Abstract P2-05-01: Whole genome sequencing reveals enrichment of mutations in mucin gene family in breast cancer diagnosed during pregnancy
Authors: Nguyen B , Venet D , Desmedt C , Pruneri G , Peccatori F , Mardis ER , Azim HA , Rothé F , Sotiriou C 
Published: February 2018

Abstract
Background
Pregnancy is known to modulate breast cancer (BC) risk. Different reproductive behaviors have been shown to impact not only the risk of developing BC but also the phenotypes of these tumors. Breast cancer diagnosed during pregnancy (BCP) is a rare disease but could serve as a good model to understand how pregnancy modulates BC biology. In this project, we aim to interrogate the effect of pregnancy on the biology of BC by performing whole genome sequencing (WGS) using a unique series of BC patients diagnosed during pregnancy (BCP).
Method
Whole genome sequencing was performed for 35 BCP and 20 non-pregnant controls matched for age and stage with available clinic-pathological data. DNA extracted from primary tumor and matched adjacent normal FFPE tissues was assessed using WGS on Illumina HiSeqXTen platform targeting 60x and 30x coverage for tumor and normal DNA respectively. Briefly, 2x150bp paired end sequence data were generated, cleaned, trimmed and aligned to the reference genome (hg19) using bwa-mem. Somatic mutations were detected using Strelka and annotated using SnpEff. Mutational signatures were extracted using deconstructSigs. Differences on mutational profiles between BCP and case controls were assessed using Wilcoxon test for continuous variables and Fisher exact test for categorical variables.
Result
No difference in clinic-pathological features was observed between BCP and control patients. A median of 10084 and 13829 SNVs and of 26 and 21 indels were identified in the BCP and controls respectively, no significant difference between the two groups being observed (p = 0.703 and p = 0.851). Of interest, a significantly higher number of mutations was found in the BCP as compared to the control group when considering only mutations associated with a deleterious effect (median: 20 vs. 12, p = 0.027). As expected, TP53 and PIK3CA were the most frequently mutated genes both in BCP and control cases without any significant difference between the groups (34.3% vs. 22.2%, p = 0.53 and 20.0% vs. 16.7%, p = 1, respectively). Interestingly, there was a significant enrichment of non-silent mutations in the mucin genes family (MUC2, MUC4, MUC12, MUC16, MUC17, MUC20) in the BCP group: 45.7% of BCP vs. 11.1% of control cases had at least one such mutation (p = 0.015). A similar significant result (45.7% vs. 23.1%, p = 0.034) was found when comparing BCP with BC control cases from the TCGA dataset (selected to have similar age, ER and PR distribution, N = 56). When comparing the distribution of the twelve BC mutational signatures, a borderline significant enrichment with a signature depicting mismatch-repair deficiency (signature 20) was observed in the BCP patients (p = 0.059).
Conclusion
This is the first study reporting the mutational landscape of breast cancer diagnosed during pregnancy using WGS. We found that BCP are associated with a higher number of putative driver mutations including mutations in mucin genes, shown to be implicated in tumorigenesis. Furthermore, BCP were enriched with a mismatch-repair deficiency signature. These results could open new avenues for the development of targeted therapeutic approaches for patients diagnosed with breast cancer during pregnancy.
Citation Format: Nguyen B, Venet D, Desmedt C, Pruneri G, Peccatori F, Mardis ER, Azim HA, Rothé F, Sotiriou C. Whole genome sequencing reveals enrichment of mutations in mucin gene family in breast cancer diagnosed during pregnancy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-01.