Abstract:
Colorectal cancer (CRC) is currently a major public health problem in Algeria.
Among the hereditary forms of this cancer, Hereditary Non-Polyposis Colorectal Cancer
(HNPCC) is an autosomal dominant disorder characterized by the early onset of CRC. This
syndrome is linked to germline defects in Mismatch Repair (MMR) genes. The work we have
done has been devoted to studying the molecular correlation between CRC and mutations
occurring in the MLH1, MSH2 and MSH6 repair genes in 27 unrelated Algerian families.
The search for germline mutations was tested by sequencing all exons and adjacent
intronic sequences. Multiplex ligand-dependent probe amplification (MLPA) technique was
used for testing large genomic rearrangements (deletion / duplication), when we observed no
point mutations.
Pathogenic mutations were identified in 15 % of families with clinical suspicion on
HNPCC. Two novel variants described for the first time in Algerian families were identified
in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young
onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T et c.1030C>T, the most
described ones, were also detected in our families. Furthermore, the families HNPCC caused
by MSH6 germline mutation may show an age of onset that is comparable to this of patients
with MLH1 and MSH2 mutations.
According to our results, we confirmed that MSH2, MLH1, and MSH6 contribute to
CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the
identification of Lynch syndrome patients in Algerian families, which can assist in the
management of these patients and the medical supervision of their relatives at risk.
