The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go

Abstract

The publication of the "Pan-Cancer Atlas" by the Pan-Cancer Analysis of Whole Genomes Consortium, a partnership formed by The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), provides a wonderful opportunity to reflect on where we stand in our understanding of the genetics of pancreatic cancer, as well as on the opportunities to translate this understanding to patient care. From germline variants that predispose to the development of pancreatic cancer, to somatic mutations that are therapeutically targetable, genetics is now providing hope, where there once was no hope, for those diagnosed with pancreatic cancer.

Fig. 1. A patient with familial atypical multiple mole melanoma syndrome (FAMMM).

Note the numerous melanocytic nevi. (Courtesy of Elise Ng, MD).

Fig. 2. Medullary carcinoma of the pancreas.

These cancers are often microsatellite unstable. Note the pushing boarder and syncytial growth pattern (a), and the loss of expression of the mismatch repair protein MLH1 (b). (a hematoxylin and eosin stain; b immunolabeling for MLH1).

Fig. 3. Peutz–Jeghers syndrome.

Note the melanocytic macules on the lips and buccal mucosa in a, and the classic hamartomatous polyp in b. (a courtesy of Sewon Kang, MD. b is a hematoxylin and eosin stain).

Fig. 4. Intraductal oncocytic papillary neoplasm (IOPN) with a characteristic PRKACA fusion.

The fusion has resulted in loss of the 5′ probe (red) for PRKACA in this fluorescent in situ hybridization. (3′PRKACA[19p13.12](Green)/5′PRKACA[19p13.12](Red)) (Courtesy of Michael Torbenson).

Fig. 5. The characteristic changes in the four most common cystic neoplasms of the pancreas.

VEGFA vascular endothelial growth factor-A.

Fig. 6. Mucinous cystic neoplasm of the pancreas.

Note the dramatically different degrees of dysplasia in the three locules. (Hematoxylin and eosin stain).

Fig. 7. Loss of SMAD4 protein in a pancreatic cancer metastatic to the ovaries.

The patient’s primary pancreatic cancer showed loss of SMAD4 as did the adenocarcinoma involving both ovaries. This pattern supports the diagnosis that the adenocarcinoma in the ovaries was a metastasis from the patient’s pancreatic primary. (Immunolabeling for SMAD4).