Catucci Irene, Casadei Silvia, Ding Yuan Chun, Volorio Sara, Ficarazzi Filomena, Falanga Anna, Marchetti Marina, Tondini Carlo, Franchi Michela, Adamson Aaron, Mandell Jessica, Walsh Tom, Olopade Olufunmilayo I, Manoukian Siranoush, Radice Paolo, Ricker Charite, Weitzel Jeffrey, King Mary-Claire, Peterlongo Paolo, Neuhausen Susan L
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
Departments of Medicine and Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Breast Cancer Res Treat. 2016 Nov;160(1):121-129. doi: 10.1007/s10549-016-3981-y. Epub 2016 Sep 13.
Breast cancer-predisposing mutations PALB2 c.1027C>T (p.Gln343*) and PALB2 c.2167_2168delAT have each been observed multiple times in breast cancer families of Italian ancestry. More recently, the c2167_2168delAT mutation was identified in unrelated breast cancer cases of various ancestries. For each mutation, we investigated whether the origin was multiple mutational events (a "hot-spot") or a single event (a founder allele).
We genotyped and reconstructed haplotypes for 36 participants of Italian, Italian-American, Hispanic, and Nigerian ancestries, using seven short tandem repeat (STR) markers that covered 3 Megabases within and flanking PALB2 on chromosome 16.
For PALB2 c.1027C>T, a shared haplotype with a minimum size of 150 kb was shared by all 19 carriers investigated, all of Italian ancestry. This result suggests that this allele arose as a single event in a shared ancestor. For PALB2 c.2167_2168delAT, all 12 carriers from American-Italian and Italian families shared a 1-Mb haplotype, the 3 Hispanic carriers shared a different haplotype of size 2 Mb, and the Nigerian carrier had different alleles at all 7 STR markers. These results suggest that PALB2 c.2167_2168delAT arose multiple times, but that within each population, PALB2 c.2167_2168delAT likely represents a single mutational event.
We identified two PALB2 mutations that are founder alleles in Italian families, one of which is, independently, also a founder mutation in American-Hispanic breast cancers.
乳腺癌易感突变PALB2 c.1027C>T（p.Gln343*）和PALB2 c.2167_2168delAT在意大利裔乳腺癌家族中均被多次观察到。最近，c2167_2168delAT突变在不同血统的非相关乳腺癌病例中被发现。对于每种突变，我们调查其起源是多个突变事件（一个“热点”）还是单个事件（一个奠基者等位基因）。
我们对36名意大利、意大利裔美国人、西班牙裔和尼日利亚血统的参与者进行基因分型并重建单倍型，使用7个短串联重复序列（STR）标记，这些标记覆盖了16号染色体上PALB2内部及侧翼的3兆碱基。
对于PALB2 c.1027C>T，所有19名被调查的携带者（均为意大利血统）共享一个最小大小为150 kb的共享单倍型。这一结果表明该等位基因起源于一个共同祖先中的单个事件。对于PALB2 c.2167_2168delAT，所有来自美籍意大利人和意大利家族的12名携带者共享一个1兆碱基的单倍型，3名西班牙裔携带者共享一个大小为2兆碱基的不同单倍型，而尼日利亚携带者在所有7个STR标记处都有不同的等位基因。这些结果表明PALB2 c.2167_2168delAT多次出现，但在每个群体中，PALB2 c.2167_2168delAT可能代表单个突变事件。
我们鉴定出两个在意大利家族中为奠基者等位基因的PALB2突变，其中一个独立地也是美籍西班牙裔乳腺癌中的奠基者突变。
