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4bases’ paper of the month – May 2021: Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers

Our team’s reading recommendation for this month goes to “Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers”[i] by Mariano Golubicki et al. from the Molecular Biology Lab, Hospital of Gastroenterology in Buenos Aires, Argentina, a very interesting paper just published in “Cancers“.

Lynch syndrome is the most prevalent hereditary form of colorectal cancer and is characterized by a tumor phenotype called microsatellite instability (MSI).

The identification of germline variants in any of the four mismatch repair (MMR) DNA genes is essential to ensure its appropriate diagnosis and to implement preventive measurements.

However, in 50% of cases, patients with MSI do not carry a germline pathogenic variant in an MMR gene and their syndrome is then termed “Lynch-like syndrome“.

Lynch-like syndrome (LLS) is a common clinical challenge with an underlying molecular basis mostly unknown.

The Buenos Aires research group, in collaboration with the Department of Cellular and Molecular Medicine of the University of California in San Diego and the pathology department of the Hospital Clínic in Barcelona focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures.

4 cases (27%) were identified with double somatic putative variants in mismatch repair (MMR) core genes, as well as 3 cases (20%) with double MSH3 somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with POLD1 potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, 9 predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in 9 probands, 4 of which also showed MMR biallelic somatic inactivation.

In conclusion, the study offers new insights into Lynch-like syndrome colorectal cancer, postulating MSH3 and POLD1 double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.

Once again, whole-exome sequencing has demonstrated its high potential in identifying more and more genetic variants that alter protein sequences.

We at 4bases have developed new solutions to support you in this extremely important task.

[i] Golubicki M, Díaz-Gay M, Bonjoch L, Franch-Expósito S, Muñoz J, Cuatrecasas M, Ocaña T, Iseas S, Mendez G, Carballido M, Robbio J, Cisterna D, Roca E, Castells A, Balaguer F, Castellví-Bel S, Antelo M. Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers. Cancers (Basel). 2021 Mar 12;13(6):1259. doi: 10.3390/cancers13061259. PMID: 33809179; PMCID: PMC7999079.

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