Are PIK3CA Mutation and Amplification Associated with Clinicopathological Characteristics of Gastric Cancer?

BackgroundRecent whole-genome sequencing identified four molecular subtypes of gastric cancer (GC), of which the subgroup of Epstein–Barr virus-associated GC (EBVaGC) showed a significant enrichment of PIK3CA mutations. We here aimed to validate independently the enrichment of PIK3CA mutations in EBVaGC of a Central European GC cohort, to correlate EBV status with clinico-pathological patient characteristics and to test for a major issue of GC, intratumoral heterogeneity.Patients and methodsIn a first step, 484 GCs were screened for EBV and PIK3CA hot spot mutations of exon 9/20 using EBER in situ hybridization and pyrosequencing, respectively. Secondly, an extended sequencing of PIK3CA also utilizing next generation sequencing was carried out in all EBVaGCs and 96 corresponding lymph node metastases.ResultsTwenty-two GCs were EBER-positive, all being of latency type I. Intratumoral heterogeneity of EBER-positivity was found in 18% of EBVaGCs. Twenty-three GCs held PIK3CA mutations in hot spot regions of exon 9 or 20, being significantly more common in EBVaGCs (P < 0.001). Subsequent extended sequencing of PIK3CA of EBVaGCs showed that 14% harvested three to five different PIK3CA genotypes (including wildtype) in the same primary tumor, albeit in histologically and spatially distinct tumor areas, and that intratumoral heterogeneity of PIK3CA was also present in the corresponding lymph node metastases.ConclusionsOur findings unravel issues of tumor heterogeneity and illustrate that the assessment of the EBV status in tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate molecular tumor classification in a more clinical setting. Moreover, this is the first report of intratumoral heterogeneity of PIK3CA mutations in GC, and our findings lead to the conclusion that PIK3CA mutant and -wildtype tumor subclones are skilled to metastasize independently to different regional lymph nodes.

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“…However, our data and previous studies were unable to find any correlation between the PIK3CA -genotype and patient outcome [16]. …”

Section: Discussioncontrasting

confidence: 98%

Epstein–Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations

Böger¹,

Krüger²,

Behrens³

et al. 2017

Annals of Oncology

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“…The current study found that PIK3CA mutations were not associated with survival in patients with gastric cancer, in agreement with three previous studies [ 26 – 28 ]. Because of their relatively large sample sizes, including this study that included samples from over 200 samples, these findings, taken together, confirm the lack of relationship between PIK3CA mutations and prognosis in gastric cancer patients.…”

Section: Discussionsupporting

confidence: 93%

“…A study in a Japanese population found that the mutation rate in PIK3CA exons 1, 9, and 20, as determined by pyrosequencing, was 8.7 % [ 26 ]. Directed sequencing found that the mutation rate in PIK3CA exons 9 and 20 was 7.7–15.9 % [ 27 , 28 ]. Thus, the PIK3CA mutation rate observed in the current study (12 %) was comparable to rates previously reported.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and clinical impact of PIK3CA mutation in gastric cancer: pyrosequencing technology and literature review

et al. 2016

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BackgroundPhosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations that activate the PI3K/AKT signaling pathway have been observed in several types of carcinoma and have been associated with patient prognosis. However, the significance of PIK3CA mutations in gastric cancer remains unclear. This retrospective study investigated the relationship between PIK3CA mutations and clinical outcomes in patients with gastric cancer. Additionally, we reviewed the rate of PIK3CA mutations in gastric cancer and the association between PIK3CA mutations and prognosis in human cancers.MethodsThe study included 208 patients with gastric cancer who underwent surgical resection at Kumamoto University Hospital, Japan, between January 2001 and August 2010. Mutations in PIK3CA exons 9 and 20 were quantified by pyrosequencing assays.ResultsPIK3CA mutations were detected in 25 (12 %) of the 208 patients. Ten patients had c.1634A > G (p.E545G), 10 had c.1624G > A (p.E542K), 13 had c.1633G > A (p.E545K), nine had c.3139C > T (p.H1047R), and 1 had c.3140A > G (p.H1047Y) mutations. PIK3CA mutations were not significantly associated with any clinical, epidemiologic, or pathologic characteristic. Kaplan–Meier analysis showed no significant differences in disease-free survival (log rank P = 0.84) and overall survival (log rank P = 0.74) between patients with and without PIK3CA mutations.ConclusionsMutations in PIK3CA did not correlate with prognosis in patients with gastric cancer, providing additional evidence for the lack of relationship between the two.

