The Genetics and Molecular Alterations of Pancreatic Cancer

The prospect that pancreatic cancer will be the second most common cause of cancer death by 2030 is worrisome. Considering that the approximate 6% overall 5-year survival has not merely changed in the past decades illustrates the need to revert the bleak prognosis. Centralization of surgery (pancreaticoduodenectomy or Whipple procedure) in the Netherlands resulted in decreased in-hospital mortality and lower in-hospital mortality for elderly patients in high-volume centers. Other initiatives include the development of reliable diagnostics to detect pancreatic cancer at an early stage (i.e. as precursor). Even though pancreatic cancer has become genetically one of the best-characterized diseases, translational efforts in the past decades have not yet led to offer patients a better prognosis. As such, the aim should be to further utilize current genetic and molecular characteristics of precursors to pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PanNETs). Herein, whole-exome sequencing of PDAC revealed that long-term survival (≥10 years) is unlikely to be mediated by commonly mutated genes (KRAS, P16/CDKN2A, TP53, SMAD4/DPC4 amongst others). For acinar cell carcinoma (ACC) of the pancreas, the LKB1 gene was not shown to be commonly mutated and molecular alterations in ACCs are different than those in PDAC. Whole-exome sequencing of PanNETs revealed the main genetic pathways, such as mammalian target of rapamycin (mTOR) signaling, altered and identified hitherto unknown tumor suppressor genes in ATRX (α thallasemia/mental retardation syndrome X-linked) and DAXX (death domain-associated protein). Clinicopathologic correlates were found in PanNETs harboring MEN1 and ATRX or DAXX mutations since these tumors were associated with better prognosis. Moreover, the assessment of telomere status in PanNETs harboring ATRX or DAXX mutations showed a perfect correlation between altered ATRX or DAXX expression and the presence of the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). Finally, the timing of altered ATRX and DAXX expression was studied in combination with the occurrence of the ALT-phenotype in PanNETs and precursors (i.e. microadenomas) hereto. This revealed loss of ATRX and DAXX expression and ALT occurred only in larger PanNETs thus suggesting that these changes are late events in PanNET tumorigenesis. The applicability of genetic and molecular alterations might guide further therapeutic options even though with current neo-adjuvant regimens this is not meaningful in PDAC. However, screening for targetable alterations in clinical setting seems beneficial for several tumor types, especially PanNETs and ACCs. The significance of the genetic signature of PanNETs warrants further study in order to determine the diagnostic, prognostic, and therapeutic value hereof. More specifically, altered chromatin remodeling that is frequently observed in these tumors should be further elaborated in order to find targetable leads. One of the primary focuses should be on establishing representative in vitro and in vivo study models, which are currently inadequate