves an extensive diagnostic work up comprising various screening tools combined with genetic and immunohistochemical tests.  Initially the tumour from an affected individual may be tested for features suggestive of this condition by either immunohistochemistry of the mismatch repair proteins and/or DNA microsatellite instability (a hallmark of faulty DNA mismatch repair).  If either of these tests are abnormal, then germline testing may be performed to identify a putative heritable mutation in one of the causative genes.

Patient selection using Amsterdam and revised Bethesda criteria have been applied to clinical pathways in the United Kingdom through the use of national guidelines.  Given the implication of family history and known mortality benefit, the early recognition of Lynch syndrome is highly desirable. There have been concerns over the sensitivity, specificity, and predictive value of already existing guidelines. About 22% of affected individuals do not fulfil either Amsterdam or the Revised Bethesda criteria. As Barnetson et al argues, there might be multiple reasons for this such as small family size, unknown or inadequately taken family history, adoption, and patients without available tumour data [9]. A number of alternative screening models have been developed, such as MMRpredict, PREMM 1,2,6, MMRPro, and MsPath whilst searching for a careening tool that is simple, accurate, and clinically useful for predicting the likelihood of Lynch Syndrome.

Bethesda (revised) Criteria (Umar et al 2003)

  • 1 CRC below age 50 yr
  • Multiple CRC or HNPCC-related cancers
  • CRC with MSI-related histology under 60 years of age
  • CRC or HNPCC-related cancer in ≥1 1st degree relative, < 50 years of age
  • CRC or HNPCC-related cancer in at least two 1st or 2nd degree relatives, any age

MSI-type Histology: Using the revised Bethesda Criteria patients aged 50-60 years should have tumour testing

There is a slight preponderance of right-sided tumours (70% proximal to the splenic flexure) in Lynch Syndrome.  It is a highly penetrant condition which also features extracolonic cancers such as endometrial and gastric cancer.  The adenoma to carcinoma sequence is rapid with interval cancers occurring in 5% of patients despite two-yearly colonoscopic surveillance (Jarvinen, Aarnio et al. 2000).  The tumours are characteristically associated with a local lymphocytic infiltrate and a good prognosis when surgically resected (Jass 2000; Takemoto et al. 2004).

Screening tumours for Lynch Syndrome – is it cost effective?

There are clinical and economic trade-offs when implementing screening protocol on a large scale. As nondirected germline mutation testing for Lynch syndrome is prohibitively expensive at £1000 per gene, MSI and IHC are the screening tests of choice. In view of high costs of testing of all colorectal cancers for MSI or loss or MMR protein, an approach described by Heather Hampel of The Ohio State University, the Revised Bethesda Guidelines were felt to be an appropriate tool to select patients for genetic testing. However, the question remains open: is the “reflex” molecular tumour testing justified clinically and economically? Kastrinos et al, have looked into the popularity of the universal testing across several centres in US. Unsurprisingly, a pessimistic picture emerged showing the low uptake of the concept. The benefits of the universal testing are counterbalanced by practical problems such as an informed consent controversy, practicalities of dealing with the complexity of test results and the resultant implications. The fact that the cost effectiveness of this approach has not been yet validated plays heavily against such approach.

In US, Ramsey et al have carried out a study looking at cost-effectiveness of different strategies for identifying of persons with Lynch syndrome. The average cost per carrier detected using Bethesda guidelines was $15,787, and expanding this strategy to include costs and benefits for first degree relatives greatly improves the cost effectiveness of the program. Expanding the program to first degree relatives leads to savings from intensive screening to exceed the cost of testing.

In Europe, Pinol et al, has carried out a similar study evaluating cost-minimization analysis of identification strategies for MSH2/MLH1-associated Lynch syndrome. Authors concluded that clinical selection of patients using the Revised Bethesda Guidelines followed by either MSI analysis (€11,989 per detected mutation) or IHC (€10,644 per detected mutation) has proved to be more cost effective than performing any of these tests directly (€32,140 and €37,956 per detected mutation, respectively).

