Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Abstract

Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

Lobular breast cancer: incidence and genetic and non-genetic risk factors

“…Only one low-penetrance variant was specifically associated with ILC in a pooled, post hoc analysis of 36 case–control studies [106]. …”

Awareness about Early Detection Methods, Symptoms and Risk Factors towards Breast and Cervical Cancer among the Female Students of Mawlana Bhashani Science and Technology University (MBSTU), Santosh, Tangail, Bangladesh

“…The ability to characterize entire genomes at base pair level using massively parallel sequencing technologies provides a unique opportunity to unravel genotypic-phenotypic associations in breast cancer, which can be exploited for the identification of drivers of tumourigenesis [17]. Invasive lobular breast cancer (ILC) is accounts for 10% -15% of all invasive breast carcinomas and it has distinct etiological, clinical and biological characteristics compared with the more common invasive ductal type carcinoma (IDC) [18]. In Iran, breast cancer is ranked first among malignancies in women [19].…”

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

“…While there are genetic risk factors which are specific for either lobular or ductal BC, a limitation of our study was that the information on histological subtype of the tumors was relatively sparse and so the power to detect DCIS specific associations was limited.…”

“…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 .…”