Schönleben Frank, Qiu Wanglong, Allendorf John D, Chabot John A, Remotti Helen E, Su Gloria H
Department of Otolaryngology/Head and Neck Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Gastrointest Surg. 2009 Aug;13(8):1510-6. doi: 10.1007/s11605-009-0917-4. Epub 2009 May 14.
Mutations of KRAS are known to occur in periampullary and ampullary adenomas and carcinomas. However, nothing is known about NRAS, HRAS, BRAF, and PIK3CA mutations in these tumors. While oncogenic BRAF contributes to the tumorigenesis of both pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasms/carcinomas (IPMN/IPMC), PIK3CA mutations were only detected in IPMN/IPMC. This study aimed to elucidate possible roles of BRAF and PIK3CA in the development of ampullary and periampullary adenomas and carcinomas.
Mutations of BRAF, NRAS, HRAS, KRAS, and PIK3CA were evaluated in seven adenomas, seven adenomas with carcinoma in situ, and 21 adenocarcinomas of the periampullary duodenal region and the ampulla of Vater. Exons 1 of KRAS; 2 and 3 of NRAS and HRAS; 5, 11, and 15 of BRAF; and 9 and 20 of PIK3CA were examined by direct genomic sequencing.
In total, we identified ten (28.6%) KRAS mutations in exon 1 (nine in codon 12 and one in codon 13), two missense mutations of BRAF (6%), one within exon 11 (G469A), and one V600E hot spot mutation in exon 15 of BRAF. BRAF mutations were present in two of five periampullary tumors. All mutations appear to be somatic since the same alterations were not detected in the corresponding normal tissues.
Our data provide evidence that oncogenic properties of KRAS and BRAF but not NRAS, HRAS, and PIK3CA contribute to the tumorigenesis of periampullary and ampullary tumors; BRAF mutations occur more frequently in periampullary than ampullary neoplasms.
已知KRAS突变发生在壶腹周围和壶腹腺瘤及癌中。然而，对于这些肿瘤中的NRAS、HRAS、BRAF和PIK3CA突变情况却一无所知。虽然致癌性BRAF参与了胰腺导管腺癌和导管内乳头状黏液性肿瘤/癌（IPMN/IPMC）的肿瘤发生，但PIK3CA突变仅在IPMN/IPMC中被检测到。本研究旨在阐明BRAF和PIK3CA在壶腹和壶腹周围腺瘤及癌发生发展中的可能作用。
对7例腺瘤、7例原位癌腺瘤以及21例壶腹周围十二指肠区域和 Vater壶腹腺癌中的BRAF、NRAS、HRAS、KRAS和PIK3CA突变进行评估。通过直接基因组测序检测KRAS的第1外显子；NRAS和HRAS的第2和第3外显子；BRAF的第5、11和15外显子；以及PIK3CA的第9和第20外显子。
我们总共在第1外显子中鉴定出10个（28.6%）KRAS突变（9个在密码子12，1个在密码子13），2个BRAF错义突变（6%），1个在第11外显子内（G469A），以及1个BRAF第15外显子的V600E热点突变。BRAF突变存在于5例壶腹周围肿瘤中的2例。所有突变似乎都是体细胞突变，因为在相应的正常组织中未检测到相同的改变。
我们的数据提供了证据，表明KRAS和BRAF而非NRAS、HRAS和PIK3CA的致癌特性参与了壶腹周围和壶腹肿瘤的肿瘤发生；BRAF突变在壶腹周围肿瘤中比在壶腹肿瘤中更频繁发生。