Further research has been carried out by Dinh et al in 2010 looking at the cost effectiveness of MMR gene mutations screening, and reached the conclusion that it is comparable to that of already established cancer screening protocols such as colorectal, cervical, and breast cancer screening. Authors argue that primary screening of individuals for MMR gene mutations, starting with the risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost effective manner relative to current practise with the average cost-effectiveness ratio of $26,000 per QALY.

These results echo several European studies, such as that carried out by Pinol V et al, 2005 in Spain, where authors suggest that MSI and IHC testing are equivalent strategies in terms of cost effectiveness when it comes to screening selected patients for MMR mutations

Large bowel surveillance for Lynch syndrome family members and gene carriers

Total colonic surveillance (at least biennial) should commence at age 25 years. Surveillance colonoscopy every 18 months may be appropriate because of the occurrence of interval cancers in some series.  Surveillance should continue to age 7075 years or until co-morbidity makes it clinically inappropriate. If a causative mutation is identified in a relative and the consultand is a non-carrier, surveillance should cease and measures to counter general population risk should be applied.

The effectiveness of colonoscopic surveillance for people with MMR gene mutations and Lynch family members has been examined in retrospective casecontrol comparisons. Screened individuals were compared to control subjects who declined, or did not receive, regular colonoscopy with respect to outcomes of cancer incidence, tumour stage and mortality, or mortality alone. Surveillance appears to provide an average of 7 years of extra life for Lynch syndrome family members.  Thus, available evidence supports regular colonoscopic surveillance as a means of early colorectal cancer detection, leading to mortality reduction as well as reduction in cancer incidence.

Surveillance should consist of total colonoscopy, since the risk of polyps and cancer is high and a substantial proportion of patients have neoplasia restricted to the proximal colon.  Colonoscopy is preferable to flexible sigmoidoscopy combined with barium enema. Because the cancer risk is high, it is not appropriate to accept an incomplete colonoscopy until the next surveillance interval. Incomplete colonoscopy should be followed soon after, or even the same day, by completion CT colonography in centres skilled in providing this technique to a high quality, but repeated radiation exposure should be avoided wherever possible. Repeat full colonoscopy or barium enema remain as options. Chromoendoscopy and narrow wavelength visible light (narrow band) endoscopy may have a place in the detection of small or flat lesions, but there is very limited experience and evidence is restricted to descriptive studies of their use in Lynch syndrome surveillance. Hence, the utility of such techniques requires further assessment and is neither recommended nor discouraged in high risk surveillance, but should not replace conventional endoscopic approaches. Evidence for commencing surveillance at 25 years of age is based on observational data that indicate that the risk increases substantially from age 25 in groups defined by family history and in groups defined by presence of a mutation.

Colorectal resection has a place as prophylaxis and for established cancer in Lynch syndrome family members and/or MMR gene carriers.

Patients who have developed a colorectal malignancy and who come from a Lynch syndrome family, or carry a mutation in an MMR gene, should be counselled and offered a surgical procedure that includes both a cancer control element and prophylaxis to counter future cancer risk. At present there is no evidence to guide decision-making on primary prophylactic surgery for patients who do not yet have cancer.

People with MMR gene mutations or those from Amsterdam positive Lynch syndrome families who have cancer will require surgery unless treatment is palliative. Case series evidence shows that the risk of metachronous colorectal cancer is high following segmental resection (16%), but substantially lower after colectomy and ileorectal anastomosis (3%).  Hence, incorporating a prophylactic element to the cancer resection is appropriate. For patients with proximal tumours, colectomy and ileorectal anastomosis is most relevant, but the retained rectum must be screened because cancer risk in the retained rectum is 3% every 3 years for the first 12 years.

