Genetic predisposition to ductal carcinoma in situ of the breast

Abstract

BackgroundDuctal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci.MethodsTo identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip.ResultsMost (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing.Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC.We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8.ConclusionIn conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0675-7) contains supplementary material, which is available to authorized users.

Genomic approaches to accelerate cancer interception

“…Cancer is thought to proceed through a multi-step process where accumulating alterations in driver genes allow cells to clonally expand and invade surrounding tissues 34 . A limited number of RNA and DNA sequencing studies interrogating a range of precancerous tissues from the breast 35–39 , colon 40–44 , lung 45,46 , head and neck 47 , skin 48,49 , and esophagus 50–55 have indicated that the path to cancer development is context-specific and involves diverse processes. Thesey studies suggest that early lesions are polyclonal and driver mutations present in late-stage disease, and that tumor development occurs via large-scale genomic rearrangements and copy number changes.…”

Molecular Fingerprints and Biomarkers of Breast Cancer

“…Other lesions associated with abnormal cell proliferation are also associated with more modestly elevated cancer risk, notably the atypical hyperplasia (ductal and lobular) and florid hyperplasia of usual type (that is, without atypia). Frequent coexistence of premalignant lesions with invasive breast cancer is consistent with progression from these lesions to cancer, but there are many controversies in this area, and clonal relationships are not always clear [4].…”

“…This morphological heterogeneity mirrors molecular heterogeneity, as well as morphologically similar tumours may differ in genetic and metabolic processes, and specific genetic abnormalities may influence clinical outcome [4,5].…”

A comprehensive analysis of polymorphic variants in steroid hormone and insulin‐like growth factor‐1 metabolism and risk of in situ breast cancer: Results from the Breast and Prostate Cancer Cohort Consortium

“…We also reported the polymorphic variant CDKN2BAS ‐rs1011970 as a potential BCIS specific variant in a study conducted within the Breast and Prostate Cancer Cohort Consortium (BPC3) . More recently, the CCND1 ‐rs75915166 and CCND1‐ rs554219 SNPs were found to be associated with low and intermediate grade DCIS risk within the BCAC study, but these associations were also observed for invasive disease …”

“…Even though a growing number of common, low‐penetrance susceptibility loci for invasive BC are being identified, comparatively few attempts to detect single nucleotide polymorphisms (SNPs) that are specific for breast carcinoma in situ (BCIS) have been made so far and of these several were underpowered . A previous study conducted within the Million Women Study identified 2p‐rs4666451 as being more strongly associated with BCIS risk than with invasive disease .…”