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Genetic susceptibility to pancreatic cancer S. Presciuttini

Genetic susceptibility to pancreatic cancer S. Presciuttini. Pancreatic cancer in Italy. Total number of deaths per year in Italy (Istat, 2000): 8,112 The vast majority of pancreatic cancers are exocrine ; among these, 95% are adenocarcinomas, usuallly beginning in the pancreatic ducts

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Genetic susceptibility to pancreatic cancer S. Presciuttini

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  1. Genetic susceptibility topancreatic cancerS. Presciuttini

  2. Pancreatic cancer in Italy • Total number of deaths per year in Italy (Istat, 2000): 8,112 • The vast majority of pancreatic cancers are exocrine; among these, 95% are adenocarcinomas, usuallly beginning in the pancreatic ducts • Cumulative risk 0-74 (Italian cancer registries, 1993-97): • Men 1.0% Women0.6% • Relative incidence among all cancers: • Men 2.2% Women 2.5% • Relative mortality: • Men 6.0% Women 5.8% • Mortality / incidence ratio: • Men 93.9% Women 95.2%

  3. Risk factors • The most consistently identified risk factors are cigarette smoking and family historyof the disease. • Alcohol and coffee consumption have been reported as possible risks in some (but not in most) studies. Diet is probably a significant factor, but is difficult to evaluate quantitatively. Other putative associations, including diabetes, probably are unimportant. • There are no striking environmental risk factors, and geographic variation is less than with other gastrointestinal cancers.

  4. Genes involved in genetic susceptibilityto pancreatic cancer • Some of the familial aggregation of PC is explained by inherited cancer syndromes • the BRCA2 gene (Hereditary Breast-Ovarian Cancer) is particularly relevant. • It is estimated that 3%–5% of all PDA cases may be caused by such genetic predisposition to the disease. • A recent breakthrough has been the discovery of a mutated palladin gene in a large family with hereditary pancreatic cancer

  5. The PALLD gene: a controversial role in FPC • Pogue-Geile KL et al. Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism.PLoS Med. 2006; 3:516. “A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members” • Slater E et al. Palladin mutation causes familial pancreatic cancer: absence in European families.PLoS Med. 2007;4:164 “… we have sequenced the locus in 74 individuals who were either affected by pancreatic cancer or who are obligate carriers (…). We did not identify the mutation in any of the individuals, neither as a heterozygote or a homozygote” • Zogopoulous G et al. The P239S palladin variant does not account for a significant fraction of hereditary or early onset pancreas cancer.Hum Genet. 2007;121:635-7 “The P239S germline variant was identified in one of 84 high-risk cases and one of 555 controls. We conclude that this variant does not appear to account for a significant fraction of hereditary or early-onset pancreas cancer” • Earl J et al. Evaluation of the 4q32-34 locus in European familial pancreatic cancer.Cancer Epidemiol Biomarkers Prev. 2006;15:1948-55. “This locus is unlikely to harbor a FPC gene in the majority of our European families.”

  6. Associazione ItalianaStudio Pancreas Cancer risk among the relatives of patients with pancreatic ductal adenocarcinoma M. Del Chiaro, L. Bertacca, U. Boggi, M. A. Caligo, F. Mosca Regional Referral Center for Pancreatic Disease – University of Pisa A. Zerbi, M. Polese, G. Casari, V. Di Carlo San Raffaele Hospital – Milano M. Falconi, N. Sartori, R. Salvia, P. Pederzoli University of Verona and S. Presciuttini Center of Statistical Genetics – University of Pisa

  7. Purposes of the study • Documenting the occurrence of familial pancreatic cancer in Italy through the collection of family histories of a series of incident cases of ductal adenocarcinoma (probands); • Determining the empirical risk of cancer, both of the pancreas and of other organs, for the relatives of the probands; • Establishing a large pedigree database useful for segregation analysis and other familial studies; • Identifying a possible set of families eligible for linkage analysis.

  8. The study database • During the first 24 months of the study, 570 families of probands with pancreatic ductal adenocarcinoma were recorded, including 3,900 first-degree and 5,336 second-degree relatives (total 9,236). • Geographic origin of the families was fairly distributed along Italy • Number of males/females and numbers of first- and second-degree relatives were not significant for heterogeneity among centers. • Among the 570 probands, 232 (41%) were females and 338 males (59%); mean ages of diagnosis were 65.2 and 64.6, respectively.

