Lynch syndrome (LS) is the first cause of inherited colorectal cancer (CRC), being responsible for 2–4% of all diagnoses. Identification of affected individuals is important as they have an increased lifetime risk of multiple CRC and other neoplasms, however, LS is consistently underdiagnosed at the population level. We aimed to evaluate the yield of LS screening in CRC in a single-referral centre and to identify the barriers to its effective implementation.
LS screening programme included individuals with CRC < 70 years, multiple CRC, or endometrial cancer at any age. Mismatch repair (MMR) protein immunohistochemistry (IHC) analysis was performed in routine practice on the surgical specimen and, if MLH1 IHC was altered, MLH1 gene promoter methylation was analysed. Results were collected in the CRC multidisciplinary board database. LS suspected individuals (altered MMR IHC without MLH1 promoter methylation) were referred to the Cancer Genetic Counselling Unit (CGCU). If accepted, a genetic study was performed. Two checkpoints were included: review of the pathology data and verification of patient referral by a genetic counsellor.
Between 2016 and 2019, 381 individuals were included. MMR IHC analysis was performed in 374/381 (98.2 %) CRC cases and MLH1 promoter methylation in 18/21 (85.7 %). Seventeen of the 20 LS suspected individuals were invited for referral at the CGCU. Two cases were not invited and the remaining patient died of cancer before completion of tumour screening. Fifteen individuals attended and a genetic analysis was performed in 15/20 (75 %) LS suspected individuals. Ten individuals were diagnosed with LS, in concordance with the IHC profile (2.7 % of the total cohort). This led to cascade testing in 58/75 (77.3 %) of the available adult relatives at risk, identifying 26 individuals with LS.
Establishing a standardized institutional LS screening programme with checkpoints in the workflow is key to increasing the yield of LS identification.
- • Establishing a Lynch syndrome CRC screening programme is key to identify Lynch syndrome individuals.
- • Checkpoints limit patient loss.
- • The workflow is easy to follow.
Colorectal cancer (CRC) is the most common cause of cancer when considering both genders, and the second cause of cancer in men and women separately, representing 15% of all tumours diagnosed in Spain in 2020 . Lynch syndrome (LS) is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes ( MLH1 , MSH2 , MSH6 , PMS2, or EPCAM gene deletions, silencing the MSH2 gene in epithelial tissues). It is the first cause of inherited CRC, being responsible for approximately 2–4% of all diagnoses . CRC cumulative incidences at 75 years are 48.3–57.1%, 46.6–51.4%, 18.2–20.3% and 10.4% for MLH1 , MSH2 , MSH6, and PMS2 mutation carriers, respectively. However, the risk of cancer for PMS2 mutation carriers is not evident before 50 years of age. LS individuals also have an increased incidence of metachronous CRC and other LS spectrum tumours (mainly endometrial, ovarian, extracolonic gastrointestinal, urinary tract, and biliary tract) . Risk-reducing surgeries can be offered to modify their cancer risk as well as family planning processes . Therefore, it is important to identify LS individuals as early as possible, along with their at-risk relatives.
Microsatellite instability (MSI) analysis or immunohistochemistry (IHC) staining of MMR proteins in CRC samples can be performed to identify individual candidates for genetic testing for LS . MSI is a molecular hallmark of mismatch repair deficiency (MMRd) CRC . IHC staining of two (PMS2, MSH6) or four (MLH1, MSH2, MSH6, PMS2) MMR proteins suggests mutations in MMR genes when proteins are not expressed in tumour tissue .
MSI/MMRd can also be identified in 4–5% of metastatic sporadic CRC and 12–20% of non-metastatic sporadic CRC due to somatic MLH1 promoter methylation. MLH1 promoter methylation or the BRAF V600E mutation (associated with MLH1 promoter methylation in CRC) should be initially tested in these cases . While both strategies are accepted, the analysis of MLH1 promoter methylation when MLH1 protein expression is absent seems to be more cost-effective . MSI testing sensitivity, as a screening test for LS in CRC, ranges from 66.7 % to 100 % and the specificity ranges from 61.1 % to 92.5 %. IHC staining sensitivity ranges from 80.0 % to 100 % and the specificity ranges from 80.5 % to 91.9 % .
The selection of suitable individuals for LS screening can be made based on clinical criteria, considering age at CRC onset or family history (Amsterdam or Bethesda criteria). These criteria, however, fail to identify up to 50 % of LS individuals, especially in unselected CRC patients . In consequence, other screening strategies have been proposed such as universal screening, screening by Bethesda criteria, age-related (Jerusalem recommendations), or combined strategies .
Despite the emerging consensus that LS screening programmes should be established, most centres and healthcare systems still rely on informal networks between professionals to identify these individuals. Networks for cancer care aim to formally organise cooperation and intend to facilitate equity of access to cancer care and implementation of clinical guidelines . While reports emphasize the importance of establishing a standardised protocol, to date, no publication has described its implementation in detail .
In 2016, in our institution (a tertiary hospital of the Spanish National Health System), we set up an LS CRC screening programme based on the selection of patients fulfilling Jerusalem criteria (age under 70) and/or at least fulfilling one Bethesda criteria This study aimed to describe the established protocol, identify the difficulties that arose during its implementation, and to evaluate the yield after four years of operation.