Germline DNA copy number variation in familial and early-onset breast cancer
© Krepischi et al.; licensee BioMed Central Ltd. 2012
Received: 12 August 2011
Accepted: 7 February 2012
Published: 7 February 2012
Genetic factors predisposing individuals to cancer remain elusive in the majority of patients with a familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy number variation (CNV) has recently been implicated in predisposition to cancers such as neuroblastomas as well as prostate and colorectal cancer. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to cause disease."
Using whole-genome comparative genomic hybridization on microarrays, we screened a cohort of women fulfilling criteria for hereditary breast cancer who did not carry BRCA1/BRCA2 mutations.
The median numbers of total and rare CNVs per genome were not different between controls and patients. A total of 26 rare germline CNVs were identified in 68 cancer patients, however, a proportion that was significantly different (P = 0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV in patients and controls had already been implicated in cancer.
This study is the first to explore the contribution of germline CNVs to BRCA1/2-negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger population samples.
It has been estimated that all known cancer susceptibility genes account for only 1% to 15% of familial cancers [1, 2]. Approximately 5% to 10% of hereditary breast and ovarian cancers result from dominant mutations in known single genes [3–6], particularly BRCA1/BRCA2. Therefore, the basis for a large fraction of genetic predisposition in families with breast and/or ovarian cancer remains to be uncovered.
Recent studies have highlighted DNA copy number variation (CNV) as the most prevalent type of structural variation in the human genome [7–9], and its role in normal development and disease has been demonstrated through its impact on gene expression and protein structure [10–13]. In particular, CNVs involving deletions have been reported as a cause of cancer susceptibility, occurring in up to 30% of highly penetrant cancer-predisposing genes, including BRCA1, BRCA2, APC, SMAD4 and TP53, as well as mismatch repair genes [14–16] (reviewed in [17, 18]).
Germline gains and losses of large DNA segments have recently been reported as factors predisposing individuals to neuroblastoma, prostate and colorectal cancer and BRCA1-associated ovarian cancer [19–24]. Nevertheless, whole-genome CNV profiling of patients fulfilling criteria for hereditary breast and ovarian cancer, but without BRCA1/BRCA2 mutations, has not been reported. In the present study, we investigated the germline CNV profiles of 68 unrelated familial and early-onset breast cancer patients who were negative for BRCA1/BRCA2 mutations, with the aim of detecting new genes contributing to breast and/or ovarian cancer predisposition.
Materials and methods
The research protocol was approved by the ethics committee of the AC Camargo Cancer Hospital, São Paulo, Brazil (protocol 1175/08), and informed consent was obtained from the subjects.
Samples of peripheral blood cells for DNA extraction were collected after informed consent was obtained from 68 women attending the AC Camargo Cancer Hospital prior to any systemic treatment. They were selected for fulfilling at least one of the criteria for hereditary breast and ovarian cancer published in the National Comprehensive Cancer Network Practice Guidelines in Oncology version 1.2010 .
Confirmation of the family history of cancer was obtained whenever possible on the basis of pathology reports, medical records and/or death certificates. All women had previously tested negative for BRCA1/BRCA2 pathogenic mutations (based on Sanger sequencing of coding sequences). Because most of the affected relatives were already dead, were inaccessible or refused to participate, we were unable to investigate CNV segregation in the majority of the cases.
The criteria used to select patients, type of cancer, and age at cancer diagnosis are given in Additional file 1. Most of the patients (n = 48) were familial cases of hereditary breast and/or ovarian cancer in which at least one other family member was affected. The remaining 20 patients were considered hereditary breast and/or ovarian cancer patients for being isolated cases of early-onset cancer (≤ 45 years of age). Most of the tumors were invasive ductal breast carcinomas. Aside from two patients who had only ovarian cancer (patients 9 and 34), all of the other sixty-six patients had breast cancer (bilateral in patient 67, and patients 10 and 16 also had ovarian cancer).
DNA samples were obtained from the peripheral blood cells of control participants after their informed consent was obtained. One hundred DNA samples (seventy-eight women and twenty-two men) were provided by the Genetic Center of the Institute of Biosciences, University of São Paulo, São Paulo, Brazil. They were obtained from noncarrier relatives of patients affected by mental impairment with clear genetic etiology unrelated to cancer predisposition (namely, fragile × syndrome or de novo chromosomal rearrangements). No information regarding their cancer history was available. Age-matching of controls and patients was considered unnecessary for this study since CNV frequency in blood is generally considered stable and unrelated to chronological age.
