Women with Saethre‐Chotzen syndrome are at increased risk of breast cancer

Abstract

The Saethre-Chotzen syndrome is an autosomal, dominantly inherited craniosynostosis caused by mutations in the basic helix-loop-helix transcription factor gene TWIST1. This syndrome has hitherto not been associated with an increased risk of cancer. However, recent studies, using a murine breast tumor model, have shown that Twist may act as a key regulator of metastasis and that the gene is overexpressed in subsets of sporadic human breast cancers. Here, we report a novel association between the Saethre-Chotzen syndrome and breast cancer. In 15 Swedish Saethre-Chotzen families, 15 of 29 (52%) women carriers over the age of 25 had developed breast cancer. At least four patients developed breast cancer before 40 years of age, and five between 40 and 50 years of age. The observed cases with breast cancer (n = 15) are significantly higher than expected (n = 0.89), which gives a standardized incidence ratio (SIR) of 16.80 (95% CI 1.54-32.06). Our finding of a high frequency of breast cancer in women with the Saethre-Chotzen syndrome identifies breast cancer as an important and previously unrecognized symptom characteristic of this syndrome. The results strongly suggest that women carriers of this syndrome would benefit from genetic counseling and enrolment in surveillance programs including yearly mammography. Our results also indicate that the TWIST1 gene may be a novel breast cancer susceptibility gene. Additional studies are, however, necessary to reveal the mechanism by which TWIST1 may predispose to early onset breast cancer in Saethre-Chotzen patients.

Methylation of the TWIST1 Promoter, TWIST1 mRNA Levels, and Immunohistochemical Expression of TWIST1 in Breast Cancer

“…Alternatively, TWIST1 promoter methylation might be an early event, which precedes compensatory TWIST1 overexpression. Indeed, TWIST1 haploinsufficiency predisposes to breast cancer in Saethre-Chotzen syndrome (28). To further elucidate these mechanisms, the relation between methylation of the TWIST1 promoter and TWIST1 expression should be addressed in in vitro models.…”

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

“…Some genes with RNAi phenotypes had homologs required for cell migration in mammals or Drosophila. Among these were two transcription factors: hlh-8, encoding a helix-loop-helix (HLH) protein orthologous to TWIST, which regulates cellular movements in Drosophila and mammals (19,20); and crh-2, paralogous to SLBO, a C/EBPγ protein required for Drosophila border cell migration (7,8). Others genes were regulators of the actin cytoskeleton, such as toca-1 and inft-1/inverted formin (21,22).…”

Progressive non-infectious anterior vertebral fusion in a baby with Saethre-Chotzen-acrocephalosyndactyly type III syndrome

“…[11] показали, что у 15 (52 %) из 29 женщин из 15 семей в возрасте старше 25 лет с синдромом Saethre-Chotzen развился рак молоч-ной железы. По крайней мере у 4 пациенток раз-вился рак молочной железы в возрасте до 40 лет и у 5 -между 40 и 50 годами.…”