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4bases’Paper of the Month – May 2022 -Identifying patients with Lynch syndrome using a universal tumor screening program in an integrate healthcare system  

Our team’s reading recommendation for this month is “Identifying patients with Lynch syndrome using a universal tumor screening program in an integrated healthcare system” 1, an excellent scientific study conducted by Crain et al and recently published in “Hereditary Cancer in Clinical Practice”.

Lynch syndrome (LS) is a genetically inherited disease that is associated with a higher risk of colorectal cancer (CRC) and endometrial cancer (EC). This syndrome is mainly caused by pathogenic variants in DNA mismatch repair (MMR) genes. Unfortunately, LS is currently underdiagnosed, because the current approaches to identify the syndrome rely on data that is not always available or are based on criteria that are not
always met by individuals affected by the disease.

A potentially more effective approach to identify LS in patients recently diagnosed with CRC or EC, is the Universal Tumor Screening (UTS). This approach involves several steps: the first step is to screen the patient’s tumor tissue by immunohistochemistry (IHC) to detect the absence of one or more of the MMR proteins whose function was stated above. In case a loss of MLH1 is detected, a reflex test is performed to detect the cases that are not related to LS and exclude them from further investigation. Individuals that are positive for LS then oriented to genetic counseling, and then genetic testing to further confirm the LS diagnosis.

The objective of the study was to evaluate the performance of the implemented UTS
approach. This was done by assessing whether all the steps of the protocol were
respected when patients were submitted to UTS. This identified areas for improving
the effectiveness of the implemented UTS approach in screening patients with LS.
The study found that 313 out of 362 CRC patients, and 61 out of 64 CE patients were
screened by IHC. 13 of 313 CRC patients and 1 of 61 CE patients had ambivalent
results after reflex testing. These 14 patients were therefore referred for genetic
counseling. Of these 14 patients, 10 underwent germline genetic testing at the end.
The result of this test showed that 5 people with CRC and none of the people with EC
had pathogenic variants.

Through this study, they were able to evaluate the effectiveness of the UTS approach
implemented to identify the patients having LS. This program allowed some patients to
undergo germline testing, which they would never have done if they had not been
tested positive for LS. On the other hand, this study identified some aspects of which
enhancement would improve the effectiveness of UTS in identifying LS. For example,
the authors noticed an inconsistent use of biopsies, which might exclude patients
having LS from the screening, preventing the syndrome identification.

At 4Bases, we are pleased to offer a genetic testing option by providing easy
procedures for the identification of mutations in genes related to certain cancers,
particularly those of the breast and ovary. In this context, we have the HEVA pro kit
which allows the identification of variants related to the homologous recombination
repair (HRD) defect. The HEVA pro kit allows the analysis of 50 genes using a
molecular protocol based on next generation sequencing technology. This kit is used
for the analysis of not only germline but also somatic DNA using only blood or body
tissue samples.

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