CDKN1B Mutation May Be Linked to Worse Survival in GEP NETs

Low nuclear expression of CDKN1B, a cyclin-dependent kinase inhibitor gene that encodes p27, in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) appears to be associated with a worse prognosis. Further, mutation of CDKN1B may also be associated with worse survival in patients with GEP NETs, said Zhi Rong Qian, MD, who presented his data at the 2014 Neuroendocrine Tumor Symposium.

Though survival was worse with mutation and low nuclear expression of CDKN1B, “these associations were not absolute,” said Qian, instructor in Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School.

In describing the function and regulation of CDKN1B, Qian said that CDKN1B is an atypical tumor suppressor that regulates the cell cycle by binding to and regulating the activity of cyclinE-CDK2 in the nucleus. CDKN1B also promotes assembly in the cytoplasm and subsequent nuclear import of cyclinD1-CDK4/6 complexes.

Studies in several tumor types indicate that CDKN1B expression levels have prognostic implications. In various human malignancies (lung, head and neck, colorectal, ovarian, prostate, and breast), low nuclear expression of CDKN1B was associated with shorter survival. High cytoplasmic expression of CDKN1B is linked to shorter survival in breast, cervical, esophageal, and uterine cancers.

Recurrent somatic mutations and deletions in CDKN1B have been identified in small intestinal (SI)-NETs using exome- and genome-sequence analysis (Nat Genet. 2013;45[12]:1483-1486). Five of the 50 patients whose tumors were profiled had mutations in CDKN1B. Frameshift mutations of CDKN1B were observed in 14 of 180 (8%) SI-NETs. The authors thus nominated p27 as a tumor suppressor, and raised the possibility that cell cycle dysregulation may play a role in the pathogenesis of SI- NETs.

In Qian et al’s study, CDKN1B expression was evaluated in 145 patients with GEP NETs, and was correlated with mutational status and overall survival (OS). Immunohistochemistry was performed using standard techniques. Low CDKN1B expression, defined as nuclear staining <50%, was detected in 18%. There was no significant association between CDKN1B nuclear expression and other clinicopathologic features.

Low nuclear expression of CDKN1B was associated with shorter OS, with a multivariate hazard ratio (HR) of 2.57 compared with high nuclear expression (P = .019). The OS from the time of metastatic disease was also shorter with low expression (multivariate HR = 2.71; P = .016).

Among 112 patients with primary SI-NETS, low nuclear expression of CDKN1B was again associated with worse OS (multivariate HR = 2.84; P = .013) and shorter OS from the time of metastatic disease (multivariate HR = 3.03; P =.011) compared with high nuclear expression.

Cytoplasmic expression of CDKN1B was not associated with clinicopathologic features or survival in GEP NETs or SI-NETS (P = .53).

Mutational status and nuclear expression was determined in 51 patients with primary SI-NETs; of these, 6 of 51 (12%) had CDKN1B mutations. There was a trend toward the presence of CDKN1B mutation and low nuclear expression in SI-NETs (P =.072) but this association was not absolute, said Qian. However, mutation of CDKN1B, observed in 4 of 34 patients with metastatic SI-NETs, was associated with OS (P = .49).

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