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“…In the patient series that Shi et al investigated [ 11 ], patients with PIK3CA amplifications were found to have with a worse prognosis were than those without PIK3CA amplifications; however, Lee et al [ 22 ] reported that PIK3CA amplifications were not associated with a worse prognosis. Lee et al [ 22 ] proposed that the possible reason for this discrepancy might be the different proportions of patients with early gastric cancer (more than 40% of the patients in their series compared with only 14% of the patients in the series of Shi et al [ 11 ]). However, the percentage of patients with early gastric cancer in our series was 15.5%, which was similar to that in the series of Shi et al Our data demonstrated no significantly difference in survival of patients with or without PIK3CA amplifications.…”

Section: Discussionmentioning

confidence: 99%

“…The frequency of PI3KCA amplifications has been reported to be 13%-67% [ 11 , 21 - 23 ]. Some studies [ 11 , 21 ] demonstrated that PIK3CA amplifications were associated with a poor prognosis for gastric cancer patients; however, others reported no association with their clinicopathological features [ 22 , 23 ]. Therefore, whether PIK3CA amplifications can serve as a prognostic indicator for gastric cancers remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Mutations in PI3K/AKT pathway genes and amplifications of PIK3CA are associated with patterns of recurrence in gastric cancers

et al. 2015

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Mutations in genes involved in the PI3K/AKT pathway and amplifications of the PIK3CA gene in gastric cancer and their associations with clinicopathological characteristics and EBV infection were analyzed in this study. A total of 431 patients with gastric adenocarcinomas were enrolled, and 39 mutation hotspots were evaluated in these patients using MALDI-TOF mass spectrometry were analyzed. PIK3CA amplifications were analyzed using real-time quantitative PCR. Regarding patients with intestinal-type gastric cancer, those with mutations in PI3K/AKT pathway genes were also more likely to have tumors located in the lower-third of the stomach than were those without mutations. Regarding patients with diffuse-type gastric cancer, those with PI3K/AKT pathway mutations were more likely to have tumors located in the upper-third of the stomach and to have more hematogenous metastases, particularly in the liver and lungs, than were patients without such mutations (22.2% vs. 4.5%). No significant survival difference was observed between patients with vs. without PI3K/AKT pathway mutations. Mutations in PI3K/AKT pathway genes were associated with hematogenous metastasis in patients with diffuse-type gastric cancer. Only when the tumors were located in the middle-third of stomach, tumor with mutations of the PIK3CA gene or mutations of the PI3K/AKT pathway genes were associated with more EBV infection than those without mutations. Patients with PIK3CA amplifications were more likely to have diffuse-type and poorly differentiated gastric cancers and were more likely to experience peritoneal recurrence compared with those without PIK3CA amplifications. Even upon subgroup analysis, PI3KCA amplifications were found to not affect the patients’ outcomes.

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Are PIK3CA Mutation and Amplification Associated with Clinicopathological Characteristics of Gastric Cancer?

Cited by 11 publications

References 26 publications

Epstein–Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations

Epstein–Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations

Prognostic and clinical impact of PIK3CA mutation in gastric cancer: pyrosequencing technology and literature review

Mutations in PI3K/AKT pathway genes and amplifications of PIK3CA are associated with patterns of recurrence in gastric cancers

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