Upper gastrointestinal surveillance for Lynch syndrome family members and/or MMR gene carriers

In families manifesting gastric cancer as part of the phenotype, biennial upper gastrointestinal endoscopy should be considered. The evidence is limited and a pragmatic recommendation is to screen from age 50 since the incidence is very low until that age. Surveillance should continue to age 75 or until the causative mutation in that family has been excluded. This recommendation is based on observations that some Lynch syndrome families have a particular propensity for gastric cancer.  There is as yet no evidence that this reduces mortality.

Other non-polyposis predisposition to colorectal neoplasia

About 15% of sporadic colorectal cancers are also microsatellite unstable and feature loss of protein staining on immunohistochemistry but are not caused by germline mutations in mismatch repair genes.  Often they are acquired sporadic type cancers caused by methylation of MLH1.  These associated with a particular genetic pathway which differs from LS by the presence of BRAF V600E mutations, the absence of β-CATENIN exon 3 mutations and a methylator genotype (Young et al. 2005) (Oliveira et al. 2005).  Recently kindreds demonstrating some inheritance of MLH1 promoter methylation have been identified (Suter et al. 2004; Hitchins, Williams et al. 2005), although the evidence for this inherited epimutation is limited to a few case studies and may be related in imprinting (Chong et al. 2007; Hitchins and Ward 2007).

In addition there are a number of families which fulfil Amsterdam criteria but do not demonstrate microsatellite instability (Dove-Edwin, de Jong et al. 2006).  These families are termed by one group familial colorectal cancer type X (Lindor et al. 2005), and have a lower incidence of colorectal cancer occurring at a later age.  The genetic aetiology is not known for these families.

Approximately 93% of colorectal cancer occurs after the age of 50 years, and thus those young patients who develop cancer are likely to have an inherited or other risk factor such as chronic colitis.  The genetic risk is partially made up by inherited mutations which cause HNPCC.  However, there are likely to be a number of other lower penetrance genes which cause cancer predisposition, many of which may have a recessive form of inheritance and few polyps, and therefore a less clearly identifiable phenotype.

UK BSG/ACPGBI Guidelines for Moderate Risk Family History/Colorectal Cancer Risk Groups



Executive summary

Dedicated Clinics: Referrals on the basis of family history are best coordinated through centres with a specialist interest, such as regional genetics services or medical/surgical gastroenterology centres. Such centralisation enables audit of family history ascertainment, assigned level of risk, collection of outcome data and research.

Screening Procedure: Total colonoscopy is the preferred mode of surveillance for the moderate risk categories defined here, owing to the propensity for proximal colonic lesions and the opportunity for snare polypectomy. Incomplete colonoscopy should initiate an alternative imaging modality on the same day, such as double-contrast barium enema or CT colonography. A repeat colonoscopy soon after an incomplete examination is acceptable, but success must be assured. However, radiation exposure should be minimised and regular radiological surveillance is not recommended.

High moderate risk group inclusion criteria comprise familial aggregations where affected relatives are first-degree relatives of each other (first-degree kinship) with at least one being a first-degree relative of the consultand. If both parents are affected, these count as being within first-degree kinship:

– Three affected relatives any age in a first-degree kinship (eg, a parent and a blood-related aunt/uncle and/or grandparent), at least one of whom is a first-degree relative of the consultand, or two siblings/one parent or two siblings/one offspring combinations, or both parents and one sibling. However, there should be no affected relative <50 years old, as otherwise the family would fulfil high risk criteria.

– Two affected relatives aged <60 years in a first-degree kinship or mean age of two affected relatives <60 years. At least one relative must be a first-degree relative of the consultand and so this category includes a parent and grandparent, >2 siblings, >2 children or child+sibling. The risk is sufficiently increased to merit low-intensity surveillance comprising 5-yearly colonoscopy between age 50 and age 75 years. Polyps should be snared; adenoma surveillance applies thereafter if a benign neoplasm is confirmed.

Low-moderate risk group. Inclusion criteria are:

– One affected first-degree relative under 50 years old or

– Two affected first-degree relatives, aged 60 or older.

