1.Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy2.Laboratoire dOncologie Moléculaire, U.119 Inserm, Institut de Cancérologie et dImmunologie de Marseille, 27 Bd. Le Roure, 13009 Marseille, France3.Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy
Invasive breast carcinomas are divided into two major categories on the basis of their cytoarchitectural features:
The recognized precursor lesions of invasive breast carcinoma are :
The terminology Invasive ductal/lobular carcinoma does not imply an origin form ducts and lobules, respectively, but the presence of cytoarchitectural and phenotypical features of ductal-type and lobular-type, respectively. Ductal adenocarcinoma is the most common.Lobular carcinoma is the second malignant breast tumour.Medullary carcinoma is rare.Hyperplasia is a proliferation without criteria of malignancy.Fibroadenomas are benign breast tumours.
Many morphologic variants of invasive ductal carcinoma exist, some of them extremely rare. They include: tubular, cribriform, medullary, mucinous, neuroendocrine, papillary, micropapillary, apocrine, metaplastic, lipid-rich, secretory, oncocytic, adenoid cystic, acinic cell, glycogen-rich (clear cell), sebaceous, and inflammatory carcinoma. The prognosis of these subtypes varies, some of them having a better and some a worse outcome than invasive ductal carcinoma, NOS.
These different forms of breast cancer may occur with (hereditary or familial forms) or without (sporadic forms) a familial background.
Alterations of chromosome arms 1q, 3p, 6q, 8p are often present; i(1q) and der t(1;16) are frequent as sole anomalies; +7, +8 and +20 are also frequent; cytogenetic signs of DNA amplification, such as homogeneously staining regions (HSR), are commonly observed in breast carcinomas and seem preferentially associated to 8p.
CGH : Comparative genomic hybridization (CGH) is a molecular cytogenetics method designed to detect and map chromosomal regions showing abnormal copy numbers in tumors; theoretically, it is possible to detect equally copy number gains (DNA amplification or polyploidies) or losses using this approach; it appears, however, that CGH has a greater sensitivity for gains than for losses; this could be related to the fact that gains are generally of higher magnitude than losses and that losses can be obscured by intratumoral heterogeneity;Overall CGH data show that breast tumor genomes undergo severe rearrangements; on average, breast tumors show 5-7 copy number changes/tumor; less than 10% of the tumors analyzed by CGH show neither gains nor losses; almost every chromosome presents at least one site with aberrant copy numbers, however, gains or losses are not evenly distributed throughout the genome.
Hot spots for gains are routinely observed at 1q (50-55% of the tumors), 8q (60%), 17q (25-30%), 20q (20-25%); gains generally involve subregions of each chromosomal arm and most prevalent regions are 1q31-q32, 8q12 and 8q24 (with MYC and other genes), 17q12 (ERBB2) and 17q23-q24, and 20q13; other regions of recurrent gains are 11q13 (20%, with CCND1), 8p12 (10-15%, and FGFR1), 16p (10-15%); recurrent losses are observed at 1p, 6q, 8p, 11q23-qter, 13q, 16q, 17p and 22q
CGH has revealed that copy number gains are common in breast tumors and involve 26 (!) chromosomal arms; these data somewhat contradict karyotypical analysis and LOH studies which indicate that losses are more frequent that gains; furthermore, it appears from CGH data that the number of events (gains and losses) increases in advanced cancer.
the germline mutations are dispersed throughout the coding sequence; although a majority of these variations are unique, recurrent mutations such as 185delAG and 5382insC are observed; they were initially described in the Ashkenazy Jewish population; more than 80% of the sequence variants lead to a truncated protein; in contrast, the majority of missense mutations are of unknown clinical significance, excepted those in the RING finger region; in the BRCA1 families, an excess of breast, ovarian, and prostate cancers are seen; all mutations combined, penetrance at age 70 years works out at 56% to 87% in the case of breast cancer, and 16% to 63% in that of ovarian cancer
BRCA1-associated breast cancers have specific morphological features; they are more frequently of histoprognostic grade 3, highly proliferating and poorly differentiated tumors with a very pleomorphotic nuclear pattern; high frequencies of P53 alterations and negativity of steroid receptors are found in these tumors; a high rate of medullary breast carcinomas is observed among BRCA1-associated breast cancers; evidence for possible genotype-phenotype correlations have been provided concerning the tumor spectrum (breast/ovarian cancer incidence rate), the penetrance, and the proliferation rate of tumors
BRCA2 germline mutations are associated with a high risk of male and female breast cancer; initially, the breast cancer risk was considered as equivalent to that of BRCA1, but in a recent work based only on the Icelandic recurrent BRCA2 999del5 mutation, the estimated risk of breast cancer at age 70 years is considered of only 37%; the ovarian cancer risk is lower than that of BRCA1; in addition, an excess of prostate and pancreas cancers is also seen
at the morphological level, BRCA2 breast cancers seem to be different from both BRCA1-associated breast cancers and sporadic cases, with a poor differentiation but no high proliferation rate; evidence for possible genotype-phenotype correlation has been provided concerning the tumor spectrum (breast/ovarian cancer incidence rate)
One such gene might be located on chromosome arm 8p; a positive linkage has first been found in a small set of French families, and then a lod score of almost 3 was obtained in one German family; in addition, the chromosome 8p12-22 region seems to be frequently involved in breast carcinogenesis as well as in different types od tumors (lung, prostate, ovarian); while the 8p12-22 region remain a strong candidate locus, whole-genome linkage studies are in progress to identify the other gene(s) that predispose to breast cancer.
In spite of the initial description of PTEN homozygous deletion in two breast tumor xenografts and biallelic inactivation of PTEN in two breast carcinoma cell lines, very few PTEN mutations have been observed in sporadic breast carcinoma (1 described mutation in more than 100 analyzed tumors).
Maria Luisa Carcangiu ; Patrizia Casalini ; Sylvie Ménard
Breast tumors : an overview
Atlas Genet Cytogenet Oncol Haematol. 2005-05-01
Online version: http://atlasgeneticsoncology.org/solid-tumor/5018/breast-tumors-an-overview
1999-01-01 Breast tumors : an overview by Daniel Birnbaum,Francois Eisinger,Jocelyne Jacquemier,Michel Longy,Hagay Sobol,Charles Theillet