Takano Shinichi, Fukasawa Mitsuharu, Maekawa Shinya, Kadokura Makoto, Miura Mika, Shindo Hiroko, Takahashi Ei, Sato Tadashi, Enomoto Nobuyuki
First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
PLoS One. 2014 Jun 4;9(6):e98718. doi: 10.1371/journal.pone.0098718. eCollection 2014.
To clarify the genetic mutations associated with intraductal papillary mucinous neoplasms (IPMN) and IPMN-related pancreatic tumours, we conducted cancer-related gene profiling analyses using pure pancreatic juice and resected pancreatic tissues.
Pure pancreatic juice was collected from 152 patients [nine with a normal pancreas, 22 with chronic pancreatitis (CP), 39 with pancreatic ductal adenocarcinoma (PDAC), and 82 with IPMN], and resected tissues from the pancreas were collected from 48 patients (six IPMNs and 42 PDACs). The extracted DNA was amplified by multiplexed polymerase chain reaction (PCR) targeting 46 cancer-related genes containing 739 mutational hotspots. The mutations were analysed using a semiconductor-based DNA sequencer.
Among the 46 cancer-related genes, KRAS and GNAS mutations were most frequently detected in both PDAC and IPMN cases. In pure pancreatic juice, GNAS mutations were detected in 7.7% of PDAC cases and 41.5% of IPMN cases (p<0.001 vs. others). All PDAC cases with GNAS mutations (n = 3) were accompanied by IPMN. Multivariate analysis revealed that GNAS mutations in IPMN cases were associated with dilated main pancreatic ducts (MPD, p = 0.016), while no statistically independent associations with clinical variables were observed for KRAS mutations. In the resected pancreatic tissues, GNAS mutations were detected in 50% of PDAC cases concomitant with IPMN, 33.3% of PDAC cases derived from IPMN, and 66.7% of IPMN cases, while no GNAS mutations were detected in cases of PDAC without IPMN.
The GNAS mutation was specifically found in the cases with IPMN and it was speculated that some PDACs might be influenced by the concomitant but separately-located IPMN in their pathogenic mechanism. Furthermore, the GNAS mutation was significantly associated with MPD dilatation in IPMN cases, suggesting its role in mucus hypersecretion.
为了阐明与导管内乳头状黏液性肿瘤（IPMN）及IPMN相关胰腺肿瘤相关的基因突变，我们使用纯胰液和切除的胰腺组织进行了癌症相关基因谱分析。
收集了152例患者的纯胰液[9例胰腺正常，22例慢性胰腺炎（CP），39例胰腺导管腺癌（PDAC），82例IPMN]，并从48例患者（6例IPMN和42例PDAC）中收集了切除的胰腺组织。提取的DNA通过针对包含739个突变热点的46个癌症相关基因的多重聚合酶链反应（PCR）进行扩增。使用基于半导体的DNA测序仪分析突变。
在46个癌症相关基因中，KRAS和GNAS突变在PDAC和IPMN病例中最常被检测到。在纯胰液中，7.7%的PDAC病例和41.5%的IPMN病例检测到GNAS突变（与其他病例相比，p<0.001）。所有发生GNAS突变的PDAC病例（n = 3）均伴有IPMN。多变量分析显示，IPMN病例中的GNAS突变与主胰管（MPD）扩张相关（p = 0.016），而KRAS突变未观察到与临床变量有统计学上的独立关联。在切除的胰腺组织中，50%与IPMN伴发的PDAC病例、33.3%源自IPMN的PDAC病例以及66.7%的IPMN病例检测到GNAS突变，而无IPMN的PDAC病例未检测到GNAS突变。
GNAS突变在IPMN病例中特异性发现，推测一些PDAC在其致病机制中可能受到伴发但位置分开的IPMN的影响。此外，GNAS突变在IPMN病例中与MPD扩张显著相关，提示其在黏液分泌过多中的作用。
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