Elsevier

Human Pathology

Volume 34, Issue 12, December 2003, Pages 1276-1282
Human Pathology

Original contribution
Abnormal expression of pRb, p16, and cyclin D1 in gastric adenocarcinoma and its lymph node metastases: relationship with pathological features and survival

Presented in part as a poster at Pathological Society of Great Britain and Ireland/International Academy of Pathology Joint Meeting, Dublin, Ireland, July 2002.
https://doi.org/10.1016/j.humpath.2003.07.005Get rights and content

Abstract

The retinoblastoma (Rb) pathway controls the G1-S checkpoint of the cell cycle. Inactivating mutations and deletions of p16 and Rb and up-regulation of cyclin D1 disrupt this pathway and occur in many cancers. However, the concurrent expression of these genes in primary and metastatic gastric cancer is unknown, and the prognostic value of their expression is unclear. In this study, the expression of cyclin D1, retinoblastoma protein (pRb), and p16 in 67 resected gastric adenocarcinomas, and of pRb and p16 in 40 associated lymph node metastases, was determined using a streptavidin-biotin-peroxidase immunohistochemical method. Relationships with clinical and pathological features were analyzed. Cyclin D1 overexpression (≥5% expression) was seen in 55% of cancers; pRb loss (<20% expression), in 33%; p16 loss (<10% expression), in 49%; and at least 1 of these abnormalities, in 92.5%. Cyclin D1 overexpression was associated with poor differentiation (P = 0.027) and signet ring cell type (P = 0.029). pRb expression was lower in lymph node metastases than in the corresponding primary tumors (P <0.001). Univariate and multivariate survival analysis (minimum follow-up 72 months or until death) revealed that <20% pRb expression, <30% pRb expression, and International Union Against Cancer stage >2 were associated with worse overall survival. The results suggest that Rb pathway disturbances play an important role in gastric carcinogenesis. The poor prognosis of cancers with low pRb expression and the reduced pRb expression in lymph node metastases raise the possibility that Rb and related genes also influence progression.

Section snippets

Tissue samples

Paraffin-embedded, formalin-fixed tissue blocks of resected gastric adenocarcinomas from 67 patients (mean age, 66 years; range, 32 to 88 years; 48 male and 19 female) were retrieved from the histopathology archives of the Royal London and St. Bartholomew’s Hospitals. No patient had received preoperative chemotherapy. Slides of primary tumors (n = 67) and lymph node metastases (n = 40) stained with hematoxylin and eosin were examined by a histopathologist (R.M.F.). Each tumor was graded as

Carcinomas

Of the 67 carcinomas, 5 were well differentiated, 30 were moderately differentiated, and 32 were poorly differentiated. Eighteen were of the signet ring cell type. Nine were categorized as UICC stage 1, 8 as stage 2, 28 as stage 3, and 22 as stage 4.

Cyclin D1

Cyclin D1 overexpression (≥5% expression) was seen in 37 (55%) of the carcinomas; >10% expression was seen in 21% of the carcinomas (mean, 6.4%; range, 0.6% to 20%) (Fig 1A).

pRb

Nonneoplastic gastric mucosa showed variable pRb expression. Staining was

Discussion

Inactivating mutations and deletions of Rb and p16 and associated loss of expression are found in many different cancers. Cyclin D1 amplification with overexpression is also common.12, 15, 17, 18, 28 Existing data suggest that abnormalities of pRb, p16, and cyclin D1 play a role in the pathogenesis of gastric cancer.22, 23, 24, 25 Comparisons are hampered by variable criteria for pRb and p16 loss,12, 13, 15, 17, 28 but (comparing directly whenever possible) <10% p16 expression, <50% pRb

Acknowledgements

The authors thank Professor Elisabeth Brambilla, Centre Hospitalier Universitaire de Grenoble, France, for kindly supplying the external positive controls as a gift. They also thank Alex Brown, Department of Histopathology, for technical support.

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