Germline mutations and age at onset of lung adenocarcinoma

Reckamp, Karen L.; Behrendt, Carolyn E.; Slavin, Thomas P.; Gray, Stacy W.; Castillo, Danielle; Koczywas, Marianna; Cristea, Mihaela; Babski, Kirsten; Stearns, Donna; Marcum, Catherine A.; Rodriguez, Yenni; Hass, Amie; Vecchio, Mary; Mora, Pamela; Cervantes, Aleck; Sand, Sharon; Mejia, Rosa; Tsou, Terrence; Salgia, Ravi; Weitzel, Jeffrey N.

doi:10.1002/cncr.33573

Cited by 16 publications

(9 citation statements)

References 24 publications

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“…Though TP53, RB1, and PIK3CA are common mutations in SCLC, the presence of these alterations was not uniform in our post-transformation genomic analyses. Therefore, it is important to consider other potential biomarkers that could be indicative of the EGFR to SCLC transformation, such as germline mutational analysis, with germline mutations in lung cancer becoming more commonly detected [ 40 ]. Any future additional therapeutic studies for EGFR TKIs should take into consideration the possibility of SCLC transformation, and perform sub-sequential histological examinations where SCLC genomic markers may not be necessarily detected by liquid biopsy.…”

Section: Discussionmentioning

confidence: 99%

Small Cell Lung Cancer Transformation following Treatment in EGFR-Mutated Non-Small Cell Lung Cancer

Mambetsariev

Arvanitis

Fricke

et al. 2022

JCM

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EGFR-mutated lung adenocarcinoma patients who received tyrosine kinase inhibitors (TKIs) may initially respond to therapy, but over time, resistance eventually occurs. In a small population (5–10%), these patients can have a histological transformation to SCLC. Nine patients with EGFR-mutated lung adenocarcinoma who transformed to SCLC were evaluated at City of Hope. Patient clinical and pathology data, including multiple next-generation sequencing (NGS) results, clinical therapies, histology, and outcomes, were collected across multiple time points. Descriptive statistics were utilized to visualize and interpret the clinical therapeutic timeline and molecular transformation profiles for these patients. All patients received at least one line of EGFR TKI therapies prior to small cell lung cancer transformation, including erlotinib, afatinib, and osimertinib. Two patients also received chemotherapy prior to transformation (one with immunotherapy). The median months to small cell lung cancer transformation was 16 months, ranging from 4–49 months. The median overall survival (OS) was 29 months from diagnosis, with the minimum of 16 months and maximum of 62 months. The majority of patients had EGFR exon 19 deletion (n = 7, 77.8%), and no patients had a change of original oncogenic EGFR mutation over the different time points. Though a TP53 mutation was detected in eight patients (88.9%) either at the first biopsy or the subsequent biopsies, an RB1 alteration was only detected in one patient at presentation, and three patients upon subsequent biopsies (n = 4, 44.4%). Each patient had a unique molecular profile in the subsequent molecular testing post-transformation, but BRAF alterations occurred frequently, including BRAF rearrangement (n = 1), fusion (n = 1), and amplification (n = 1). Our results showed that EGFR-mutated lung adenocarcinoma to SCLC transformation patients have a unique histological, molecular, and clinical profile over multiple time points, with further heterogeneity that is not currently reported in the literature, and we suggest more work is required to better understand the molecular heterogeneity and clinical outcomes over time for this EGFR TKI resistance subtype.

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Section: Discussionmentioning

confidence: 99%

Small Cell Lung Cancer Transformation following Treatment in EGFR-Mutated Non-Small Cell Lung Cancer

Mambetsariev

Arvanitis

Fricke

et al. 2022

JCM

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“…Studies other than the two presented in the introduction [7,8] have found an unusually high prevalence of BRA1/2gl variants among LC patients. In a national Chinese multicenter retrospective study conducted in advanced stage (stage III-IV) non-small cell lung cancer (NSCLC), Hu et al [10] found a 1.03% (64 of 6220 participants) prevalence of BRCA1/2glpv which was higher than the estimated frequency in East Asians (0.2%) [11].…”

Section: Discussionmentioning

confidence: 92%

“…There was an excess of PV in cases compared to controls, resulting in an OR of 5.18 (95%CI 2.34-11-33). In addition, Reckamp et al observed that LC development was accelerated by 12 years in BRCA2glpv women carriers (95%CI, 2.5 -20.6) [8]. The main objective of the present work was to describe clinical and outcome characteristics of a series of LC patients harboring BRCA1/2gl.…”

Section: Introductionmentioning

confidence: 88%

Characterization of lung cancers in patients with BRCA germline variants: A multicenter series

