Multiple primaries in pancreatic cancer patients: indicator of a genetic predisposition?

Berthold Gerdesa, Andreas Zieglerb, Annette Ramaswamyc, Anja Wilda, Peter Langera and Detlef K Bartscha

a Department of General Surgery,
b Institute of Medical Biometry and Epidemiology and
c Department of Pathology, Philipps University of Marburg, D-35033 Marburg, Germany.

Reprint requests: Berthold Gerdes, Department of General Surgery, Philipps University of Marburg, Baldingerstraße, 35033 Marburg, Germany. E-mail: Gerdes{at}mailer.uni-marburg.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background The genetic basis of several familial cancers including breast and colon cancers has been identified recently. The occurrence of multiple cancers in one individual is also suggestive of a genetic predisposition. To evaluate inherited predisposition in pancreatic cancer we compared the clinical data of pancreatic cancer patients with and without multiple primaries as well as the frequency of malignancies among their relatives.

Methods Detailed data on 69 pancreatic cancer patients included survival time and TNM-classification. Index case data were separated into two groups. The first group (group 1) developed only pancreatic cancer during their lifetime, whereas the second group (group 2) developed additional primary tumours. A systematic family history was taken from 59 of these pancreatic cancer patients using a standardized questionnaire. The pancreatic cancers and the multiple primaries of the 59 patients were histologically proven.

Results Of the 69 pancreatic cancer patients, 13 (18.8%) had multiple primaries. Neither the clinical data nor the survival data of the index cases revealed differences between the two groups (all nominal P-values >0.05). In the family history study blood relatives developed a malignancy in 51% (24 of 47) of the families in group 1 compared to 75% (9 of 12) in group 2. The risk of relatives in group 2 of developing a malignant tumour was significantly higher (P = 0.034) than in group 1 after adjustments for family size and age of disease onset of the index case. The cancer spectrum of the 59 families mainly included tumours of the digestive tract and the reproductive organs.

Conclusions A multiple primary cancer history is a common condition among pancreatic cancer patients. Relatives of these patients seem to have an increased risk for the development of distinct malignant solid tumours, which might be caused by an inherited predisposition. Clinical and genetic investigation of pancreatic cancer patients with multiple primaries and their families might lead to the identification of predisposing gene defects providing a new goal for the understanding of a shared genetic basis of different solid tumours.

Keywords Multiple primaries, pancreatic carcinoma, family history method, genetics

Accepted 19 April 2000


    Introduction
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
A familial aggregation of the same cancer indicates a hereditary predisposition for the development of these tumours. For some of these the causative gene defect has already been identified. For example, familial breast and ovarian cancer is associated with germline mutations in the BRCA1 or BRCA2 tumour suppressor genes and germline mutations in the APC gene cause familial adenomatosis polyposis coli.1–3 In some families a clustering of pancreatic cancer has also been observed although the responsible gene defect has yet not been identified.4,5 Lynch6 hypothesized that 5% of pancreatic cancers are based on a genetic predisposition. Ghardirian et al.7 and Fernandez et al.8 reported a positive family history for this cancer in 3.9% and 7.8% of pancreatic cancer patients, respectively. In some families with an aggregation of pancreatic cancer and malignant melanomas germline mutations in the p16 INK4a tumour suppressor gene have been identified.9,10 Goggins et al.11 detected germline mutations in the BRCA2 tumour suppressor gene in 7% of apparently sporadic pancreatic cancer patients. In addition, Phelan et al.2 described an aggregation of pancreatic cancers in breast cancer families associated with distinct BRCA2 germline mutations.

The appearance of different primaries in particular individuals may also indicate a genetic predisposition to different neoplasms resulting in an aggregation of tumours among their relatives.4 The term ‘second primary’ is not used homogeneously in the literature. In the Connecticut Tumor Registry only tumours following pancreatic cancers are registered as second or multiple primaries,12 whereas Hruban et al. 4 count simultaneous and metachronous cancers as second primaries. Due to the short survival time of most pancreatic cancer patients these different definitions lead to different frequencies of second primaries in patients with pancreatic cancer. Hoar et al.12 reported less than 1% of second primaries in pancreatic cancer patients, while Hruban et al.4 observed almost 20% of second primaries in patients without a family history of pancreatic cancer. Furthermore, data of the National Familial Pancreatic Tumor Registry in the US showed 23.8% of familial pancreatic cancer patients with one relative who also developed a pancreatic cancer and 36.8% with more than one relative with pancreatic cancer developed second primaries.4

In the present study we hypothesized that multiple primaries in patients with ductal pancreatic carcinoma coincides with an increased risk of malignancies among their first- and second-degree relatives, possibly indicating a shared genetic predisposition.


