Background: International guidelines recommend universal screening for Lynch syndrome (LS) through somatic DNA
mismatch repair deficiency (dMMR) testing in all colorectal cancers (CRCs). However, LS remains largely
underdiagnosed. Mainstreaming LS diagnosis through oncologist-driven genetic testing could increase detection
rates, thus extending the benefits of precision prevention to patients with LS and their families. We aim to evaluate
the feasibility of the mainstreaming diagnostic algorithm for LS.
Patients and methods: ItaLynch is an ongoing, prospective, observational, multicenter, multidisciplinary, Italian study in
patients with dMMR CRC. Being descriptive in nature, it does not attempt to test any specific, a priori, hypothesis.
Patients with dMMR CRC are selected by universal screening by immunohistochemistry (IHC). In MLH1-deficient
patients, reflex testing for BRAFV600E and, when appropriate, for MLH1 promoter hypermethylation is carried out.
For all dMMR CRC, a ‘Lynch Alert’ is added to the pathology report: positive when a patient is at high risk for LS,
due to reflex testing results or to loss of non-MLH1 proteins. Conversely, a ‘Lynch Alert’ is negative when the
patient is likely to be a nonhereditary case (i.e. MLH1 loss and BRAFV600E or MLH1 promoter hypermethylation). In
patients with a positive ‘Lynch Alert’, after providing a brief explanation about the risks and benefits of genetic
testing, the oncologist asks patients for their consent to mainstream genetic testing. Thus a blood sample is drawn for constitutional variants of the MMR genes. Carriers of a germline variant are then referred to post-test genetic
counseling. Referral to clinical genetic services is also advised for patients with clinical suspect criteria.
