Somatic mutations in early onset luminal breast cancer

Giselly Encinas, Veronica Y Sabelnykova, Eduardo Carneiro de Lyra, Maria Lucia Hirata Katayama, Simone Maistro, Pedro Wilson Mompean de Vasconcellos Valle, Gláucia Fernanda de Lima Pereira, Lívia Munhoz Rodrigues, Pedro Adolpho de Menezes Pacheco Serio, Ana Carolina Ribeiro Chaves de Gouvêa, Felipe Correa Geyer, Ricardo Alves Basso, Fátima Solange Pasini, Maria Del Pilar Esteves Diz, Maria Mitzi Brentani, João Carlos Guedes Sampaio Góes, Roger Chammas, Paul C Boutros, Maria Aparecida Azevedo Koike Folgueira, Giselly Encinas, Veronica Y Sabelnykova, Eduardo Carneiro de Lyra, Maria Lucia Hirata Katayama, Simone Maistro, Pedro Wilson Mompean de Vasconcellos Valle, Gláucia Fernanda de Lima Pereira, Lívia Munhoz Rodrigues, Pedro Adolpho de Menezes Pacheco Serio, Ana Carolina Ribeiro Chaves de Gouvêa, Felipe Correa Geyer, Ricardo Alves Basso, Fátima Solange Pasini, Maria Del Pilar Esteves Diz, Maria Mitzi Brentani, João Carlos Guedes Sampaio Góes, Roger Chammas, Paul C Boutros, Maria Aparecida Azevedo Koike Folgueira

Abstract

Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA germline mutation and for somatic mutations in luminal (HER2 negative) breast cancer. Thirteen of 79 unselected very young patients were BRCA1/2 germline mutation carriers. Of the non-BRCA tumors, eight with luminal subtype (HER2 negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were PIK3CA, GATA3, TP53 and MAP2K4. Potential cancer drivers affected in the present non-BRCA tumors include GRHL2, PIK3AP1, CACNA1E, SEMA6D, SMURF2, RSBN1 and MTHFD2. Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as ATR, BAP1, ERCC6, FANCD2, FANCL, MLH1, MUTYH, PALB2, POLD1, POLE, RAD9A, RAD51 and TP53, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation.

Keywords: breast cancer; germline mutation; luminal subtype; somatic mutation; young patients.

Conflict of interest statement

CONFLICTS OF INTEREST All authors declare that they have no conflicts of interest.

Figures

Figure 1. Trinucleotide mutational profile of current…
Figure 1. Trinucleotide mutational profile of current luminal samples
Trinucleotide barplot showing the number of Single Nucleotide Variants (SNVs) in the context of each of the 96 trinucleotide mutation types. The blue covariates at the bottom of the plot represent the 5' and 3' ends. All the 310 SNVs were considered.
Figure 2. Landscape of coding somatic SNVs
Figure 2. Landscape of coding somatic SNVs
Each of the 54 genes in which at least one significant SNV was identified is listed down the left hand side. The genes are listed by their significant SeqSig q-value (FDR adjusted p-value). Type and number of mutations (top panel), significantly mutated genes (middle panel) and percentage of Single Nucleotide Variants (SNVs) (bottom panel) per tumor sample.
Figure 3. Distribution of mutated candidate driver…
Figure 3. Distribution of mutated candidate driver genes among 28 tumor samples retrieved from the literature and COSMIC database
All cancer genes listed at “Cancer Gene Census” (CGC) database (http://cancer.sanger.ac.uk/cosmic/census) and all driver candidates listed in “Candidate Cancer Gene Database” (CCGD), ranked as A (http://ccgd-starrlab.oit.umn.edu/about.php), are shown. Note: Sample TCGA-04 is shown exclusively in Supplementary Table 10 (but not in the figure), due to a large number of somatic mutations (CGC= 30; CCGD rank A= 56). Green: CGC; Red: CCGD, rank A [18]. Causal relationship with cancer was based on a scoring system, described in Materials and Methods. All reported genes affected by SNVs appear in Supplementary Table 10.
Figure 4. Most frequently mutated genes in…
Figure 4. Most frequently mutated genes in luminal tumors
Samples (n=27) presenting SNVs in at least one of the nine most frequently mutated genes were included (current analysis, n=4; and COSMIC Database, n=23). Type of gene alteration and BRCA1/2 status are shown. Each column represents a single patient. UK: unknown.

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