    Patients and Methods
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
At the Department of General Surgery of the Philipps University of Marburg 72 pancreatic resections were performed for ductal pancreatic cancer from 1 April 1992 to 30 September 1998. The data base was closed at 31 March 1999 so that the minimum follow-up of each patient was 6 months.

One aim of our study was to investigate the survival rate of patients with and without multiple primary tumours. For this reason, we a priori excluded those three patients from our study who died of postoperative complications. Thus detailed data including gender, age at resection, survival, TNM-classification and UICC-stage were collected for 69 patients and their tumours. The TNM-classification was based on the 5th edition of the TNM-classification of malignant tumours.4 These patients were asked to participate in our family history study, if they were still alive. If they were deceased, we tried to contact their first-degree relatives or their spouses. If none of these individuals could be contacted successfully, the patient was excluded from the study (10). Hence, the total sample consisted of 59 (81.9%) pancreatic cancer cases (index cases) with a follow-up of at least 6 months.13

The family history of the index cases was collected by one surgeon (BG) in a telephone interview or at outpatient attendance. A standardized questionnaire was used with information on pedigree structure covering first- and second-degree blood relatives in a family with 25–100% of genes shared15 including their children with offspring, grandparents, parents, uncles and aunts, siblings, nieces, and nephews. Since the precise determination of the age of disease onset for family members seems to be problematic, we refrained from calculating person-years of risk. Smoking data was not collected because we did not expect good validity using the family history method.

The data of the 69 index cases were separated into two groups. The first group (group 1) consisted of index cases who developed only pancreatic cancer during their lifetime, whereas the second group (group 2) developed additional primary cancers. We defined the term ‘second primaries’ analogously to Hruban et al. 4 who included all additional primaries in the whole lifetime of pancreatic cancer patients. Group 2 encompassed 13 of the 69 (18.8%) index cases. All primary tumours of the index cases were verified histologically by an experienced pathologist (AR).

The main aim of this study was to investigate whether family members of pancreatic cancer patients with multiple primaries had an increased risk for the development of cancer compared with family members of pancreatic cancer patients without multiple primaries. For this purpose, we applied the Independence Estimating Equations (IEE16) with logit link and binomial variance function. This method adequately deals with the relationship of family members and allows a one-sided Wald-test of our hypothesis. Furthermore, we computed an asymptotic two-sided 95% CI for the corresponding odds ratio (OR). All reported P-values except for this test are considered as nominal. Adjustments for age of disease onset of the index cases and family size were performed. Since the quality of the family history information is likely to be better for first-degree relatives than for second-degree relatives, we also examined the data based on the inclusion of only first and both first- and second-degree relatives of the index patients.

Contingency table analyses were performed as follows: If the expected frequency within each cell was >5, the asymptotic Yates-corrected {chi}2 test was applied, otherwise Pearson's exact test was used. The survival time was compared for patients of group 1 and group 2 using the log-rank test. Analogously, the Mann-Whitney test was applied to compare age of patients in group 1 and group 2.


    Results
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Of the 69 pancreatic cancer patients, 13 (18.8%) suffered from second primaries (Table 1Go). One of the 13 patients developed four cancers originating at discordant sites. He developed a vocal cord cancer and a basal cell carcinoma 4 years before pancreatic cancer. One year following pancreatic cancer he developed an anaplastic thyroid carcinoma, which caused his death. The other 12 patients developed two primary cancers until 31 March 1999. The period between pancreatic cancer and the detection of the additional primaries ranged from 24 years before the occurrence of pancreatic carcinoma (–24) to 2 years after this cancer (+2).


View this table:
[in this window]
[in a new window]
 
Table 1 Occurrence of multiple primaries in relationship to the occurrence of the pancreatic cancera
 
No difference in the median age was detected between patients of group 2 (mean ± SD 67.33 ± 8.36 years) and group 1 (63.77 ± 9.68 years; P = 0.29). Furthermore, no gender difference was observed in index cases of groups 1 and 2 (P = 0.40). The survival time in both groups was similar (P = 0.23). Table 2Go shows that the two groups did not differ with regard to TNM-classification (T with P = 0.59; N with P = 0.39; M with P = 0.35) and UICC-stage (P = 0.25).


