1658P - Molecular subtyping of familial pancreatic ductal adenocarcinoma identifies novel pathogenic germline variants

Background

The 5-year survival rate of pancreatic ductal adenocarcinomas (PDAC) is around 7.2% in spite of recent advances in therapeutics, as most patients are diagnosed at an advanced stage. 10-15% of pancreatic ductal adenocarcinoma (PDAC) cases cluster in families with an unknown genetic basis, known as familial pancreatic cancer (FPC). Targeted panel and exome sequencing of FPC cases was performed to identify new variants related to PDAC risk.

Methods

Targeted panel sequencing of 60 genes associated with hereditary cancer was performed in germline from 85 PDAC cases, 53 from families with an apparent familial pancreatic cancer syndrome and 32 cases with sporadic PDAC. Exome sequencing was also performed in 11 PDAC cases that were negative for a germline mutation by panel sequencing. The presence of a somatic mutation in KRAS codons 12, 13, 59, 61, 117 and 146 was determined in cfDNA in 54 PDAC cases.

Results

By panel sequencing, pathogenic variants were identified in 4 FPC cases (7.5%) in the MLH1 and CDKN2A and none of the sporadic cases via panel sequencing. Likely pathogenic variants were found in 5 FPC cases (5.7%) in POLQ, CHEK2 and FANCM and in 3 sporadic cases (9.4%) in MUTYH, TERT and ATM. By exome sequencing, missense variants with a damaging effect were found in all 11 FPC cases tested. However, stop gain, stop loss or frameshift variants were found in 5 FPC cases (45.45%), affecting WWOX, C2orf83, CYP3A5 and TANGO2. KRAS somatic mutations in codons 12 and 13 were more frequently detected in sporadic PDAC cases (70%) compared to familial cases (16%). Interestingly, the median overall survival for sporadic and familial PDAC cases was 10.2 vs. 21.7 months (p=>0.01), respectively, even though all patients are treated the same in the clinic.

Conclusions

Familial pancreatic cancer cases harbor pathogenic germline mutations in DNA repair genes and other genes related with tumorigenesis that could explain the aggregation of PDAC in these families. FPC seems to show a different molecular and clinical profile to the sporadic form of the disease.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

IRYCIS.

Funding

ISCIII.

Disclosure

A. Carrato Mena: Financial Interests, Personal and Institutional, Advisory Board: Bayer, Shire, Celgene; Financial Interests, Personal and Institutional, Advisory Role: Bristol Myers Squibb (BMS). All other authors have declared no conflicts of interest.