Comparative genomic hybridization based on microarray (array-CGH)
We performed comparative genomic hybridization based on microarray (array-CGH) using a 180 K whole-genome platform (design 22060; Agilent Technologies, Santa Clara, CA, USA), which has an average probe spacing of 18 kb. Briefly, samples were labeled with Cy3- and Cy5-deoxycytidine triphosphates by random priming. Purification, hybridization and washing were carried out as previously reported [26, 27]. Scanned images of the arrays were processed using Feature Extraction software (Agilent Technologies).
We applied the Genomic Workbench software (Agilent Technologies) for calling DNA CNV using the aberration detection method 2 statistical algorithm with a sensitivity threshold of 6.7. Poor quality hybridization (QC > 0.3) was disregarded. Duplication or deletion of genomic segments was considered when the log2 ratio of the Cy3/Cy5 intensities of a given region encompassing at least three probes was > 0.3 or < -0.3, respectively. All hybridizations were gender-matched and processed in reverse-labeling duplicates as described previously . CNVs that were not detected in both experiments were disregarded.
Copy number validation by real-time PCR
Selected CNVs detected in the patient group were validated by real-time quantitative PCR (qPCR)  using the SYBR Green system (Roche Applied Science, Indianapolis, IN, USA) on a 7500 Fast Real-Time PCR System apparatus (Applied Biosystems, Foster City, CA, USA). As controls or for copy number calibration, we used three DNA samples obtained from healthy donors and the qPCR values for the GAPD and HPRT genes for normalization. All samples were run in duplicate, and the data were analyzed with Microsoft Excel software (Microsoft Corp, Redmond, WA, USA) using the comparative ΔΔCt cycle threshold method (Applied Biosystems), which assumes that the calibrator DNA has two copies of the control genes.
Detected CNVs were compared to CNV data from oligoarray studies documented in the Database of Genomic Variants (DGV) . We classified the CNVs into "rare" and "common," with rare being those that encompassed coding sequences which had never been documented as variable in the general population (DGV). CNVs were evaluated regarding proportion of total and rare CNVs, frequency of deletions and duplications, length, and gene content using the Mann-Whitney U test and Fisher's exact test.
Gene annotation was performed using the University of California Santa Cruz Genome Browser (UCSC) , BioMart in the Ensembl Genome Browser  and Catalog of Somatic Mutations. We investigated the biological features of genes contained within the rare CNVs using GOTree Machine (GOTM) software  to measure the enrichment in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) categories. GOTM reports only those enrichments that are statistically significant as determined by the hypergeometric test .
Summary of DNA copy number variation data from breast and/or ovarian cancer patients and controlsa
Copy number variation
Controls (n= 100)
Patients (n= 68)
Median CNVs per individual (IQR)b
7.0 (4 to 9)
7.5 (5 to 10)
Only 49 of the 1,238 CNVs could be classified as rare, and none of them were recurrent. Those CNVs classified as rare based on DGV data corresponded to 4% (49 of 1,238 CNVs) of all CNVs detected in our study. The log2 ratios of the rare CNVs (all outside the log2 -0.65 to log2 0.45 range) were not suggestive of mosaicism, indicating that these CNVs are likely constitutive. In the control group, 3.28% (23 of 702) of CNVs detected in 23 of 100 individuals (23%) were classified as rare, whereas 26 of 536 rare CNVs (4.85%) were found in 25 of 68 patients (37%). The median numbers of total and rare CNVs per genome did not differ between controls and patients. However, the proportion of rare CNVs in patients was higher than in the controls (P = 0.0311, Fisher's exact test). The relative frequencies of duplications and deletions among rare CNVs were similar between controls (14 duplications and 9 deletions) and patients (14 duplications and 12 deletions).
Size and gene content of rare copy number variationsa
Control group (n= 23 CNVs)
Patient group (n= 26 CNVs)
Length range (kb)
31 to 684
32 to 1,592
Median size (IQR)b (kb)
225.5 (125.8 to 275.3)
136.7 (70.3 to 278.0)
127.2 (43.7 to 225.5)
145.0 (124.6 to 229.5)
249.5 (202.9.4 to 350.4)
119.2 (50.0 to 278.0)
0.4 (44 of 100)
0.8 (57 of 68)
Genomic positions (build 36-Hg18), size, type and affected genes of the 26 rare copy number variations identified in patientsa
ST6GALNAC3, ST6GALNAC5, PIGK
INSL6, INSL4, RLN2
PALM2-AKAP2, AKAP2, C9orf152, TXN, TXNDC8, SVEP1
POLR2G, TAF6L, TMEM179B, TMEM223, NXF1
ANKRD26P1, SHCBP1, VPS35
ACOX1, TEN1, CDK3
C21orf7, LINC00189, BACH1, GRIK1
YBEY, C21orf58, PCNT, DIP2A
HDHD1, STS, VCX, PNPLA4
Figure 1 depicts two additional rare CNVs identified by array-CGH and validated by qPCR in unrelated patients. Figure 1B shows a 137 kb deletion at 9p21.3 detected in patient 13. Figure 1C illustrates a 640-kb duplication mapped at Xq13.1 (patient 27).