View this table:
[in this window]
[in a new window]
 
Table 2 Comparison of TNM-stage and UICC-stage in pancreatic cancer patients with and without second primaries
 
A total of 1436 blood relatives were identified in the 59 pancreatic cancer patients who participated in our family study, 1171 in group 1 and 265 in group 2. Sixty-nine tumours (Table 3Go) developed among these relatives (4.8%), 48 (4.1%) and 21 (7.9%) in groups 1 and 2, respectively. Relatives of pancreatic cancer patients developed malignant tumours in 33 of the 59 families (55.9%). There was a tendency for malignancies to occur more frequently in families of group 2 (75.0% of the families) than in group 1 (51.1%; P = 0.07).


View this table:
[in this window]
[in a new window]
 
Table 3 Distribution of tumours in families of patients with pancreatic cancer without (group 1) and with (group 2) a second primary history
 
The risk of relatives in group 2 (second primary) of developing a tumour was significantly higher (P = 0.014) than in group 1 (no second primary) (OR = 2.09, 95% CI : 1.08–4.04). It was significant even after adjustment for family size and age of disease onset in the index patients (one-sided P = 0.034; OR = 1.83, 95% CI : 0.96–3.51). The results were similar when only first-degree and both first- and second-degree relatives of the index cases were included in the analyses. The effect remained significant when both first- and second-degree relatives were considered (P = 0.012 with n = 872 relatives; OR = 1.99; 95% CI : 1.10–3.62), however, due to the low number of relatives (n = 444), it was not significant when only first-degree relatives were included (P = 0.12). The risk of relatives for developing a tumour increased significantly with decreasing family size (P = 0.010). There was, however, no dependency between the risk of relatives for developing a tumour and the age of disease onset in the index patient (P = 0.97).

The tumour spectrum in both groups mainly encompassed tumours of the aerodigestive tract and the reproductive organs (Table 3Go). Three basal cell carcinomas and two bladder cancers were observed among the primaries of the index patients (Table 1Go). Nevertheless, none of the families showed the characteristic tumour spectrum of known cancer syndromes (e.g. hereditary non-polyposis colorectal carcinoma (HNPCC), familial atypical multiple mole-melanoma (FAMMM), Peutz-Jeghers, Li-Fraumeni) that are associated with pancreatic cancer. However, an atypical phenotype of one of these syndromes could not be excluded. Three female relatives of different families in group 1 suffered from multiple primary cancers: one developed colon cancer, breast cancer and an endometrial cancer, one endometrial cancer and breast cancer and the third had a pancreatic cancer and an oesophageal cancer.


    Discussion
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The occurrence of multiple primary cancers in particular individuals has intrigued clinicians and scientists for more than a century. The earliest case reports were published in the 19th century. Since then numerous works have appeared summarizing data that have been collected over many years on simultaneous and metachronous cancers.17

First we surmised that the prognosis of patients with a positive cancer history (group 2) is better than in sporadic cancer patients (group 1) due to an observational bias.17 Curtis described this phenomenon in prostate cancer which was detected more frequently in patients who were under observation because of a former diagnosed cancer. However, about 80% of pancreatic cancer patients suffer from advanced tumours at the time of diagnosis since no screening markers are currently available.18 Thus, no difference in the two groups could be identified concerning TNM-classification, UICC-stage and survival in our study. Secondly, this retrospective study focused on differences in the family history between pancreatic cancer patients with (group 2) and without (group 1) second or multiple primaries. A positive cancer family history for cancers at different sites could be detected in 75.0% of the families of group 2 in comparison to 51.1% of the families of group 1 (mean 55.9%) in this study. Similarly, Dergham et al.19 detected a family history of cancer in 52% of pancreatic cancer patients. According to our study, multiple primaries in ductal pancreatic cancer patients coincide with an increased risk of malignancies among their close relatives (OR = 1.83), since significantly more tumours developed among relatives of patients with multiple primaries compared to patients without multiple primaries (P = 0.034) even after adjustment for family size and age of disease onset in the index cases. The results were similar when only first- and both first- and second-degree relatives were included in the analysis. Information on the occurrence of malignancies among relatives was, however, obtained by the family history method, which is a methodological limitation of our study. Nevertheless, our findings lead to the hypothesis that multiple primaries in pancreatic cancer patients with a positive family history for cancer might be caused by an inherited predisposition.

