A hypothesis-generating search for new genetic breast cancer syndromes - a national study in 803 Swedish families

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Among Swedish families with an inherited predisposition for breast cancer, less than one third segregate mutations in genes known to be associated with an increased risk of breast cancer in combination with other types of tumours. In a search for new putative familial breast cancer syndromes we studied Swedish families undergoing genetic counselling during 1992-2000. Four thousand families from counselling clinics in Sweden were eligible for study. Families with breast cancer only were excluded, as were families with mutations in genes already known to be associated with malignant diseases. We identified 803 families with two or more cases of breast cancer and at least one other type of cancer. The observed proportion of different types of non-breast cancer was compared with the percentage distribution of non-breast cancer tumours in Sweden in 1958 and 1999. We found tumours in the colon, ovary, endometrium, pancreas and liver, as well as leukaemia in a significantly larger proportion of the study population than in the general population in both years. These tumours were also seen among families where several members had one additional tumour, suggesting that malignancies at these sites, in combination with breast tumours, could constitute genetic syndromes. Endometrial carcinoma has not previously been described in the context of breast cancer syndromes and the excess of malignancies at this site could not be explained by secondary tumours. Thus, we suggest that endometrial carcinoma and breast cancer constitute a new breast cancer syndrome. Further investigation is warranted to categorize phenotypes of both breast and endometrial tumours in this subgroup.

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Publié le 01 janvier 2007
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Hereditary Cancer in Clinical Practice 2007; 5(1) pp. 17-24
A hypothesis-generating search for new genetic breast cancer syndromes – a national study in 803 Swedish families
1 2 3 4 Anna von Wachenfeldt , Annika Lindblom , The South Swedish Oncogenetic Study Group , Henrik Grönberg , 5 6 7 8 Zakaria Einbeigi , Richard Rosenquist , Camilla Gardman , Lennart Iselius
1 2 Department of Oncology, Karolinska University Hospital, Sodersjukhuset, Karolinska Institute, Stockholm, Sweden, Department of Molecular Medicine and Surgery, 3 4 CMM, Karolinska University Hospital, Stockholm, Sweden, Departments of Clinical Genetics and Oncology, University Hospital Lund, Lund, Sweden, Oncologic 5 6 Center, Umeå University Hospital, Umeå, Sweden, Department of Oncology, Sahlgrenska Academy at Goteborg University, Goteborg, Sweden, Department of 7 8 Genetic and Pathology, Uppsala University, Uppsala, Sweden, Department of Clinical Genetics, Linkoping University Hospital, Linkoping, Sweden, Department of Surgery, Karolinska University Hospital, Stockholm, Sweden
Key words: breast cancer, endometrial cancer, family history, syndromes, genetics
C o r r e s p o n d i n g a u t h o r : A n n a v o n Wa c h e n f e l d t , D e p a r t m e n t o f O n c o l o g y, S o d e r s j u k h u s e t , 1 1 8 8 3 S t o c k h o l m , S w e d e n , phone +46 86 16 44 83, fax + 46 86 16 44 22, Email: anna.vonwachenfeldt-vappling@karolinska.se
Submitted: 9 February 2007 Accepted: 9 February 2007
Abstract
Among Swedish families with an inherited predisposition for breast cancer, less than one third segregate mutations in genes known to be associated with an increased risk of breast cancer in combination with other types of tumours. In a search for new putative familial breast cancer syndromes we studied Swedish families undergoing genetic counselling during 1992-2000. Four thousand families from counselling clinics in Sweden were eligible for study. Families with breast cancer only were excluded, as were families with mutations in genes already known to be associated with malignant diseases. We identified 803 families with two or more cases of breast cancer and at least one other type of cancer. The observed proportion of different types of non-breast cancer was compared with the percentage distribution of non-breast cancer tumours in Sweden in 1958 and 1999. We found tumours in the colon, ovary, endometrium, pancreas and liver, as well as leukaemia in a significantly larger proportion of the study population than in the general population in both years. These tumours were also seen among families where several members had one additional tumour, suggesting that malignancies at these sites, in combination with breast tumours, could constitute genetic syndromes. Endometrial carcinoma has not previously been described in the context of breast cancer syndromes and the excess of malignancies at this site could not be explained by secondary tumours. Thus, we suggest that endometrial carcinoma and breast cancer constitute a new breast cancer syndrome. Further investigation is warranted to categorize phenotypes of both breast and endometrial tumours in this subgroup.
Introduction
Breast cancer is by far the most frequently diagnosed malignant tumour in females: one Swedish woman in ten
Hereditary Cancer in Clinical Practice2007; 5(1)
will be affected during her lifetime [1]. Most cases occur late in life and are sporadic. A Scandinavian twin study has revealed that hereditary factors are important in 27% of all breast cancers [2], and 5-10% of the cases appear
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