Evaluation of the 4q32-34 locus in European familial pancreatic cancer.

BACKGROUND: Familial pancreatic cancer (FPC) describes a group of families where the inheritance of pancreatic cancer is consistent with an autosomal-dominant mode of inheritance. The 4q32-34 region has been previously identified as a potential locus for FPC in a large American family. METHODS: The region was allelotyped in 231 individuals from 77 European families using nine microsatellite markers, and haplotyping was possible in 191 individuals from 41 families. Families were selected based on at least two affected first-degree relatives with no other cancer syndromes. RESULTS: Linkage to most of the locus was excluded based on LOD scores less than -2.0. Eight families were excluded from linkage to 4q32-34 based on haplotypes not segregating with the disease compared with a predicted six to seven families. Two groups of families were identified, which seem to share common alleles within the minimal disease-associated region of 4q32-34, one group with an apparently earlier age of cancer death than the other pancreatic cancer families. Four genes were identified with potential tumor suppressor roles within the locus in regions that could not be excluded based on the LOD score. These were HMGB2, PPID, MORF4, and SPOCK3. DNA sequence analysis of exons of these genes in affected individuals and in pancreatic cancer cell lines did not reveal any mutations. CONCLUSION: This locus is unlikely to harbor a FPC gene in the majority of our European families.

Familial pancreatic cancer syndromes.

Hereditary pancreatic cancer (PC) is rare and extremely heterogeneous, and it accounts for approximately 2% of all PC cases. The major component of hereditary PC is the familial pancreatic cancer syndrome. Although up to 20% of hereditary PC cases are associated with germline mutations in the BRCA2, CDKN2A, PRSS1,STKI1, or MMR genes, the major underlying gene defect(s) is still unknown. Although hereditary PC is rare, the data on PC families that have been collected by various study groups worldwide provide a unique opportunity to evaluate the natural history, causative gene alterations, new diagnosis and chemoprevention strategies as well as treatment modalities.

Low frequency of CHEK2 mutations in familial pancreatic cancer.

Familial pancreatic cancer (FPC) is a rare tumour syndrome and its underlying major gene defect is still unknown. Recently, CHEK2 has been identified as multi-organ cancer susceptibility gene associated with a predisposition to breast, prostate and colon cancer. Since these cancers also are associated with some FPC families, we have analysed 35 index patients of German FPC families for CHEK2 mutations. The CHEK2 * 1100delC mutation was found in 1 (3%) of 35 FPC families. Given the low expected mutation rate of up to 1.4% for CHEK2 * 1100delC in the European population our data are suggestive for possible contribution of CHEK2 mutations to a small subset of FPC.

BRCA2 germline mutations in familial pancreatic carcinoma.

BACKGROUND: Although as many as 10% of pancreatic cancer cases may have an inherited component, familial pancreatic cancer has not been linked to defects in any specific gene. Some studies have shown that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer. To study these relationships in more detail, we examined whether BRCA2 germline mutations are associated with familial pancreatic cancer. METHODS: We identified 26 European families in which at least two first-degree relatives had a histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. We sequenced genomic DNA isolated from peripheral blood lymphocytes obtained from participating family members to identify germline mutations in BRCA2. RESULTS: Three (12%, exact 95% confidence interval [CI] = 2% to 30%) families carried germline frameshift mutations in the BRCA2 gene that are predicted to result in a truncated BRCA2 protein. Two additional families harbored mutations previously designated as unclassified variants of BRCA2. Thus, 19% (exact 95% CI = 7% to 39%) of the families in our study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in our study met the criteria for familial breast or ovarian cancer. CONCLUSIONS: Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. BRCA2 mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least two first-degree relatives affected with ductal adenocarcinoma of the pancreas.

No evidence for germline mutations of the LKB1/STK11 gene in familial pancreatic carcinoma.

Familial pancreatic cancer (FPC) (approximately 3% of all cases) has not been linked to defects in any specific gene. Germline inactivation of the gene LKB1/STK11 have been shown to cause Peutz-Jeghers syndrome (PJS) associated with a approximately 100-fold higher risk for the development of pancreatic cancer. We have analysed 39 index patients from European FPC families for mutations of LKB1/STK11 by sequencing of their DNA. No germline mutation was found within the complete coding region. Therefore, our results indicate that LKB1/STK11 is not altered in the germline of patients with hereditary pancreatic cancer.

[Familial pancreatic cancer--concept for study of the National Case Collection and early diagnosis program for high risk people]. / Familiäres Pankreaskarzinom--Studienkonzept einer Nationalen Fallsammlung mit Früherkennungsprogramm für Hochrisikopersonen.

Ductal pancreatic cancer is a public health problem on the increase. The lethality and incidence of this disease are almost identical. A number of these cancers cluster in families. By definition, pancreatic cancer appearing in at least two first degree relatives is named familial pancreatic cancer (FPC). The "National Case Collection Familial Pancreatic Cancer" (FaPaCa) was founded at the Philipps University of Marburg, Germany, in July 1999 within the scope of the project "Clinical and genetic examinations of familial exocrine pancreatic cancer including the foundation of a national case collection" (http://www.med.uni-marburg.de/fapaca). The aims of this project are 1 to evaluate the share of FPC of all pancreatic cancers by performing a multi-centered study, 2 to identify epidemiological risk factors that predispose to pancreatic cancer in these families, 3 to identify families with a likely genetic predisposition to pancreatic cancer, 4 to offer a screening program for high risk individuals in these families, which is to be evaluated in an observational study, and finally to identify presumed genetic defects that predispose to pancreatic cancer in FPC families. This manuscript presents the scientific concept behind the FaPaCa project and reports on its attendant screening program for FPC families.

