A high proportion of founder BRCA1 mutations in Polish breast cancer families.
Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention.
Górski
Bohdan
B
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland. gorskib@sci.pam.szczecin.pl
Jakubowska
Anna
A
Huzarski
Tomasz
T
Byrski
Tomasz
T
Gronwald
Jacek
J
Grzybowska
Ewa
E
Mackiewicz
Andrzej
A
Stawicka
Malgorzata
M
Bebenek
Marek
M
Sorokin
Dagmara
D
Fiszer-Maliszewska
Łucja
Ł
Haus
Olga
O
Janiszewska
Hanna
H
Niepsuj
Stanisław
S
Góźdź
Stanisław
S
Zaremba
Lech
L
Posmyk
Michał
M
Płuzańska
Maria
M
Kilar
Ewa
E
Czudowska
Dorota
D
Waśko
Bernard
B
Miturski
Roman
R
Kowalczyk
Jerzy R
JR
Urbański
Krzysztof
K
Szwiec
Marek
M
Koc
Jan
J
Debniak
Bogusław
B
Rozmiarek
Andrzej
A
Debniak
Tadeusz
T
Cybulski
Cezary
C
Kowalska
Elzbieta
E
Tołoczko-Grabarek
Aleksandra
A
Zajaczek
Stanisław
S
Menkiszak
Janusz
J
Medrek
Krzysztof
K
Masojć
Bartłomiej
B
Mierzejewski
Marek
M
Narod
Steven Alexander
SA
Lubiński
Jan
J
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D005192:Family Health; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D011044:Poland