Table 1.
Hereditary/Familial Syndromes Associated with Increased Risk of Pancreatic Cancer
| Syndrome | Phenotype | Causative Gene | Function of Gene and Mechanism | Cumulative PC Risk | PC Relative Risk |
|---|---|---|---|---|---|
| Peutz Jeghers syndrome (PJS) | Mucocutaneous pigmentation, gastrointestinal hamartomatous polyps. High risk of gastrointestinal, breast, ovary, endometrial and lung cancers |
STK11/LKB1 | Tumor suppressor AMPK signalling |
8-11% at 70 years of age Up to 36% lifetime risk9–11,109 |
132 fold10,109 |
| Hereditary pancreatitis (HP) | Chronic pancreatitis and recurrent acute pancreatitis | PRSS1,SPINK1, PRSS2, CTRC | Encodes cationic trypsinogen/encodes trypsinogen inhibitor | Up to 53% at 75 years of age13–15 | 26–87 fold12,16,17,110 |
| Familial atypical multiple mole melanoma (FAMMM) | Multiple atypical nevi (>50) and history of melanoma. Other tumours: breast, lung, endometrium. |
P16/CDKN2A | Tumor suppressor Cell cycle |
17% at 75 years of age24 | 13–46.6 fold20,111 |
| Hereditary breast-ovarian cancer syndrome (HBOC) | Breast and ovarian cancer |
BRCA1, BRCA2, PALB2 |
Tumor suppressors Homologous repair |
1.5–4% at 70 years of age (specifically increased in BRCA2)112,113 |
BRCA1: 4–6 fold29,112 BRCA2: 3.5–22 fold29,113,114 PALB2: 6 fold30,31 |
| Familial adenomatous polyposis syndrome (FAP) | Colorectal polyposis. Increased risk of colorectal cancer, hepatoblastoma, thyroid cancer, desmoid tumours. | APC | Tumor suppressor | 1.7% at 80 years of age34 | 4.5 fold115 |
| Lynch syndrome (LS) | Nonpolyposis colorectal or endometrial cancer. Other cancers: stomach, small intestine, urinary tract, brain. |
MLH1, MSH2, MSH6, PMS2 | Mismatch repair system | 3.7% at 70 years of age32 | 8.6 fold32 |
| Li-Fraumeni syndrome (LFS) | Sarcoma, adrenocortical, breast and/or brain carcinoma | TP53 | Tumor suppressor DNA repair |
<5%28,35 | - |
| Ataxia telangiectasia (AT) | Cerebellar ataxia/telangiectasias | ATM | Tumor suppressor DNA repair |
<5%28,36 | 2.7 fold36 |
| Cystic fibrosis (CF) | Respiratory infections, pancreatic insufficiency | CFTR | Encodes transmembrane conductance regulator | <5%28 | 5.3 fold116 |
| Familial pancreatic cancer (FPC) | Familial PC aggregation | – | – | −3 or more FDR with PC: 16%-40% cumulative risk53 -2 FDR with PC: up to 12% cumulative risk53 -1 FDR with PC: up to 6%47 |
−3 FDR with PC: 32-fold47 -2 FDR with PC: 6 fold47 -1 FDR with PC: 2–5 fold44 |
Abbreviations: PC, pancreatic cancer; FDR, first degree relative.