RNASEL germline variants are associated with pancreatic cancer.

The RNASEL (encoding ribonuclease L) gene Glu265X mutation has been implicated in familial prostate cancer, and an association between the RNASEL Arg462Gln variant and sporadic and familial prostate cancer, has also been suggested. Because prostate cancer occurs in some familial pancreatic cancer families, we evaluated the role of the RNASEL gene variants Glu265X and Arg462Gln in the etiology of pancreatic cancer. Exon 2 of the RNASEL gene was directly sequenced in the germline of 36 familial and 75 sporadic pancreatic cancer patients and in 108 controls. The Glu265X mutation was identified in one (2.8%) familial and one (1.3%) sporadic pancreatic cancer case, but not in any of the controls. Arg462Gln variants were identified in 61 (56%) controls and in 55 (73%) sporadic pancreatic cancer cases with 8 (7%) and 12 (16%) homozygotes, respectively (p = 0.009). For homozygous carriers the increased risk for pancreatic cancer was 3.5 (odds ratio [OR] = 3.53, 95% confidence interval [CI] = 1.11-11.46, p = 0.03). The population attributable fraction (PAF) was 38.7% (95% CI = 0.08-0.80). In familial pancreatic cancer no association between Arg462Gln genotypes and pancreatic cancer risk was evident. In sporadic pancreatic cancer there were no significant differences between Arg462Gln genotypes regarding clinical characteristics. In familial pancreatic cancer, however, patients with Arg462Gln variants had more aggressive tumors with more high grade cancers (OR = 15.40, p = 0.009) and more distant metastases (OR = 7.00, p = 0.04) than patients with the wild-type genotype. Our results suggest that RNASEL variants Glu265X and Arg462Gln may contribute to the tumorigenesis of sporadic and familial pancreatic cancer, which has to be proven in large scale studies.

CDKN2A germline mutations in familial pancreatic cancer.

OBJECTIVE: To evaluate the prevalence of mutations in the CDKN2A gene encoding p16 and p14 in familial pancreatic cancer (FPC). SUMMARY BACKGROUND DATA: The genetic basis of FPC is still widely unknown. Recently, it has been shown that germline mutations in the p16 tumor suppressor gene can predispose to pancreatic cancer. The presence of p14 germline mutations has yet not been determined in this setting. METHODS: Eighteen families with at least two first-degree relatives with histologically confirmed pancreatic cancer and five families with at least one patient with pancreatic cancer and another first-degree relative with malignant melanoma of the German National Case Collection for Familial Pancreatic Cancer were analyzed for CDKN2A germline mutations including p16 and p14 by direct DNA sequencing. All participating family members were genetically counseled and evaluated by a three-generation pedigree. RESULTS: None of 18 FPC families without malignant melanoma revealed p16 mutations, compared to 2 of 5 families with pancreatic cancer and melanoma. Truncating p16 germline mutations Q50X and E119X were identified in the affected patients of pancreatic cancer plus melanoma families. None of the 23 families revealed p14 germline mutations. CONCLUSIONS: CDKN2A germline mutations are rare in FPC families. However, these data provide further evidence for a pancreatic cancer-melanoma syndrome associated with CDKN2A germline mutations affecting p16. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16 mutations to identify high-risk family members who should be enrolled in a clinical screening program.

Prevalence of familial pancreatic cancer in Germany.

Based on several case-control studies, it has been estimated that familial aggregation and genetic susceptibility play a role in up to 10% of patients with pancreatic cancer, although conclusive epidemiologic data are still lacking. Therefore, we evaluated the prevalence of familial pancreatic cancer and differences to its sporadic form in a prospective multicenter trial. A total of 479 consecutive patients with newly diagnosed, histologically confirmed adenocarcinoma of the pancreas were prospectively evaluated regarding medical and family history, treatment and pathology of the tumour. A family history for pancreatic cancer was confirmed whenever possible by reviewing the tumour specimens and medical reports. Statistical analysis was performed by calculating odds ratios, regression analysis with a logit-model and the Kaplan-Meier method. Twenty-three of 479 (prevalence 4.8%, 95% CI 3.1-7.1) patients reported at least 1 first-degree relative with pancreatic cancer. The familial aggregation could be confirmed by histology in 5 of 23 patients (1.1%, 95% CI 0.3-2.4), by medical records in 9 of 23 patients (1.9%, 95% CI 0.9-3.5) and by standardized interviews of first-degree relatives in 17 of 23 patients (3.5%, 95% CI 2.1-5.6), respectively. There were no statistical significant differences between familial and sporadic pancreatic cancer cases regarding sex ratio, age of onset, presence of diabetes mellitus and pancreatitis, tumour histology and stage, prognosis after palliative or curative treatment as well as associated tumours in index patients and families, respectively. The prevalence of familial pancreatic cancer in Germany is at most 3.5% (range 1.1-3.5%) depending on the mode of confirmation of the pancreatic carcinoma in relatives. This prevalence is lower than so far postulated in the literature. There were no significant clinical differences between the familial and sporadic form of pancreatic cancer.