High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia

Abstract

The BLM gene belongs to the RecQ helicase family and has been implicated in the maintenance of genomic stability. Its homozygous germline inactivation causes Bloom syndrome, a severe genetic disorder characterized by growth retardation, impaired fertility and highly elevated cancer risk. We hypothesized that BLM is a candidate gene for breast cancer (BC) predisposition. Sequencing of its entire coding region in 95 genetically enriched Russian BC patients identified two heterozygous carriers of the c.1642 C>T (Q548X) mutation. The extended study revealed this allele in 17/1,498 (1.1%) BC cases vs. 2/1,093 (0.2%) healthy women (p 5 0.004). There was a suggestion that BLM mutations were more common in patients reporting first-degree family history of BC (6/251 (2.4%) vs. 11/1,247 (0.9%), p 5 0.05), early-onset cases (12/762 (1.6%) vs. 5/736 (0.7%), p 5 0.14) and women with bilateral appearance of the disease (2/122 (1.6%) vs. 15/1376 (1.1%), p 5 0.64). None of the BLM-associated BC exhibited somatic loss of heterozygosity at the BLM gene locus. This study demonstrates that BLM Q548X allele is recurrent in Slavic subjects and may be associated with BC risk.Hereditary risk factors are strongly implicated in breast cancer (BC) predisposition. Mutations in BRCA1 and BRCA2 genes account for approximately 15-20% of familial BC clustering among first degree relatives.

Establishing a Clinic-Based Pancreatic Cancer and Periampullary Tumour Research Registry in Quebec

“…The founder populations represent a genetically enriched subgroup ideal for gene discovery studies 8,[37][38][39] . The enrichment of the qpcs with participants of French-Canadian descent is particularly valuable because fpdac is prevalent in that population 40 .…”

First Two Cases of Bloom Syndrome in Russia: Lack of Skin Manifestations in a BLM c.1642C>T (p.Q548X) Homozygote as a Likely Cause of Underdiagnosis

“…We recently analyzed the BLM gene as a candidate for hereditary breast cancer (BC), and revealed its association with BC risk [Sokolenko et al, 2012]. The BC-predisposing role of BLM was later confirmed by exome sequencing and case-control studies [Thompson et al, 2012;Prokofyeva et al, 2013], although a negative report has been published as well [Anisimenko et al, 2014].…”

“…However, it is still appropriate to expect an increased occurrence of BS in this part of the world. After the initial publication on high frequency of the BLM c.1642C>T (p.Q548X) mutation [Sokolenko et al, 2012], we contacted all major genetic centers operating in Russia by telephone, but no patients with BS were identified upon this effort. …”

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

“…A large deletion of exons 20-22 was characteristic among persons with BS from Portugal or Brazil, Gln700 * was found among BS Italians or Americans with Italian ancestry, and Ser186 * as well as Asn515fs account for most Japanese BS chromosomes. The mutation Gln548 * is more frequent in Slavic populations with a carrier frequency of 0.1% [Sokolenko et al, 2012;Prokofyeva et al, 2013].…”

“…Among 64 different mutations that were reported by German et al [2007], 19 were recurrent, including several from Portugese/Brazilian, Japanese, Anglo-German, and Italian American persons. A recurrent founder allele (c.1642C>T) of BLM has also been identified in Slavic populations of Eastern Europe [Sokolenko et al, 2012].…”