by ecancer reporter, Janet Fricker

An international collaboration has identified that at the molecular level pancreatic cancer (PC) consists of four different subtypes of tumour, finds a study in Nature.

PC, the fourth leading cause of death in the West, has a median survival measured in months and a five year survival of less than 5%.

Advances in therapy have only achieved incremental improvements in overall outcome, but can provide notable benefits for undefined subgroups.

Sean Grimmond, from The University of Queensland, Australia, and over 100 international colleagues working with the International Cancer Genome Consortium (ICGC) identified an urgent need for better understanding of the molecular pathology of PC to improve patient selection for current treatment options, and to develop novel therapies.

Over seven years the team performed a comprehensive integrated genomic analysis of 456 resected PCs tumours using a combination of whole-genome and deep-exome sequencing.

Overall investigators identified 32 recurrently mutated genes that fed into 10 pathways: KRAS, TGF-β, WNT, NOTCH. ROBO/SLIT signalling, G1/S transition, SW1-SNF, chromatin modification, DNA repair and RNA processing.

Additionally, the team identified mutations that were associated with the four different subtypes of PC– squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX).

Squamous tumours, they found, were enriched for TP53 and KDM6A mutations.

Pancreatic progenitor tumours preferentially expressed genes involved in early pancreatic development (FOXa2/3, PDX1 and MNX1).

ADEX tumours displayed upregulation of genes regulating networks involved in KRAS activation, exocrine (NR5A2 and RBPIL) and endocrine differentiation (NEUROD1 and NKX2-2).

Immogenic tumours contained upregulation of CTLA4 and PD1 acquired tumour immune suppression pathways.

“Knowing which sub-type a patient has would allow a doctor to provide a more accurate prognosis and treatment recommendations,” said Professor Grimmond.

Some strains of PC, he added, were associated with mutations normally linked to colon cancer or leukaemia for which experimental drugs are available.

References

Bailey P, Chang D, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature.

Published online 24 February 2016