# Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

Source: https://onco.cc/key-papers/paper-yurgelun-germline-second-hits-resected-pancreatic-genet-med-2019/  
OnCo record `paper-yurgelun-germline-second-hits-resected-pancreatic-genet-med-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Nearly one in ten of 289 unselected patients with resected pancreatic cancer carried an inherited cancer-gene variant, but the tumour had lost the second copy in fewer than half, which matters for whether PARP inhibitors will work.

## Summary

Germline and somatic DNA from 289 patients with resected pancreatic ductal adenocarcinoma, ascertained without preselection, were analysed on a customised panel. 28 of 289 (9.7%) carried pathogenic or likely pathogenic germline variants: 21 (7.3%) in double-strand DNA damage repair genes (3 BRCA1, 4 BRCA2, 14 in ATM, BRIP1, CHEK2, NBN, PALB2, RAD50 or RAD51C), 3 Lynch syndrome and 4 other (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry found second hits in 12 of 27 (44.4%). Carriers of double-strand repair variants had superior overall survival (hazard ratio 0.54).

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Genetics in Medicine
- Year: 2019
- DOI: 10.1038/s41436-018-0009-5
- Authors: Yurgelun MB, Chittenden AB, Morales-Oyarvide V, et al.
- Findings: Germline variants in 9.7%; double-strand repair genes 7.3%.; Somatic second hit in 12 of 27 carriers, 44.4%.; Repair-gene carriers: overall survival hazard ratio 0.54.
- What it means: A germline result is not the whole story: without loss of the second allele the tumour may not be repair-deficient, which is why tumour sequencing and, in trials, HRD signatures are read alongside.
- Caveats: Resected patients; survival advantage may reflect platinum exposure.; Second-hit assessment on a panel misses epigenetic silencing.

## Sources

- Yurgelun et al., Genet Med 2019: germline variants and somatic second hits in 289 resected cancers: https://doi.org/10.1038/s41436-018-0009-5
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29961768/

## Connected records

- biomarkers: [Germline BRCA1/2 pathogenic variant (gBRCAm)](https://onco.cc/biomarkers/brca-germline/), [Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations](https://onco.cc/biomarkers/brca-somatic/)
- cancers: [BRCA or PALB2-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/brca-palb2-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/resectable-pdac/)
- technologies: [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/)
- targets: [ATM](https://onco.cc/targets/atm/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [CDKN2A](https://onco.cc/targets/cdkn2a/), [PALB2](https://onco.cc/targets/palb2/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- terms: [Germline vs somatic mutations](https://onco.cc/terms/germline-vs-somatic/)
- people: [Andrew J. Aguirre](https://onco.cc/people/andrew-aguirre/)

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