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. 2025 Jun 24;20(6):e0326343.
doi: 10.1371/journal.pone.0326343. eCollection 2025.

Genetic profiling of inherited colorectal cancer syndromes in Tunisian patients

Rania Abdelmaksoud-Dammak  1 , Nihel Ammous-Boukhris  1 , Amena Saadallah-Kallel  1 , Dorra Ben Ayed-Guerfali  1 , Souhir Guidara  2 , Imen Miladi-Abdennadher  1 , Ikhlas Ben Ayed  2 , Hassen Kamoun  2 , Slim Charfi  3 , Tahya Sellami-Boudawara  3 , Imen Zribi  4 , Foued Frikha  4 , Salah Boujelbene  4 , Raja Mokdad-Gargouri  1
Affiliations

Genetic profiling of inherited colorectal cancer syndromes in Tunisian patients

Rania Abdelmaksoud-Dammak et al. PLoS One. .

Abstract

Objective: Colorectal cancer (CRC) is among the most commonly diagnosed cancers worldwide, with 2% to 5% of cases being linked to inherited syndromes.

Material and methods: A cohort of 30 Tunisian patients was selected and divided into two groups based on clinical features and family history: Group 1 included patients clinically diagnosed with hereditary polyposis syndromes, including MUTYH-Associated Polyposis (MAP: 15 cases) and Familial Adenomatous Polyposis (FAP: 5 cases). Group 2 consisted of patients clinically diagnosed with non-polyposis syndromes, including Lynch Syndrome (LS: 7 cases) and other rare syndromes (OS: 3 cases). Genetic testing was performed using either Sanger sequencing or targeted next-generation sequencing (NGS) with a cancer panel including 31 cancer-related genes.

Results: In Group 1, MAP was confirmed in 13 patients who were homozygous carriers of the pathogenic variant (c.1143_1144dup p.Glu382fs) in the MUTYH gene. For patients suspected of having FAP, pathogenic variants in the APC gene were identified in only two patients (c.3183_3187del p.Lys1061_Gln1062insTer, and c.2016_2017del p.His672Ter), while another patient carried a frameshift variant (c.502_503del, p.Ile168SerTer11) in the PTEN gene, indicating Cowden Syndrome. In Group 2, genetic testing confirmed Peutz-Jeghers Syndrome in a young girl who had a large deletion in the STK11 gene. For patients suspected to have LS, only variants of unknown significance (VUS) were identified in MMR. Further genetic investigations are required to identify the pathogenic variant in these patients.

Conclusion: Overall, our results highlight the importance of genetic testing to better understand hereditary CRC syndromes in Tunisian families, and to improve the management of patients and their relatives.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Workflow showing group of patients according to their clinical features and family history of cancer, and the methodology used for genetic investigation.
Fig 2
Fig 2. Pedigrees of patients with MAP, and chromatograms showing the c.1143_1144dup PV in the MUTYH gene at homozygous
(a), combined with the c.1103 G > A (b), and at heterozygous genotypes (c). Males are indicated by squares, females by circles. An arrow indicates the proband, and cancer history in the family is indicated in red.
Fig 3
Fig 3. Pedigrees of FP1 and FP2 patients showing PVs in
(a) APC (c.3183_3187del), and (b) PTEN (c.502_503del) genes. Probands are indicated by arrows; affected members are indicated in red.
Fig 4
Fig 4. Pedigrees of patients suspected of Lynch Syndrome: a (LSP2), and b (LSP3) carrying missense variants classified as Conflicting of Pathogenicity in MSH2 (c.728G > A,p. Arg243Gln) and in BRIP1A (c.1394G > A,p.Cys465Tyr).
The 3D protein models for both the mutated and wild-type forms of p. Arg243Gln (c), and p.Cys465Tyr (d) were presented.
Fig 5
Fig 5. (a) Pedigrees of patient LSP4 suspected of Lynch Syndrome, (b) chromatogram showing the c.3500T > C missense variant in MSH6 gene at heterozygous state, (c) The 3D protein models for both the mutated and wild-type forms of the p. Leu1167Pro in MSH6, (d) IHC showing the expression of MMR proteins: immunostaining was positive for MLH1, MSH2 PMS2, and negative for MSH6.
An arrow indicates the proband, and cancer history in the family is indicated in red.
Fig 6
Fig 6. (a) Pedigree of patient OS1 and (b) the MLPA result showing the CNV ratio chart in the STK11 gene.
An arrow indicates the proband, and familial cancer history is indicated in red.
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