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Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data

Nature Reviews Cancer volume 22, pages 131–142 (2022)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC), already among the deadliest epithelial malignancies, is rising in both incidence and contribution to overall cancer deaths. Decades of research have improved our understanding of PDAC carcinogenesis, including characterizing germline predisposition, the cell of origin, precursor lesions, the sequence of genetic alterations, including simple and structural alterations, transcriptional changes and subtypes, tumour heterogeneity, metastatic progression and the tumour microenvironment. These fundamental advances inform contemporary translational efforts in primary prevention, screening and early detection, multidisciplinary management and survivorship, as prospective clinical trials begin to adopt molecular-based selection criteria to guide targeted therapies. Genomic and transcriptomic data on PDAC were also included in the international pan-cancer analysis of approximately 2,600 cancers, a milestone in cancer research that allows further insight through comparison with other tumour types. Thus, this is an ideal time to review our current knowledge of PDAC evolution and heterogeneity, gained from the study of preclinical models and patient biospecimens, and to propose a model of PDAC evolution that takes into consideration findings from varied sources, with a particular focus on the genomics of human PDAC.

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Fig. 1: Stepwise model versus punctuated model of pancreatic ductal adenocarcinoma progression.
Fig. 2: Histological stages in pancreatic ductal adenocarcinoma progression.
Fig. 3: Expression-based subtypes of pancreatic ductal adenocarcinoma.
Fig. 4: Evolutionary model of pancreatic ductal adenocarcinoma.

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Acknowledgements

The authors acknowledge G. O’Kane and F. Notta for proofreading the manuscript.

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Authors and Affiliations

  1. Department of Surgery, Houston Methodist Hospital, Houston, TX, USA

    Ashton A. Connor

  2. Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada

    Steven Gallinger

  3. PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada

    Steven Gallinger

  4. Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, ON, Canada

    Steven Gallinger

  5. Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, ON, Canada

    Steven Gallinger

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  1. Ashton A. Connor
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The authors contributed equally to all aspects of the article.

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Correspondence to Steven Gallinger.

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Related links

Know Your Tumor: https://www.pancan.org/for-healthcare-professionals/know-your-tumor/

Precede Consortium: https://precedeconsortium.org/

SEER: https://seer.cancer.gov

Glossary

Pancreatitis

Inflammation of the pancreas, the causes of which include gallstones, alcohol and germline predisposition.

Pancreatic intraepithelial neoplasms

(PanINs). Microscopic lesions, either flat or papillary, arising in the lining of the intrapancreatic ducts and composed of cuboidal or columnar cells with degrees of cytological and architectural atypia.

Intraductal papillary mucinous neoplasms

Microscopic to macroscopic lesions arising in the lining of the intrapancreatic ducts, either main or branch ducts, and composed of mucinous epithelial cells with degrees of cytological and architectural atypia.

Mucinous cystic neoplasms

Macroscopic cystic lesions arising in the pancreas, usually the body and tail, without communication with the pancreatic duct, and composed of mucinous epithelial cells with degrees of cytological and architectural atypia.

Lynch syndrome

The result of heterozygous germline deficiency in mismatch repair genes (MLH1, MSH2, MSH6 and PMS2), which causes an increased risk of certain cancers, especially colorectal, endometrial and pancreatic adenocarcinomas.

Cytological atypia

Abnormal cellular appearance, which could be the shape, colour or size of the entire cell or intracellular contents, often including large, irregularly shaped and hyperchromic nuclei.

Acinar-to-ductal metaplasias

Metaplasias formed from a process that involves pancreatic acinar cells differentiating into duct-like cells.

Mutational signatures

Reproducible patterns of somatic changes in DNA, most commonly identified by considering the 96 possible single-nucleotide substitutions in a trinucleotide context (mutated base and bases immediately 5′ and 3′ to it), that are thought to arise from different mutational processes active during the course of cancer development, including endogenous DNA repair deficiencies and exogenous carcinogens (for example, UV radiation and smoking).

Biallelic inactivation

Two-step process by which both alleles of a gene are lost, often consisting of an inactivating mutation of one copy of the gene and a structural deletion of the other copy, resulting in loss of heterozygosity and loss of that gene’s function, thus commonly observed with tumour suppressor genes during carcinogenesis.

Structural variants

Alteration of a region of DNA, typically 1 kb or greater, by a number of mechanisms, including duplication, deletion, inversion and translocation.

Polyploidization

The acquisition of one or more additional sets of chromosomes by a normally haploid or diploid cell, often consisting of whole-genome duplication in carcinogenesis.

Chromothripsis

A mutational process characterized by up to thousands of structural variations occurring as a single event in localized regions of one chromosome or a few chromosomes.

Allelic imbalance

The unequal expression of two alleles of a gene, which can be caused by several mechanisms, including copy number changes or epigenetic inactivation.

Jaccard similarity index

A statistic used to measure the similarity (or inversely diversity) of two or more sample sets, calculated as the intersection divided by the union of the members of those sets.

Breakage–fusion–bridge cycles

This structural variation arises due to telomere loss at one end of a chromosome, leading to fusion at that identical site on the sister chromatid in prophase, then breakage of the chromosomes at a random site during chromatid separation in anaphase, causing uneven distribution of genetic material to daughter nuclei, and repetition of the cycle with subsequent cell divisions.

Synchronous PDAC

Defined as two or more neoplasms identified simultaneously or up to 6 months apart in the same patient.

Metachronous PDAC

Defined as two or more neoplasms identified more than 6 months apart in the same patient.

Neutral mutations

A DNA mutation that is independent of natural selection, such as a synonymous base substitution.

Synthetic lethality

Cellular or organismal death due to the simultaneous perturbation of two genes, often when inactivation of either gene alone has minimal effect.

Somatic BRCA mutation reversion

Somatic restoration of one or more BRCA1 or BRCA2 alleles, resulting in functional restoration of homologous recombination DNA repair.

Umbrella trials

A clinical trial design involving patient inclusion and exclusion criteria based on tumour biomarkers rather than tissue or site of origin, especially as those biomarkers inform therapeutic vulnerability.

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Connor, A.A., Gallinger, S. Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data. Nat Rev Cancer 22, 131–142 (2022). https://doi.org/10.1038/s41568-021-00418-1

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