Levels of cyclin D increase upon AMBRA1 lossAMBRA1-knockout cells showed increased phosphorylation of RB and cell-cycle gene expression with palbociclib treatment compared to control cells (Fig. 1e, Extended Data Fig. 1p, q), which suggested an increased activity of cyclin-dependent kinases. Accordingly, we observed a notable increase of proteins in the cyclin-D family and

Human cancers arise from environmental, heritable, and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced cancer patients, we identified pathogenic germline variants in cancer predisposition genes and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.

Background: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer. Methods: We studied clinical and tumor characteristics of germline PV in 5118 patients who underwent prospective genomic profiling using paired tumor-normal tissue samples in 468 cancer genes. Results: Germline PV in high/moderate penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n=54), CHEK2 (n=30) and ATM (n=26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared to non-carriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1 and MEN1) were diagnosed at younger age compared to non-carriers, and of tumor suppressors, 75% demonstrated bi-allelic inactivation in tumors. Significantly higher proportion of germline PV in high/moderate penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors or early age at diagnosis compared to unselected patients (10.5% vs 4.1%; p-value=1.7e-04). Conclusions: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer. Impact: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance.