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Digital archive of theses discussed at the University of Pisa


Thesis etd-04212023-102244

Thesis type
Tesi di dottorato di ricerca
Thesis title
Genetic and genomic susceptibility of pancreatic cancer
Academic discipline
Course of study
tutor Prof. Campa, Daniele
  • cancro pancreatica
  • case-control association studies
  • pancreatic cancer
  • polimorfismi a singolo nucleotide
  • sequencing
  • sequenziamento
  • single nucleotide polymorphisms
  • studi di associazione caso-controllo
Graduation session start date
Release date
Pancreatic ductal adenocarcinoma (PDAC) is a neoplasm characterized by a high mortality rate due to the absence of specific symptoms, diagnostic markers for early detection and efficient therapies. The identification of high-risk individuals genetically predisposed to PDAC development may improve the diagnosis at early stages of the disease. So far, common genetic variants and high penetrance mutations have been associated to PDAC risk, but PDAC genetic architecture has been only partially discovered. In this Ph.D. project, to identify novel low-frequency and rare variants associated with PDAC risk, a fine mapping of known PDAC risk loci has been conducted through the sequencing of 480 PDAC patients. In addition, the genotypes and the summary statistics from genome-wide association studies conducted on PDAC risk were used to perform case-control association studies based on biological hypothesis. Through this approach, called secondary analysis, 127,887 common variants were analysed in 20,320 PDAC cases and 225,365 controls.
The fine mapping approach showed eight pathogenic genetic variants with a frequency of alternative alleles higher than what reported. In particular, the most interesting variant is MSH2-rs193922376-T that was already associated with Lynch syndrome, that has several clinical manifestations among which PDAC. Secondary analyses identified three novel susceptibility loci for PDAC: rs1412832-T (P=5.25×10-9) in the long non-coding gene CDKN2B-AS1 and two missense rs9581957-C (P=2.46x10-9) and rs2277598-T (P=1.53x10-6) in URAD and BBS4, respectively.
In conclusion, in our study we identified several common, low-frequency and rare genetic variants that could be used in future screening programs of PDAC high-risk individuals.