Institut Bergonié
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Michel Longy

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Michel Longy graduated in medicine from the University of Bordeaux in 1983. After training in pathology and cytogenetics he joined the prenatal diagnostic lab at the Maternity Hospital in Bordeaux in 1985. He moved to the pathology department at the Bergonié Cancer Institute in 1990, where he now runs a clinical genetics service and a molecular diagnostic research lab. His main interest is in genes predisposing to breast cancer, in particular the PTEN tumour suppressor gene. 949_img

Research projects

Genetic predisposition to breast cancer

We have analysed CGH and gene expression profiles of tumours from patients with a familial clustering of breast cancer seen in the genetics clinic at the Bergonié Cancer Institute. The main goal was to identify novel breast cancer predisposition genes, but some tumours with known BRCA1 and BRCA2 mutations were included in order to generate signatures that could be used to exclude patients with de novo mutations or mutations missed by conventional screening. The immediate goals are now to validate the resulting CGH and gene expression signatures for BRCA1 and BRCA2-mutant tumours on new samples, and to screen for mutations in candidate loci in the patients without mutations in known predisposition genes. Given the rapid evolution of sequencing technology, the screening will be performed by next generation sequencing.

Role of PTEN in genetic instability

Comparison of tumours with germline or somatic PTEN mutations showed that the former have few genetic changes visible on CGH arrays, whereas the latter are heavily rearranged. Furthermore, the germline-mutant tumours are frequently heterozygous for PTEN, suggesting a haploinsufficient role for PTEN. We suspect that PTEN has different tumour suppressor functions depending on when it acts in tumorigenesis. A possible model is that early reduction to homozygosity of a germline mutation is not favoured because it triggers senescence in an otherwise normal cell, whereas homozygous somatic mutations are not constrained by senescence because they arise after inactivation of p53. Recent work indicating a role for PTEN in DNA repair suggests that the PTEN loss may directly explain the heavily rearranged profiles of the somatically mutated tumours. The lentiviral transformation system described by the Iggo lab (Duss 2007) will be used to address these points by changing the order of addition of the viruses and by testing cells on CGH arrays sequentially to detect genetic instability.

Molecular apocrine tumour formation.

We have shown that breast tumours arising in patients with germline PTEN mutations have a molecular apocrine profile (Banneau 2010). This reinforces the view that apocrine metaplasia commonly arises in the context of ERBB2 pathway activation. To identify critical factors in this transition we are collaborating with the Iggo lab to create genetically defined models of breast cancer by targeting PTEN in normal mammary epithelial cells.
 
 

Publications:

Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations. Banneau G, Guedj M, Macgrogan G, de Mascarel I, Velasco V, Schiappa R, Bonadona V, David A, Dugast C, Gilbert-Dussardier B, Ingster O, Vabres P, Caux F, de Reynies A, Iggo R, Sevenet N, Bonnet F, Longy M.
Breast Cancer Res. 2010;12(4):R63. Epub 2010 Aug 16

Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Caux F, Plauchu H, Chibon F, Faivre L, Fain O, Vabres P, Bonnet F, Selma ZB, Laroche L, Gérard M, Longy M.
Eur J Hum Genet. 2007 Jul;15(7):767-73. Epub 2007 Mar 28.

High-resolution integrated map encompassing the breast cancer loss of heterozygosity region on human chromosome 16q22.1. Frengen E, Rocca-Serra P, Shaposhnikov S, Taine L, Thorsen J, Bepoldin C, Krekling M, Lafon D, Aas KK, El Monéim AA, Johansen H, Longy M, Prydz H, Dorion-Bonnet F.
Genomics. 2000 Dec 15;70(3):273-85.

Localization of the gene for Cowden disease to chromosome 10q22-23. Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C.
Nat Genet. 1996 May;13(1):114-6.