Several hereditary cancer syndromes coincide with an increased risk of pancreatic cancer. Patients with HNPCC have an increased risk of pancreatic cancer as well as stomach, breast, small bowel, endometrial and renal pelvis cancer.20–22 Among the index patients in the present study 3 of 16 multiple primaries and 9 of 21 tumours in their families fell into the HNPCC tumour spectrum (Tables 1 and 3GoGo). Furthermore 3 of the 13 index patients of group 2 had additional basal cell carcinomas, that may occur in a subset of HNPCC families (Muir-Torre syndrome).23,24 None of the families in group 2, however, fulfilled the Amsterdam criteria.25 It is well known that not all HNPCC families with detectable germline mutations in the mismatch repair genes meet the Amsterdam criteria.26 Furthermore, an increased risk of synchronous and metachronous tumours of the colorectum and other organs in HNPCC patients has been described.20 Therefore, it seems possible that one of the HNPCC causing mismatch repair genes may underlie the tumour development in some of the presented families. Several other well-characterized genetic syndromes have been shown to predispose affected family members to the development of pancreatic cancers.21 Syndromes associated with pancreatic cancer include hereditary pancreatitis, ataxia teleangiectasia, a subset of FAMMM syndrome and Peutz-Jeghers syndrome. The history of the patients in this study did not indicate one of these rare syndromes in any case. No patient was a member of a family with a hereditary pancreatitis. Multiple melanomas did not occur in any index patient nor in one of their relatives.

Familial breast cancer has also been associated with pancreatic cancer in some families.5 Tulinius found more cases of pancreatic cancer than expected in male first-degree relatives of breast cancer patients (relative risk 1.66).27 Phelan could show an excess of pancreatic cancer in some families with BRCA2 germline mutations.2 In the present study, there was one breast cancer among the second primary cancers in group 2, which had occurred 23 years before the pancreatic cancer of this female patient when she was 43 years old. Since no family member of this patient has developed breast cancer an inherited predisposing BRCA2 germline mutation is not likely, although a de novo mutation might be possible.

Another cancer syndrome associated with an increased risk of pancreatic cancer was described by Li and Fraumeni. In those families tumours such as different sarcomas, adrenocortical carcinomas, breast cancers, brain tumours, leukaemias, pancreatic cancers, carcinomas of the lung and others were described.28,29 The occurrence of neoplasms originating at discordant sites is caused by a predisposing gene defect of TP53 tumour suppressor gene in those families. Epidemiological studies have confirmed that the neoplasms in Li-Fraumeni syndrome often tend to develop as multiple primaries in affected individuals.30 A follow-up study of the original four families found that over a 12-year period 10 of the 31 surviving family members had developed 16 additional cancers, in comparison with less than one expected from general population rates.28 In addition, a multicentre study in 59 patients with multiple primaries has shown that four of the 59 patients (6.8%) carried germline mutations in the TP53 tumour suppressor gene, although they did not have a family history suggestive for the Li-Fraumeni syndrome.31 Since some of the tumours in the Li-Fraumeni tumour spectrum appeared among the index patients of group 2, it seems to be worthwhile to determine the role of TP53 in these patients and their families by genetic analysis.

Patients with genetically caused cancers such as familial colon cancer and familial breast cancer are frequently characterized by younger age of onset of the disease.4 In some of the patients in group 2 the second primary occurred as an early onset cancer (breast cancer at age 43 and cervical cancer at 31 years). We investigated whether pancreatic cancer patients with multiple primaries were younger than those patients without a cancer history when pancreatic cancer occurred, however, no difference was found (P = 0.29). This is not surprising, since it is known that familial pancreatic cancer is not characterized by early onset.4

In summary, the data of the present study and the literature imply that multiple primaries in some pancreatic cancer patients might be caused by a genetic predisposition. Thus, a careful clinical and genetic analysis of pancreatic cancer patients with multiple primaries and their families, including analyses of known cancer predisposing genes (e.g. TP53, p16, BRCA2 and Mismatch-Repair-genes) and allelotyping should be performed to verify or negate this hypothesis. Such an approach may be useful for identifying predisposing gene defects for the development of different solid neoplasms and thus understanding the shared genetic alterations of different tumour types.


    Acknowledgments
 
We thank C Erbe and U Danner for collecting the clinical data and the histological confirmation of the index cases. This study was supported by the PE Kempkes-Foundation Marburg (Grant No. 4/97).


    References
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
1 Groden J, Thliveris A, Samowitz W et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;66:589–95.[ISI][Medline]

2 Phelan CM, Lancaster JM, Tonin P et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996; 13:120–22.[ISI][Medline]

3 Tavtigian SV, Simard J, Romens J et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 1996;12: 333–37.[ISI][Medline]

4 Hruban RH, Petersen GM, Ha PK, Kern SE. Genetics of pancreatic cancer—from genes to families. Surg Oncol Clin North Am 1998;7:1–23.[Medline]

