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Pancreas Carcinoma, FPC - PALB2, p16

Clinical Features

Breast cancer is the most common tumor disease in women. Approximately 5-10% of patients have a family anamnesis indicating an inherited form with an autosomal dominant pattern of inheritance. In approx. 30-50% of these familial cases, mutations are found in the genes BRCA1 or BRCA2. In addition, mutations in PALB2 are associated with familiar breast cancer - however to a small percentage. While BRCA1- and BRCA2-germline mutation carriers have an approx. 70 % lifetime risk to develop breast cancer, PALB2 mutation carriers display only an approx. 4-times increased risk in comparison to the general population. According to a Finnish study, PALB2 mutation carriers are associated with triple-negative breast cancer in a frequency of 55 %.
The prevalence of ductal adenocarcinoma of the pancreas (PC) in the German population is approx. 1:10.000. In addition to exogenous risk factors (such as smoking), genetic causes are triggers for PC. For approx. 3 % of all ductal pancreas carcinomas a genetic predisposition is responsible. These hereditary forms can be subdivided into three entities:
1. Familiar pancreas carcinoma syndrome (FPC) accounts for approx. 70 % of hereditary PC, however, no responsible gene could as yet be identified. It has been recently demonstrated that germline mutations in PALB2 are not only responsible for familial breast cancer but seem to be responsible for a small part of the FPC cases as well.
2. PRSS1-, SPINK1- and CFTR-mutations give rise to hereditary pancreatitis.
3. Tumor syndromes associated with an increased risk for PC, e.g., Peutz-Jeghers syndrome, familial atypical multiple mole-melanoma (FAMMM) syndrome, Li-Fraumeni syndrome, hereditary breast and ovarian cancer (HBOC) syndrome.

Genetic Information

PALB2 (partner and localizer of BRCA2; also referred to as FANC-N) is located on chromosome 16 (16p12.1) and consists of 13 coding exons. It is involved in DNA repair processes together with BRCA2 and other genes.
In the literature, mutations in PALB2 are described with an increase in risk for PC (Jones et. al., Science; 2009) and breast cancer (approx. 4-fold). Biallelic PALB2 germline mutations lead to Fanconi anaemia subtype N as well as additional tumors in children. The most frequently identified gene defect in FPC so far are germline mutations in BRCA2 (one of two breast cancer genes and functional partners of the PALB2 protein). Nevertheless, BRCA2 germline mutations could only be found in 6 % of all FPC families.

Diagnostic