breast cancer: easier identification of women at high risk

16 January 2009
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Breast cancer
Easier identification of women at high risk
At the Institut Curie, Marc-Henri Stern’s team (U830 Inserm) has discovered a simple way to identify
women at high risk of breast cancer, as reported in the 15 January 2009 issue of Cancer Research.
Five to 10% of breast cancers occur in a setting of genetic predisposition linked, for example, to
mutations of the BRCA1 and BRCA2 genes. However, screening for mutations in these genes is
time-consuming and difficult. Hereditary breast cancers do, though, have other distinctive features.
Histologically, they usually belong to a so-called basal-like tumor subtype. Genetically, Institut Curie
researchers have discovered that these cancers display complex mutations of the TP53 gene, and
these are easier to detect than BRCA1 mutations. Screening for complex mutations of the TP53 gene
in all patients diagnosed with a basal-like tumor would seem to be an additional means of identifying
high-risk families.
Five to 10% of breast cancers are diagnosed in women with a genetic predisposition. Two main
predisposition genes have been identified: BRCA1 and BRCA2. Other known and unknown genes are
doubtless implicated in hereditary breast cancers, but their alterations may be associated with a lower
cancer risk.
Alterations in BRCA1 and BRCA2 account for 95% of the hereditary familial forms of breast and ovarian
cancer, and for 65% of the hereditary familial forms of breast cancer alone. Yet a mutation in BRCA1 or
BRCA2 is only identified in 15% of the familial forms tested. And only half of the women carrying a
BRCA1/2 mutation and treated for breast cancer have a family history that prompts genetic testing. It is
therefore clear that some families potentially at risk are not identified by these selection criteria (few cases,
“small” family…), and so do not have suitable follow-up. But it seems difficult to extend mutation screening
using current testing procedures.
A different approach to identifying women carrying a BRCA1 mutation
At the Institut Curie, the “Genomics and Biology of Hereditary Breast Cancer” team headed by Marc-Henri
Stern (U 830 Inserm) has re-examined the genetics of hereditary breast cancers and studied mutations in
TP53, a tumor suppressor gene frequently mutated in carcinogenesis.
In collaboration with three other teams of the Paris (Ile-de-France) Region Cancer Research Network, the
Institut Curie researchers have shown that the frequency of TP53 mutations in breast cancer with a BRCA1
mutation is correlated with histological type: 85% of hereditary breast cancers are basal-like. This form of
breast cancer, recently identified from its gene and protein expression profiles, has a poor prognosis,
particularly as it expresses neither hormone receptors nor HER2 protein and cannot therefore be targeted
therapeutically. Like hereditary breast cancer, basal-like cancers are characterized by a high level of TP53
mutations. Marc-Henri Stern points out though that “the nature of the mutations differentiates between
hereditary tumors and basal-like cancers. Complex mutations of the TP53 gene are characteristic of
the hereditary forms.” Whence the researchers’ idea to screen the tumor for complex TP53 mutations in
all patients diagnosed with basal-like breast cancer. This screening is easier than testing for BRCA1
mutations and will pick out at-risk women who would not have been identified by a high frequency of breast
cancer in their family.
Further information
Breast cancer
The National Institute for Public Health Surveillance in France estimated that in 2005 there were 50 000
new cases of breast cancer. This most frequent cancer among women accounts for half of all additional
cases of cancer recorded in women over the last 25 years in France.
There are numerous forms of breast cancer, depending on its stage and site, and the cells from which it
originates. The mammary gland principally comprises lobules that produce milk and ducts that transport it.
The early stages of breast cancer occur among epithelial cells of the ducts or lobules. As long as the
cancer cells are confined to the ducts or lobules, the cancer is in situ. With more extensive use of screening
mammography, close to 20% of breast cancers are now diagnosed at this stage, compared with just 2% in
the past.
However, once the cancer cells cross the basal membrane of the ducts or lobules and enter neighboring
tissues, the cancer is invasive. The cancer cells can then spread to the axillary nodes in the armpits and
possibly throughout the body. There are also other less frequent forms of invasive cancer: mucinous
carcinoma, micropapillary carcinoma, ductal carcinoma, and certain rare forms, like medullary carcinoma.
Classification
Cancer is currently classified morphologically using certain criteria: histological type, tumor size, lymph node
invasion, presence of hormone receptors (estrogen or progesterone or both), overexpression of HER2
protein. These parameters are then used to determine the most appropriate treatment.
This classification has recently been refined thanks to the development and clinical application of genomic
analyses. These distinguish between the different types of breast cancer—luminal, basal-like, HER2+—
generally as a function of the coupled expression of certain proteins, notably estrogen and HER2 receptors.
Reference
High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas, but not in BRCA1
luminal breast tumors.
Elodie Manié1,2, Anne Vincent-Salomon1,2,3, Jacqueline Lehmann-Che4,5, Gaelle Pierron3, Elisabeth
Turpin4,5, Mathilde Warcoin1,2, Nadège Gruel1,2,6, Ingrid Lebigot3, Xavier Sastre-Garau3, Rosette Lidereau7,
Audrey Remenieras8, Jean Feunteun8,9, Olivier Delattre1,2,3, Hugues de Thé4,5, Dominique StoppaLyonnet1,2,3,10, Marc-Henri Stern1,2,3
1
2
3
Institut Curie, Centre de Recherche, Paris; INSERM U830, Paris; Institut Curie, département de Biologie des tumeurs, Paris;
5
département de Biochimie, Hôpital Saint-Louis APHP, Paris; CNRS UMR 7151, Institut Universitaire d'Hématologie, Université
6
7
Paris 7 Denis Diderot, Paris; Institut Curie, département de Transfert, Paris; INSERM, U735, Centre René Huguenin, Saint8
9
10
Cloud; Institut Gustave Roussy, Villejuif; CNRS-Université Paris XI FRE#2939, Villejuif; Université Paris Descartes, France.
4
Cancer Research, 15 January 2009, vol. 69 (2).
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