Loss of LRIG1 locus increases risk of early and late relapse of stage I/II breast cancer

Abstract

Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse≥5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients.

Figure 1.

Kaplan Meier curves for unadjusted analyses of time to relapse and overall survival by LRIG1 tumor copy number.

Figure 2.

The log10 p-values for association with any recurrence across chromosome 3. A small region that includes LRIG1 (red dots) on the short arm of chromosome 3 is associated with recurrence. The length of the region is narrow and it only includes LRIG1 and its close neighbor SLC25A26.

Figure 3.

Kaplan Meier curves for unadjusted analyses of A. time to distant metastasis free survival and B. overall survival by level of LRIG1 gene expression. --- low, --- medium, --- high.