Sanchis-Borja¹,

Fallet²,

Fabre³

et al. 2022

Lung Cancer

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“…Rare germline PVs in genes known to cause hereditary cancer syndromes have been associated with an earlier onset of disease in different cancers including RCC [58][59][60][61][62] , and detection of these variants with genetic testing can guide clinical management in at elevated genetic risk for cancer 63 . To further characterize the clinical impact of the rare germline PVs identified in the genes with a significantly higher burden of PVs in RCC patients, we compared the age of disease onset between the groups defined by genetic status: (1) patients carrying germline PVs in the known RCC risk genes; FH, MET, and VHL; (2) patients carrying germling PVs in CHEK2; These results, taken together with the only modest enrichment of germline PVs in CHEK2, suggests caution for considering CHEK2 as a RCC predisposition gene.…”

Section: Genesmentioning

confidence: 99%

Integrative Analysis of Germline Rare Variants in Clear and Non-Clear Cell Renal Cell Carcinoma

Han

Camp

Chu

et al. 2023

Preprint

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IMPORTANCE RCC encompasses a set of histologically distinct cancers with a high estimated genetic heritability, of which only a portion is currently explained. Previous rare germline variant studies in RCC have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification that may significantly impact the interpretation and discovery of certain candidate risk genes. OBJECTIVE To evaluate the enrichment of germline PVs in established cancer-predisposing genes (CPGs) in clear cell and non-clear cell RCC patients compared to cancer-free controls using approaches that account for population stratification and to identify unconventional types of germline RCC risk variants that confer an increased risk of developing RCC. DESIGN, SETTING, AND PARTICIPANTS In 1,436 unselected RCC patients with sufficient data quality, we systematically identified rare germline PVs, cryptic splice variants, and copy number variants (CNVs). From this unselected cohort, 1,356 patients were ancestry-matched with 16,512 cancer-free controls, and gene-level enrichment of rare germline PVs were assessed in 143 CPGs, followed by an investigation of somatic events in matching tumor samples. MAIN OUTCOMES AND MEASURES Gene-level burden of rare germline PVs, identification of secondary somatic events accompanying the germline PVs, and characterization of less-explored types of rare germline PVs in RCC patients. RESULTS In clear cell RCC (n = 976 patients), patients exhibited significantly higher prevalence of PVs in VHL compared to controls (OR: 39.1, 95% CI: 7.01-218.07, p-value:4.95e-05, q-value:0.00584). In non-clear cell RCC (n = 380 patients), patients carried enriched burden of PVs in FH (OR: 77.9, 95% CI: 18.68-324.97, p-value:1.55e-08, q-value: 1.83e-06) and MET (OR: 1.98e11, 95% CI: 0-inf, p-value: 2.07e-05, q-value: 3.50e-07). In a CHEK2-focused analysis with European cases and controls, clear cell RCC patients (n=906 European patients) harbored nominal enrichment of the previously reported low-penetrance CHEK2 variants, p.Ile157Thr (OR:1.84, 95% CI: 1.00-3.36, p-value:0.049) and p.Ser428Phe (OR:5.20, 95% CI: 1.00-26.40, p-value:0.045) while non-clear cell RCC patients (n=295 European patients) exhibited nominal enrichment of CHEK2 LOF germline PVs (OR: 3.51, 95% CI: 1.10-11.10, p-value: 0.033). RCC patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset compared to patients without any germline PVs in CPGs (Mean: 46.0 vs 60.2 years old, Tukey adjusted p-value < 0.0001), and more than half had secondary somatic events affecting the same gene (n=10/15, 66.7%, 95% CI: 38.7-87.0%). Conversely, patients with rare germline PVs in CHEK2 exhibited a similar age of disease onset to patients without any identified germline PVs in CPGs (Mean: 60.1 vs 60.2 years old, Tukey adjusted p-value: 0.99), and only 30.4% of the patients carried secondary somatic events in CHEK2 (n=7/23, 95% CI: 14.1-53.0%). Finally, rare pathogenic germline cryptic splice variants underexplored in RCC were identified in SDHA and TSC1, and rare pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL. CONCLUSIONS AND RELEVANCE This systematic analysis supports the existing link between several RCC risk genes and elevated RCC risk manifesting in earlier age of RCC onset. Our analysis calls for caution when assessing the role of germline PVs in CHEK2 due to the burden of founder variants with varying population frequency in different ancestry groups. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants, such as cryptic splice variants and CNVs.

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Germline mutations and age at onset of lung adenocarcinoma

Cited by 16 publications

References 24 publications

Small Cell Lung Cancer Transformation following Treatment in EGFR-Mutated Non-Small Cell Lung Cancer

Small Cell Lung Cancer Transformation following Treatment in EGFR-Mutated Non-Small Cell Lung Cancer

Characterization of lung cancers in patients with BRCA germline variants: A multicenter series

Integrative Analysis of Germline Rare Variants in Clear and Non-Clear Cell Renal Cell Carcinoma

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