Genetic+Factors

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Familial Inheritance
In order to perform research on the link between familial inheritance and an individual's chances of obtaining pancreatic cancer, registeries such as the [|National Familial Pancreas Tumor Registery] (NFPTR) have been created to oberserve and study family members of individuals who either have sporadic or familial pancreatic cancer. The goal of this registery is to find the cause of pancreatic cancer, improve early detection, and most importantly find the most effective methods to cure it. Created in 1994 by [|Dr. Ralph Hruban], this registery allows for scientists to study families and obtain a better understanding of how pancreatic cancer behaves within families such as the families depicted below in the family trees.





One [|study] conducted in 2001 studied the families enrolled in the NFPTR prior to September 1 1998. By studying the family members of both sporadic and familial pancreatic patients, researchers were able to determine that individuals who are first-degree family members of with pancreatic cancer are at a higher risk of obtaining both pancreatic cancers and non-pancreatic cancers. These non-pancreatic cancers included breast, colon, and lung cancer (see table below).



Risk was estimated by comparing the expected numbers of new cases given by the United States population based [|Surveillance, Epidemiology, and End Results Program] to the number of new cases observed during the study. Final results showed the following expected incident for family members of different forms of pancreatic members were as followed: 6.5 Sporadic, 18.3 Familial, and 56.6 of individuals with 3 or more members with familial pancreatic cancer. Results also suggested that the increased rate of incidence in family members may have been caused by genetic [|aggregation] within families. Familial inheritance has been connected with five genetic syndromes associated with familial aggregation of pancreatic cancer. These include: Another [|study] which studied family member of the NFPTR focused in more on these genetic syndromes to attempt to understand the patterns of inheritance for groups of the same genes which are inactivated in both familial and sporadic pancreatic cancer. They concluded that due to these genetic aggregations, even second degree members of patients with pancreatic cancer have an increased risked of being diagnosed. Their final conclusion described (see below) in more detail how some the genetic syndromes and gene mutation above are link above are linked with pattern of inheritance within families.
 * ~ Genetic Syndrome ||~ Gene Mutation ||
 * < Familial Breast Cancer ||< BRCA2 ||
 * < Familial Atypical Multiple-Mole Melanoma (FAMMM) ||< [|Germline] mutation in p16 tumor suppressor gene ||
 * < Peutz-Jeghers Syndrome (PJS) ||< Germline mutations in STK11/LKB1 ||
 * < Hereditary Non-Polyposis Colorectal Cancer (HNPCC) ||= Germline muation in one DNA mismatch repair gene ||
 * < Hereditary Pancreatitis ||< Germline mutaiton in Cationic Trypsinogen gene ||

BRAC2 and Breast Cancer
[|﻿Breast cancer] is the most common inherited predisposition to pancreactic cancer. Family with a history of pancreatic cancer have shown to have higher riske of breast cancer in succeeding family members. 947 breast cancer paitents from the Icelandic Tumor Registry showed that their first degree relatives had a 1.66 greater odds ratio of being diagnosed with pancreatic cancer than males who did not have breast cancer in their family. This link between breast and pancreatic cancer are germline mutations in the [|BRCA2] gene. BRCA2 is a tumor suppressor gene which is responsible for chromosome damage repair and plays an important role in repairing breaks in DNA. Carries of BRCA2 mutations have a 10-fold risk of developing pancreatic cancer. Oddly enough though many of these indivduals may never develop pancreatic cancer due to the low [|penetrance] of this trait. One theory states that numerous forms of pancreactic cancer which may appear to be sporadic are actually cuased by BRAC2 mutations. Becuase of its low penetrance however, these cases are overlooked and are designated as the sporadic form of the cancer.

STK11/LKB1 and Peutz-Jeghers Syndrome
[|﻿Peutz-Jeghers Syndrome], the development of polyps in the digestional tract, is anther autosmal dominant trait which can be passed down through a family line. Like pancreatic cancer, PJS can either be familial or sporadic. Individuals with PJS have an increased risk of developing pancreactic cancer, and numerous patients with PJS have died due too pancreatic cancer. Biopsies of two PJS patients with pancreatic cancer, and 135 individuals with just pancreatic cancer showed a common mutation with the [|STK11/LKB1] gene between the two conditions. The biopsies displayed either a germline splice mutation in the gene, or loss of the wild type gene. Both conditions led to the loss of function of the gene within the carcinoma. Under normal function STK11/LKB1 is a protein kinase which acts as a tumor suppressor gene and regulates cell polarity.

p16 and FAMMM Syndrome
[|FAMMM] is a [|autosomal dominant] form of malignant melanomas which has been shown to be linked with pancreatic cancer. "Pancreatic cancer is the second most diagnosed cancer to patients with FAMMM. Once study estimated an association with pancreatic cancer in 25% of FAMMM kinderds". Mutations in [|p16] have shown to cause melanomas, such as FAMMM, and and eventually lead to different cancers. p16 acts as a tumor suppressor gene which helps regulate the cell cycle. More then 95% of all sporadice pancreatic patients have shown to have an inactived p16 gene. Of these inactivated p16 genes, 40% is due to loss of heterozygosity, another 40% due to homozygous deletion, and around 15% due to hypermethylation of the p16 promoter. Individuals with germline mutations in p16 have a 22-fold greater risk of being diagonsed wtih pancreatic cancer.

Mismatch Repair Genes and HNPCC
[|HNPCC] is caused by a germline mutation in mismatch repair genes such as hMSH2 and hMLH1. These genes are responsible for coding specific proteins which act during replication when errors occur. Individuals with HNPCC can develop a phenotype called [|micosatellite instability]. This is characterized by copies of base pair sequences in DNA which, through mutations, are too long or too short causing the overall sequence to become unstable. This phenotype has been seen in around 4% of pancreatic cancer patients showing a minor link between the too.

Trypsinogen and Hereditary Pancreatitis
As described in the environmental factors page, pancreatic cancer has been linked to pancreatitis due to heavy alcohol consumption. Pancreatic cancer now has also been linked to hereditary pancreatitis due to dominant inheritance from families who have a history of reoccuring episodes of environmentally caused pancreatitis. Research has shown that pancreatitis is cuased by a germline mutation in cationic trysinogen gene. This mutation blocks the inactivation of [|trypsin,] which results in the autodigestion of the pancreas. In families with hereditary pancreatitis, children will usually develop this mutation and over time develop chronic pancreatitis due to chronic injury and repair of the pancreas. Individuals with chronic pancreatitis are at higher risks of obtaining pancreatic cancer.

Race and Gender
Statistics from pancreatic cancer patients suggest that an individuals gender and ethnicity will affect their risk of obtaining pancreatic cancer. Generally it appears that black males are the most susceptible to this cancer. How and why men have had more cases or pancreatic cancer, along with variance within different races, is not clear and much more research needs to be done. Statistics such as the one provided below from [|SEER from the National Cancer Institute] show strong evidence that this theory is true. There evidence supports that black men compared to all other groups have the higher rates of both incidence and death rates.