  9. Smoking as a risk factor • The proportion of heavy smokers was markedly over-represented among patients, both in males and in females (about 6-fold in females and 3-fold in males).

  10. Familial aggregation of pancreatic cancer • Considering first and second degree relatives (9,204 total relatives), 53 probands (9.3%) reported positive history of pancreatic cancer, 47 with one affected relative, 5 with two affected relatives, and 2 with three affected relatives (62 total affected relatives). Familial aggregation of PC was tested by tabulating the family data (probands excluded) by total number of relatives (rows) and total number of affecteds (columns) and computing expectations in each cell by the binomial distribution with parameter p calculated from the observed proportion of affected individuals.

  11. Families with excess PC Family D Family F Some 1%–1.5% of the families (7/570) explains the bulk of the observed excess of PC cases; in particular, two families (0.4%) included four affected subjects.

  12. A truncating mutation in BRCA2 * * * * WT * * * WT WT WT • In family D, a pathogenic mutation in BRCA2 had been identified in a niece of the proband, and was later confirmed in the proband, in his brother with prostate cancer (obligate carrier), and two sisters with ovary or breast and ovary cancer over 60 years of age

  13. Familial aggregation of all cancers The r by s table analysis was extended to all cancers. A total of 975 relatives out of 9,204 relatives (10.5%) were reported with cancer. The distribution of the number of cancer cases per family was highly skewed (total chi square 62.9, 5 d.f., p < 0.00001). The family with the most striking aggregation of cancers was again family D.

  14. Families with excess of all cancers Families with ≥ 7 cases of any cancer. Family D belongs to this group also. Family K is another case of suspected HBOC; in addition, a further suspected case of HBOC was identified among the five families with six affected relatives.

  15. Cancer mortality among the 1.st degree relatives • We investigated the cumulative risk of dying from cancer among the first-degree relatives of the probands by the method of life table analysis, using age intervals of one year. A total of 405 deaths from cancer were reported among the 3,900 relatives (10.3%). • These curves were compared with the cumulative mortalities from cancer of the Italian population, calculated from the data of the Italian Association of Cancer Registries. These report the age-specific death rates (per 100,000 inhabitants, per year) for five-year age intervals for 44 anatomical sites. • 67% of all deaths were caused by the following cancers: 1) LGI (20.2%); 2) Respiratory tract (19.5%); 3) Pancreatic cancer (10.1%); 4) UGI (8.9%); 5) breast cancer (8.1%, 20.2% among females)

  16. Mortality from pancreatic cancer With 46 deaths, pancreatic cancer ranked third among the deaths from cancer; it was the only cancer showing a highly significant increase over the baseline

  17. A closer look at the mortality from pancreatic cancer The relative risk (RR) with respect to the general population is higher than 1.0 over age 50, though statistical significance at a = 0.05 is reached at about 60 years of age. The lifetime risk (85 years) of dying was 4.1% for the first-degree relatives, compared with 1.5% of the general population, or a 2.7-fold increase. The risk for the relatives of probands under 60 (n = 160 ) was still higher, 4.2 on average (P = 0.014, logrank test). The lifetime risk for this subset was 7.2% (95% C.I. 4%–12.2%).

  18. Conclusions • An important fraction of the risk for the families at high risk of pancreatic cancer may be due to already known genes, in particular BRCA2, or to unknown genes that predispose to a similar cancer spectrum • In addition to BRCA2, genetic susceptibility to pancreatic cancer may be attributable other genes specific for this cancer • Three different lines of evidence support this notion, which are typical of genes associated with known hereditary cancer syndromes : (1) the presence of significant familial aggregation; (2) the excess of mortality above the population background for the first-degree relatives; and (3) the increased mortality for relatives under 60.

  19. Perspectives • Although the evidence for genetic susceptibility to pancreatic cancer may be compelling, the extent to which the features of hereditary cancers are exhibited in our series is lower than in other known syndromes: • the non-random distribution of cases among families could be proved because of our large sample size, but no extraordinary pedigree was identified with aggregation of pancreatic cancer only; • it is difficult to distinguish, among the multiplex families, between those that may carry the gene and those that represent a chance aggregation of cases; • the effect of the age of the proband could be proved because of our large sample size, but this effect is lower than that generally observed for known cancer susceptibility genes. • All that seems to suggest that increased susceptibility to pancreatic cancer results from moderate- to low-penetrance genes. • Specific studies should be designed to identify these genes.

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