Abstract 448: High prevalence of pathogenic germline variants in patients with oncogene-driven non-small cell lung cancer
Authors: Mezquita Laura , Iurchenko Andrei , Benitez Jose Carlos , Baz Maria , Nikolaev Sergey , Planchard David , Blanc-Durand Felix , Aldea Mihaela , Martín-Romano Patricia , Loriot Yohann , Nicotra Claudio , Ngocamus Maud , Scoazec Jean-Yves , Michiels Stefan , Postel-Vinay Sophie , Viot Julien , Friboulet Luc , Italiano Antoine , Andre Fabrice , Massard Christophe , Soria Jean-Charles , Rouleau Etienne , Gautheret Daniel , Besse Benjamin 
Published: July 2021

Abstract
BACKGROUND: Preliminary data has highlighted inherited predisposition to lung cancer related to certain genes. The frequency of pathogenic germline variants (PGV) PGV in patients (pts) with lung cancer according to the presence of an oncogenic driver is unknown. We studied the PGV of genes predisposing to cancer in pts with non-small cell lung cancer (NSCLC), and the somatic molecular profile of lung tumors.
METHODS: Retrospective study of whole exome sequencing (WES) from tissue biopsies performed in pts with advanced NSCLC enrolled, after signature of the inform consent, in the MOSCATO/MATCH-R trials between 2012 and 2018. Variants were considered as PGVs in the cancer predisposing genes (PMID: 29625052) if they satisfied the following criteria: (i) they had a “PASS” flag in HaplotypeCaller, (ii) were annotated as “Pathogenic” or “Likely Pathogenic” in ClinVar (PMID: 29165669) or InterVar (PMID: 28132688), or (iii) were truncating variants. Somatic driver mutations and Loss of Heterozygocity (LOH) of PGV harboring genes were further evaluated. The overlap to loss of heterozygocity regions was reported only when the variant allele frequency of the PGV was significantly higher than in the normal tissue. Cancer history, clinical and molecular data were retrospectively collected. The somatic mutations (m) in EGFR/BRAF/MET/HER2/KRAS and fusions in ALK/ROS1/RET were also considered for analysis.
RESULTS: Among 134 pts, 48% were women, median age was 61 (range 24-83), 45% were nonsmokers, 74% had adenocarcinoma. The most common somatic oncogenic driver alterations were: EGFRm in 44 pts (33%), KRASm in 19 pts (14%), BRAFm in 12 pts (9%) and ALK in 12 pts (9%).PGV were found in 22 out of 152 (15%) cancer-predisposing genes; 4 pts had additional somatic mutations (2) or LOHs (2) in the same genes. 77% of PGVs were in genes which are part of DNA repair pathways including 3.6% nucleotide excision repair (ERCC1/2/3, XPA), 6.5% homologous recombination/Fanconi Anemia: (FANC/A/C/M/D2, BRCA1, RECQL), 2.1% base excision repair (MUTYH, NTHL1), while the others were represented by genes related to cell signaling and metabolism (NF1, MET, ELANE, PRDM9, TRIM37).In the 22 PGV-carriers, 68% had a somatic oncogene-driven alteration (15/22) : EGFRm (n=7; 5 ex19del, 2 ex21(L858R)), KRASm (n=3; 2 G12D, 1 G12V), METm (n=2), HER2m (n=1), ROS1 (n=1) and RET (n=1). PGV were observed in 16% of EGFRm (7/44), 67% of METm (2/3), 15% in KRASm (3/19), 33% of HER2m (1/3), 25% of ROS1 (1/4), 50% of RET (1/2); but no PGV was identified in pts with BRAFVm (12) or ALK (12).
CONCLUSION: In our cohort, 15% of pts with NSCLC were PGV-carriers; 68% of PGV-carriers had oncogene-driven tumors, particularly with somatic EGFR mutations. PGV and oncogene-driven lung carcinogenesis need further evaluation.
Citation Format: Laura Mezquita, Andrei Iurchenko, Jose Carlos Benitez, Maria Baz, Sergey Nikolaev, David Planchard, Felix Blanc-Durand, Mihaela Aldea, Patricia Martín-Romano, Yohann Loriot, Claudio Nicotra, Maud Ngocamus, Jean-Yves Scoazec, Stefan Michiels, Sophie Postel-Vinay, Julien Viot, Luc Friboulet, Antoine Italiano, Fabrice Andre, Christophe Massard, Jean-Charles Soria, Etienne Rouleau, Daniel Gautheret, Benjamin Besse. High prevalence of pathogenic germline variants in patients with oncogene-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 448.