In both high-moderate and low-moderate categories, pathology tumour material from an affected relative may be available to test for Lynch syndrome gene involvement.

Excluding such instances, there is a modest excess risk meriting a single colonoscopy at age 55 (if older at presentation then instigate forthwith), in the lowmoderate group to identify polyp formers. Polyps should be snared; adenoma surveillance applies thereafter if a benign neoplasm is confirmed. If colonoscopy is clear, reassure and discharge with recommendations relevant to population risk (uptake of faecal occult blood test screening in the UK).

Early-onset colorectal cancer (<50 years). The elevation of risk in relatives of an early-onset case is modest. However, the heightened anxiety and emotive nature of cancer in this age group merit special mention because this frequently initiates requests for surveillance. Such cases are covered by the above risk categorisation, but algorithms can also be used to predict whether the affected relative is a carrier of a mutation in a Lynch syndrome gene. These approaches identify affected individuals where tumour immunohistochemistry and/or microsatellite instability analysis could lead to identification of a DNA mismatch repair gene mutation. Bethesda criteria are not discriminatory within this group because all patients fulfil these criteria due to age alone.

Low Risk Group: People with only one affected relative and who do not fulfil any of the above criteria, and do not fulfil high risk criteria, should be reassured and encouraged to avail themselves of population-based screening measures. The low level residual risk over that of the general population should be explained.

Outcome of screening in Moderate Risk Groups (Dove-Edwin et al BMJ 2005)

Advanced neoplasia and age at initial colonoscopy.

Colonoscopic surveillance is effective in preventing colorectal cancer in individuals from families with hereditary non-polyposis colorectal cancer (group 4) and in individuals with a family history of colorectal cancer that does not meet the Amsterdam criteria. However, colonoscopic surveillance in the families at moderate risk seems not indicated until age 45 (or even 50), and this is true even for the relatives of young patients. Furthermore, surveillance intervals of more than five years may be appropriate in individuals with a moderate risk family history (groups 1-3) in whom no advanced pathology is found.

Colonoscopic polypectomy has been shown to decrease the incidence of colorectal cancer in a large cohort study as well as in clinical practice and to decrease both the incidence and mortality of colorectal cancer in individuals with a family history of hereditary non-polyposis colorectal cancer. It is also considered by some to be a safe tool for population screening. Clear guidelines exist for colorectal surveillance in hereditary non-polyposis colorectal cancer families, but guidelines and practices for individuals at moderate risk on the basis of their family history are heterogeneou.

Concerns exist about colonoscopic surveillance in individuals with a moderate risk family history, as some will not be at increased risk. Dunlop et al calculated that if surveillance were offered to individuals aged 30-70 who have two direct relatives affected or one under age 45 then 235 000 individuals would be eligible in the United Kingdom. Even if the age of initiating surveillance is raised, the potential burden on resources is immense. Colonoscopy is associated with a small risk of serious complications, and this may substantially outweigh any benefits in people at low risk.

In this study, only one incident cancer was detected on surveillance in an individual with a moderate risk family history during 9281 person years of follow-up. In families at moderate risk, advanced neoplasia is very rare below the age of 45 and, if not seen initially, it remains uncommon (under age 65) if follow-up colonoscopy is carried out within six years. These findings are important because individuals with a moderate risk family history who are under age 65 with no advanced neoplasia can be considered to be at low risk and extended surveillance intervals may be sufficient. Individuals with a moderate risk family history in whom advanced neoplasia is seen on initial colonoscopy should continue with colonoscopy every three years. The low yield of advanced neoplasia under the age of 45 is true also of those with a first degree relative affected under age 45. Only 4% of 139 individuals in group 1—families with one case of colorectal cancer diagnosed under age 45, and no other cases—screened under age 45 (mean age 33) had an adenoma of any description. Despite the increased risk of colorectal cancer in this group individuals’ absolute risk therefore remains small and the benefit of screening seems minimal below the age of 45.


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