City of Hope Comprehensive Cancer Center, Duarte, California.
Sutter Roseville Medical Center, Roseville, California.
Cancer. 2021 Aug 1;127(15):2801-2806. doi: 10.1002/cncr.33573. Epub 2021 Apr 15.
To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset.
The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model.
Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking.
Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.
为了确定肺癌筛查的其他高危人群，该筛查针对有长期吸烟史的人群，从而错过了更年轻或不吸烟的病例。作者评估了肺腺癌患者种系致病性变异（PVs）与加速发病之间的关联。
作者组建了一个回顾性队列（1999-2018 年），该队列由肺腺癌肿瘤遗传诊所的患者组成。合格条件需要有癌症家族史、吸烟数据以及种系生物样本，以便通过多基因面板进行筛查。通过加速失效时间模型，对种系 PVs（TP53/EGFR、BRCA2、其他范可尼贫血[FA]途径基因和非 FA DNA 修复基因）与诊断时的年龄进行关联分析。
研究对象（n=187；年龄 28-89 岁；女性占 72.7%；西班牙裔占 11.8%）包括吸烟者（最低 5 包/年；n=65）和不吸烟者（轻度曾吸烟者[n=18]和从不吸烟者[n=104]）。总体而言，26.7%的患者携带 1 到 2 种种系 PVs：TP53（n=5）、EGFR（n=2）、BRCA2（n=6）、另一种 FA 基因（n=11）或另一种 DNA 修复基因（n=28）。在调整吸烟、性别和种族因素后，BRCA2 PVs 使肺腺癌的诊断提前了 12.2 年（95%置信区间[CI]，2.5-20.6 年），TP53/EGFR PVs 提前了 9.0 年（95%CI，0.5-16.5 年），其他 FA 基因的 PVs 提前了 6.1 年（95%CI，-1.0 至 12.6 年）。其他 DNA 修复基因的 PVs 与发病无关联。种系相关性与吸烟无关。
在肺腺癌病例中，种系 PVs（TP53、EGFR、BRCA2 和可能的其他 FA 基因）可能与发病较早有关。随着进一步研究，肺癌筛查的标准可能需要包括高危 PVs 的携带者，这一发现可能会影响精准治疗并通过早期诊断降低肺癌死亡率。
