Gallbladder Cancer Pathway Identified

A genetic analysis has shown that gallbladder cancer patients could stand to benefit from existing drugs targeting the ErbB pathway.

AsianScientist (Jul 14, 2014) – Scientists have found that mutations in the ErbB signalling pathway are a major cause of gallbladder cancer, a disease which disproportionally affects East Asians and Northern Indians. The results of their genetic analysis have been published in the journal Nature Genetics.

Gallbladder cancer is a relatively rare cancer, affecting 2.5 out of every 100,000 individuals. However, incidence rates have been increasing, particularly within certain ethic groups such as Chinese and Northern Indians, suggesting that there is a strong genetic component. No reliable diagnosis methods currently exist; symptoms typically do not show up until the disease has progressed significantly, leaving many patients with a poor prognosis of less than a year on average.

“The incidence and mortality of gallbladder cancer is increasing in many parts of the world, including China,” said one of the study’s corresponding authors, Dr. Liu Yingbin, a biliary tract surgeon in Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai.

“A major challenges in finding novel therapeutic approaches is our limited understanding of the complex pathogenesis and genomic alternation of gallbladder cancer and the lack of reliable prognostic molecular markers. Understanding the genomic alterations in gallbladder may lead to the development of more efficient methods of prevention, diagnosis and treatment,” he told Asian Scientist Magazine.

In this study, researchers analysed the DNA of 57 gallbladder cancer patients paired with healthy controls. Focusing on the parts of the genome that encode for proteins (the exome), they performed whole exome sequencing as well as ultra-deep sequencing of a panel of 283 candidate genes.

Apart from the usual suspects TP53 and KRAS, genes found to be mutated in most cancers, the team uncovered mutations in the genes ERBB3 and ERBB2 which have not been previously associated with gallbladder cancer. ERBB3 and ERBB2, together with epidermal growth factor (EGFR), belong to the ErbB signalling pathway which has been implicated in cancers such as breast cancer.

“Silencing of EGFR, ERBB2, and ERBB3 inhibited the growth of gallbladder cells in a time-dependent manner and impaired cell motility,” said Dr. Liu Yun, corresponding author from Fudan University. “Moreover, we found 36.8 percent of gallbladder cancer patients had protein sequence-altering mutations in the ErbB pathway, including the ErbB family and their upstream/downstream genes. Patients with ErbB pathway mutations had worse outcome than the others, suggesting that the ErbB pathway mutation defined a more malignant subgroup of gallbladder cancers.”

These findings are good news for gallbladder cancer patients, as ErbB pathway modifying drugs have already been developed and could be used to treat the intractable disease, said Dr. Wang Hui, Professor from Institute for Nutritional Sciences at the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

“Thus, gallbladder cancer patients harboring mutations of ErbB pathway may benefit from ErbB targeted therapies. We are currently testing the efficacy of candidate drugs that target ErbB family members and their downstream components in gallbladder cancer models with patient-derived ErbB mutations,” she told Asian Scientist Magazine.

The article can be found at: Li M et al. (2014) Whole-Exome and Targeted Gene Sequencing of Gallbladder Carcinoma Identifies Recurrent Mutations in the ErbB Pathway.


Copyright: Asian Scientist Magazine; Photo: Liu Ying-Bin.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Rebecca did her PhD at the National University of Singapore where she studied how macrophages integrate multiple signals from the toll-like receptor system. She was formerly the editor-in-chief of Asian Scientist Magazine.

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