Everything you ever wanted to know about Genetics and CCA

Here are some answers to the many questions we have:

Frequency of Occurrence
Gentic Changes
Inheritance Pattern

The three types of cholangiocarcinoma do not usually cause any symptoms in their early stages, and this cancer is usually not diagnosed until it has already spread beyond the bile ducts to other tissues. Symptoms often result when bile ducts become blocked by the tumor. The most common symptom is jaundice, which is a yellowing of the skin and the whites of the eyes. Other symptoms can include itching, dark-colored urine, loss of appetite, unintentional weight loss, abdominal pain, and light-colored and greasy stools. These symptoms are described as “nonspecific” because they can be features of many different diseases.

Most people who develop cholangiocarcinoma are older than 65. Because this cancer is often not discovered until it has already spread, it can be challenging to treat effectively. Affected individuals can survive for several months to several years after diagnosis.

Cholangiocarcinoma affects 2,000 to 3,000 people each year in the United States. This type of cancer occurs much more frequently in Southeast Asian countries such as Thailand, where it is related to infection with a parasite that is common there. For unknown reasons, cholangiocarcinoma occurs slightly more often in men than in women.

Cancers occur when a buildup of mutations in critical genes—those that control cell division, for example—allow cells to grow and divide uncontrollably to form a tumor. In most cases of cholangiocarcinoma, these genetic changes are acquired during a person’s lifetime and are present only in bile duct cells that give rise to the tumor.

The genetic changes, which are called somatic mutations, are not inherited. Somatic mutations in many different genes have been found in cholangiocarcinoma. Some of these genes act as tumor suppressors, which means they help keep the growth and division of cells tightly regulated. Mutations in or deletions of tumor suppressor genes can allow cells to grow and divide without control or order, which is a hallmark of cancer.

Other genes associated with cholangiocarcinoma are classified as oncogenes; when they are turned on (activated) abnormally, these genes have the potential to cause normal cells to become cancerous. Identifying somatic mutations in cholangiocarcinoma may provide clues to how quickly the cancer will grow and spread, and which treatments might be most effective.

Researchers have also investigated inherited variations in several genes as possible risk factors for cholangiocarcinoma. These genetic changes, which are classified as germline mutations, are present in essentially all of the body’s cells. However, no specific inherited changes have been found to be major risk factors for this disease.

Several non-genetic risk factors for cholangiocarcinoma have been identified. These include a bile duct disease called primary sclerosing cholangitis, bile duct stones or cysts, and exposure to certain chemical toxins used in manufacturing. In Southeast Asia, infection with parasitic worms that live in the human bile ducts greatly increase the risk of developing cholangiocarcinoma. Other risk factors that have been studied include long-term infection with hepatitis B or C, scarring of the liver (cirrhosis), and chronic diseases such as irritable bowel syndrome and diabetes. Researchers suspect that certain lifestyle factors, including smoking, alcohol use, and obesity, may also contribute to the risk of developing cholangiocarcinoma.

Studies suggest that a combination of genetic, environmental, and lifestyle factors influence whether a person will develop cholangiocarcinoma. However, most people who develop the disease do not have any of the identified risk factors.

CHOLANGIOCARCINOMA IS NOT INHERITED. Studies suggest that blood relatives of a person with cholangiocarcinoma may have an increased risk of developing this cancer compared with the general population. However, most people with cholangiocarcinoma do not have a family history of the disease

Reference: https://ghr.nlm.nih.gov/condition/cholangiocarcinoma#resources

Somatic Mutations

Jiao et al. (2013) performed exome sequencing of 32 intrahepatic cholangiocarcinomas and discovered frequent inactivating mutations in multiple chromatin-remodeling genes, including BAP1 (603089), ARID1A (603024), and PBRM1 (606083). Mutation in 1 of these genes occurred in almost half of the carcinomas sequenced. Jiao et al. (2013) also identified frequent mutations at reported hotspots in the IDH1 (147700) and IDH2 (147650) genes, encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 (191170) was the most frequently altered gene in a series of 9 gallbladder carcinomas.

Chan-on et al. (2013) profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non-O. viverrini-related etiologies. Whole-exome sequencing in 15 tumors and prevalence screening in 194 tumors identified recurrent somatic mutations in BAP1 and ARID1A. Comparisons between intrahepatic O. viverrini-related and non-O. viverrini-related

cholangiocarcinomas demonstrated statistically significant differences in mutation patterns: BAP1, IDH1, and IDH2 were more frequently mutated in non-O. viverrini cholangiocarcinomas, whereas TP53 mutations showed the reciprocal pattern.

Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in cholangiocarcinoma pathogenesis. Chan-on et al. (2013) concluded that these findings indicated that different etiologies may induce distinct somatic alterations, even within the same tumor type.

Reference: http://omim.org/entry/615619