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. 2024 Jan 27;22(1):108.
doi: 10.1186/s12967-024-04923-3.

Combination of mutations in genes controlling DNA repair and high mutational load plays a prognostic role in pancreatic ductal adenocarcinoma (PDAC): a retrospective real-life study in Sardinian population

Maria Cristina Sini #  1 , Maria Grazia Doro #  1 , Laura Frogheri #  1 , Angelo Zinellu  2 , Panagiotis Paliogiannis  3 , Alberto Porcu  3 , Fabrizio Scognamillo  3 , Daniele Delogu  3 , Davide Adriano Santeufemia  4 , Ivana Persico  1 , Grazia Palomba  1 , Giovanni Battista Maestrale  1 , Antonio Cossu  3 , Giuseppe Palmieri  5   6
Affiliations

Combination of mutations in genes controlling DNA repair and high mutational load plays a prognostic role in pancreatic ductal adenocarcinoma (PDAC): a retrospective real-life study in Sardinian population

Maria Cristina Sini et al. J Transl Med. .

Abstract

Background: Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia.

Methods: A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms.

Results: Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival.

Conclusions: The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.

Keywords: Genome damage repair; Mutation analysis; Mutation load rate; Pancreatic ductal adenocarcinoma; Prognosis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Oncoplot of somatic non-synonymous and pathogenic/likely pathogenic mutations. Total number of variants are reported non right side
Fig. 2
Fig. 2
Oncoplot of somatic non-synonymous and pathogenic/likely pathogenic mutations in MMR and DR genes. Mutation load rate (MLR) values are indicated according to the total number of detected mutations
Fig. 3
Fig. 3
A model representing the main effects of the occurrence of combined mutations in repair genes in our PDAC series
See this image and copyright information in PMC

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