Germline mutations and developmental mosaicism underlying EGFR -mutant lung cancer.

Autor: Burr R; Massachusetts General Hospital Cancer Center, Boston, MA, USA., Leshchiner I; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Costantino CL; Massachusetts General Hospital Cancer Center, Boston, MA, USA.; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Blohmer M; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Sundaresan T; Massachusetts General Hospital Cancer Center, Boston, MA, USA., Cha J; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Seeger K; Massachusetts General Hospital Cancer Center, Boston, MA, USA., Guay S; Massachusetts General Hospital Cancer Center, Boston, MA, USA., Danysh BP; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gore I; St Vincent's Hospital, Birmingham, AL, USA., Jacobs RA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Slowik K; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Utro F; IBM Research, Yorktown Heights, NY, USA., Rhrissorrakrai K; IBM Research, Yorktown Heights, NY, USA., Levovitz C; IBM Research, Yorktown Heights, NY, USA., Barth JL; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Dubash T; Massachusetts General Hospital Cancer Center, Boston, MA, USA., Chirn B; Massachusetts General Hospital Cancer Center, Boston, MA, USA., Parida L; IBM Research, Yorktown Heights, NY, USA., Sequist LV; Massachusetts General Hospital Cancer Center, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Lennerz JK; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Mino-Kenudson M; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Maheswaran S; Massachusetts General Hospital Cancer Center, Boston, MA, USA.; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Naxerova K; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Getz G; Massachusetts General Hospital Cancer Center, Boston, MA, USA.; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Haber DA; Massachusetts General Hospital Cancer Center, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Howard Hughes Medical Institute, Bethesda, MD, USA.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 Sep 29. Date of Electronic Publication: 2023 Sep 29.
DOI: 10.1101/2023.09.28.23296274
Abstrakt: While the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple primary tumors in individuals with EGFR -mutant lung cancer who lack known environmental exposures remains unexplained. We identified ten patients with early-stage, resectable non-small cell lung cancer who presented with multiple anatomically distinct EGFR -mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole exome sequencing (WES) and hypermutable poly-guanine (poly-G) repeat genotyping, as orthogonal methods for lineage tracing. In two patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro . In four other patients, developmental mosaicism is supported by the poly-G lineage tracing and WES, indicating a common non-germline cell-of-origin. Thus, developmental mosaicism and germline variants define two distinct mechanisms of genetic predisposition to multiple EGFR -mutant primary tumors, with implications for understanding their etiology and clinical management.
Databáze: MEDLINE