Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2017 Dec;30(12):1720-1727. doi: 10.1038/modpathol.2017.88. Epub 2017 Aug 4.
GNAS mutations have been described in mucinous and non-mucinous epithelial neoplasms of the appendix, pancreas, and colon, with hotspot GNAS mutations found in up to two-thirds of pancreatic intraductal papillary mucinous neoplasms. Additionally, many GNAS-mutated tumors have concurrent mutations in the Ras/Raf pathway. The clinicopathologic features of GNAS-mutated lung carcinomas, however, have not yet been characterized. Primary lung carcinomas from Brigham and Women's Hospital (n=1282) or Massachusetts General Hospital (n=1070) were genotyped on a targeted massively parallel sequencing panel of oncogenes and tumor suppressor genes including GNAS. Clinical and pathological features were reviewed, and TTF-1 immunohistochemistry was performed when material was available. Nineteen lung adenocarcinomas with hotspot GNAS mutations were identified (19/2352, 0.8%) including 14 at codon 201 and 5 at codon 227. GNAS-mutated lung adenocarcinomas occurred predominantly in female patients (16/19, 84%). Ten (10) were classified as invasive mucinous adenocarcinomas (IMA), and nine (9) were non-mucinous adenocarcinomas. All IMAs had GNAS codon 201 mutations and concurrent Ras/Raf pathway mutations (9 KRAS, 1 BRAF). No tumors with GNAS codon 227 mutations had mucinous histological features. 86% of GNAS-mutated non-mucinous adenocarcinomas (6/7) were positive for TTF-1 immunohistochemistry, while only 25% of GNAS-mutated IMAs (1/4) were positive for TTF-1. Patients with GNAS-mutated non-mucinous adenocarcinomas were more likely to have a history of smoking (9/9, 100%) compared to patients with GNAS-mutated IMAs (2/10, 20%) (P<0.001). Hotspot GNAS mutations can occur in primary lung adenocarcinomas. When associated with concurrent mutations in the Ras/Raf pathway, these neoplasms often present as IMAs. GNAS mutations are not specific to neoplasms of the gastrointestinal tract, and clinicopathologic correlation is necessary in GNAS-mutated adenocarcinomas in the lung to determine the primary site of origin.
GNAS 突变已在阑尾、胰腺和结肠的黏液性和非黏液性上皮肿瘤中被描述，在多达三分之二的胰腺内导管乳头状黏液性肿瘤中发现热点 GNAS 突变。此外，许多 GNAS 突变的肿瘤同时存在 Ras/Raf 通路的突变。然而，GNAS 突变的肺癌的临床病理特征尚未得到描述。来自布莱根妇女医院（n=1282）或马萨诸塞州综合医院（n=1070）的原发性肺癌在包括 GNAS 的肿瘤基因和肿瘤抑制基因的靶向大规模平行测序面板上进行了基因分型。回顾了临床和病理特征，并在有材料时进行了 TTF-1 免疫组化。鉴定出 19 例具有热点 GNAS 突变的肺腺癌（19/2352，0.8%），包括 14 例在密码子 201 处和 5 例在密码子 227 处。GNAS 突变的肺腺癌主要发生在女性患者（16/19，84%）。其中 10 例被归类为浸润性黏液腺癌（IMA），9 例为非黏液腺癌。所有的 IMA 均有 GNAS 密码子 201 突变和同时存在 Ras/Raf 通路突变（9 个 KRAS，1 个 BRAF）。没有密码子 227 突变的肿瘤具有黏液组织学特征。86%（6/7）的 GNAS 突变非黏液腺癌 TTF-1 免疫组化阳性，而 GNAS 突变的 IMA 中只有 25%（1/4）TTF-1 阳性。与 GNAS 突变的 IMA 患者（2/10，20%）相比，具有 GNAS 突变的非黏液腺癌患者（9/9，100%）更有可能有吸烟史（P<0.001）。热点 GNAS 突变可发生在原发性肺腺癌中。当与 Ras/Raf 通路的同时突变相关时，这些肿瘤通常表现为 IMA。GNAS 突变不仅限于胃肠道肿瘤，在肺 GNAS 突变的腺癌中，需要进行临床病理相关性分析，以确定原发部位。