5 Lynch HT, Smyrk T, Kern SE et al. Familial pancreatic cancer: a review. Semin Oncol 1996;23:251–75.[ISI][Medline]

6 Lynch HT. Genetics and pancreatic cancer. Arch Surg 1994;129:266–68.[ISI][Medline]

7 Ghadirian P, Boyle P, Simard A, Baillargeon J, Maisonneuve P, Perret C. Reported family aggregation of pancreatic cancer within a population based case-control study in the francophone community in Montreal, Canada. Int J Pancreatol 1991;10:183–96.[ISI][Medline]

8 Fernandez E, Vecchia CL, Dávanzo B, Negri E, Franceschi S. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 1994;3:209–12.[Abstract]

9 Whelan AJ, Bartsch D, Goodfellow PJ. A familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med 1995;333:975–77.[Free Full Text]

10 Goldstein AM, Fraser MC, Struewing PJ et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16 INK4a mutations. N Engl J Med 1995;333:970–74.[Abstract/Free Full Text]

11 Goggins M, Schutte M, Lu J et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinoma. Cancer Res 1996;56:5360–64.[Abstract]

12 Hoar SK, Wilson J, Blot WJ, McLaughlin JK, Winn DM, Kantor AF. Second cancer following cancer of the digestive system in Connecticut, 1935–82. Natl Cancer Inst Monogr 1985;68:49–82.[Medline]

13 Bauer H, Köbberling J, Peter K. Zweck und Verfahrensweise. EBM 1997;1:4.

14 Sobin LH, Wittekind Ch. TNM Classification of Malignant Tumors, 5th Edn. 1997.

15 Bonthron DT, Fitz Patrick DR, Porteous MEM, Trainer AH. Clinical Genetics—A Case-based Approach. London Philadelphia Toronto Sydney Tokyo: WB Saunders, 1998, p.4.

16 Ziegler A, Kastner C, Blettner M. The generalized estimating equations: an annotated bibliography. Biom J 1998;40:115–39.[ISI]

17 Curtis RE, Boice JD, Kleinermann RA, Flannery JT, Fraumeni JF Jr. Summary: multiple primary cancers in Connecticut, 1935–82. Natl Cancer Inst Monogr 1985;68:219–42.[Medline]

18 Flanders TY, Foulkes WD. Pancreatic adenocarcinoma: epidemiology and genetics. J Med Genet 1996;33:889–98.[Abstract]

19 Dergham ST, Dugan MC, Arlauskas P et al. Relationship of family cancer history of the expression in pancreatic adenocarinoma. Int J Pancreatol 1997;21:225–34.[ISI][Medline]

20 Watson P, Lynch HAT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 1993;71:677–85.[ISI][Medline]

21 Lumadue JA, Griffin JA, Osman M, Hruban RA. Familial pancreatic cancer and the genetics of pancreatic cancer. Surg Clin N Am 1995;75: 845–55.[ISI][Medline]

22 Silverman DT, Schiffman M, Everhart J et al. Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer 1999;80:1830–37.[ISI][Medline]

23 Lynch HT, Lynch PM, Pester J, Fusaro RM. The cancer family syndrome: rare cutaneous phenotypic linkage of Torres syndrome. Arch Intern Med 1980;141:607–11.[ISI]

24 Lynch HT, Fusaro RM, Roberts L, Voorhees GJ, Lynch JF. Muir-Torre syndrome in several members of a family with a variant of cancer family syndrome. Br J Dermatol 1985;113:295–301.[ISI][Medline]

25 Vasen HFA, Mecklin JP, Khan PM, Lynch HAT. The International Collaborative Group on Hereditary Non-polyposis Colorectal Cancer. Dis Colon Rect 1991;34:424–25.[ISI][Medline]

26 Boland CR. Hereditary nonpolyposis colorectal cancer. In: Vogelstein B, Kinzler KW (eds). The Genetic Basis of Human Cancer. New York: McGraw-Hill, 1998, pp.333–46.

27 Tulinius H, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Bjarnadottir K. Neoplastic diseases in families of breast cancer patients. J Med Genet 1994;31:618–21.[Abstract]

28 Li FP, Fraumeni JF Jr. Prospective study of a family cancer syndrome. JAMA 1982;247:2692–94.[ISI][Medline]

29 Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni JF Jr, Li FP. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 1991;51:6094–97.[Abstract]

30 Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986;53:661–71.[ISI][Medline]

31 Malkin D, Jolly KW, Barbier N et al. Germ line mutations of the p53 tumor suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med 1992;326:1309–15.[Abstract]





This Article
Abstract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (2)
Request Permissions
Google Scholar
Articles by Gerdes, B.
Articles by Bartsch, D. K
PubMed
PubMed Citation
Articles by Gerdes, B.
Articles by Bartsch, D. K