We characterized the function of genes located in rare CNVs in both patients and controls by GO term and KEGG pathway analysis using the Gene Ontology Tree Machine. We did not detect any significant difference in gene content in either patients or controls.
We used array-CGH to investigate the role of rare germline CNVs in probands of individuals with a familial history of breast and ovarian cancer. Because evaluation of CNV profiles depends on ethnic background, array platform and method of analysis [35–38], all experiments were performed using the same platform, the same analytical parameters and a Brazilian control group. We disregarded the possibility that the CNVs were somatically acquired because none of the results were suggestive of mosaicism. Furthermore, the limited data available indicate that CNV profiles are rather stable in adult tissues (reviewed in ).
Common CNVs often contain cancer-related genes and likely play a role in carcinogenesis . However, only a minority of CNVs, those with low population frequencies (rare CNVs), would be likely to contain genes that are highly penetrant genetic factors for disease susceptibility, including cancer [7, 41]. In our study, the median numbers of total and rare CNVs per genome were quite similar in patients and controls, reflecting a lack of genomic instability in this cohort of patients. These results are in agreement with data derived from a study of BRCA1-associated ovarian cancer patients . Nevertheless, the patients did present a higher proportion of rare CNVs compared to controls. None of these rare CNVs were present in an independent cohort of more than 150 individuals, providing support for their nonpolymorphic nature in the Brazilian population. Assuming that some of these rare CNVs are cancer-related, the patients would carry an increased cancer risk proportionate to the number of rare genomic imbalances. The reason why we found a greater proportion of rare CNVs in patients than in controls is not clear. We could speculate that deleterious CNVs tend to be eliminated and, for some reason, conceivably less efficient apoptosis or DNA repair mechanisms, this selection would be less stringent in these patients. Whatever the reason may be, the connection between this finding and the patients' phenotypes deserves investigation.
Part of the rare genomic imbalances harbors genes that could potentially affect cancer susceptibility (see Table 3). For example, a 540 kb microdeletion at 1p31.1 was detected in two affected sisters (Figure 1A). Among the genes mapped to this deleted segment, the most relevant to cancer progression is probably ST6GALNAC5, a sialyltransferase recently reported to mediate breast cancer metastasis to the brain . Another interesting alteration detected in a patient, an approximately 137 kb deletion at 9p21.3, encompassed the KIA1797 and the MIR491 genes (Figure 1B). A germline CNV affecting this genomic segment was recently reported in a colorectal cancer cohort . The finding of a similar 9p21.3 deletion in independent cohorts of cancer patients strengthens their pathogenic role in cancer predisposition.
Our data support the hypothesis that germline DNA CNV is a genetic factor contributing to breast cancer predisposition, which is in accord with the findings of other studies indicating CNVs as risk factors in cancer, including neuroblastoma , colorectal cancer [22, 23], hepatocellular carcinoma , aggressive prostate cancer , nasopharyngeal carcinomaand BRCA1-associated ovarian cancer. Our findings of a possible association of a cancer predisposition phenotype with rare CNVs affecting different genes are in line with the genetic heterogeneity reported in breast cancer. This picture is different from most of the aforementioned studies, which detected recurrent common CNVs associated with cancer risk, except for prostate, colorectal and ovarian cancer CNV studies, which exhibited high CNV heterogeneity.
Our analysis of rare CNVs in a small cohort of BRCA1/BRCA2 mutation-negative breast and/or ovarian cancer families suggests an intriguing excess in the proportion of rare CNVs compared to controls. The future challenge will be to expand sample sizes and to follow cosegregation of given CNVs with cancer phenotype within families to identify which of the genes involved in the rare CNVs might contribute to familial breast cancer predisposition.
copy number variation
comparative genomic hybridization on microarray
Database of Genomic Variants
University of California Santa Cruz.
This work was supported by grants from the Brazilian National Institute of Science and Technology in Oncogenomics (FAPESP 2008/57887-9 and CNPq 573589/08-9) and FAPESP (2009/00898-1). We thank the Biobank of the AC Camargo Hospital for providing DNA samples. We are indebted to the patients and their families for their participation in the trial.
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