Breast Cancer: Recurrent Genomic Alterations

Table 1 - Clinically significant copy number alterations in breast cancer

Alteration	Relevant Gene(s)	CGC Evidence Level	Subgroup Association(s)
1q gain	unknown	2	Most common copy number alteration, often with 16q loss; all subtypes
8p11.2 amplification	FGFR1, ZNF703	2	METABRIC IntClust6, ER positive
8q24 amplification	MYC	2	METABRIC IntClust9, ER positive
9p24 amplification	JAK2, CD274, PDCD1LG2	2	Enriched in TNBC
10q23.3 loss or LOH	PTEN	2	Enriched in TNBC and in lobular carcinoma
11q13-q14 gain / amplification	CCND1, EMS1, and others	2	METABRIC IntClust2
16q loss / LOH	CDH1	2	METABRIC IntClust2, ER positive
17p loss / LOH	TP53	2	TNBC, basal-like intrinsic subtype
17q12 amplification	ERBB2 (HER2)	1	METABRIC IntClust5, HER2-enriched
17q21 amplification	TOP2A	2	METABRIC IntClust5, HER2-enriched
17q23 amplification (“17q distal amplicon”)	RPS6KB, others	2	METABRIC IntClust1
19q12	CCNE1	2	METABRIC IntClust5; HER2-enriched
20q gain; 20q13 amp	AURKA, GNAS, ZNF217	2	METABRIC IntClust1, ER Positive

Table 2 - Major clinically significant genes associated with somatic sequence alterations in breast cancer

Gene(s)	CGC Evidence Level	Clinical Significance and Subgroup Association(s)	Therapy Implication(s)
AKT1	2	Metastatic BC	AKT inhibitors
ATM	1	Possible hereditary risk; TNBC	PARP inhibitors (germline)
BRCA1, BRCA2	1	Often hereditary risk; TNBC	Platinum based therapy; PARP inhibitors (germline)
CBFB	2	ER-positive, Metastatic BC
CCND1, CCNE1*	2	HER2-enriched	CDK4/6 inhibitors
CDK4, CDK6*	2	ER-positive, Metastatic BC	CDK4/6 inhibitors
CDH1	1	Lobular histology; Possible hereditary risk
CDKN2A	2	Metastatic BC
CHEK2	1	Often hereditary risk	PARP inhibitors (germline)
ERBB2*	1	Rare activating sequence alterations; kinase domain  resistance mutations; HER2-enriched	HER2-targeted therapy
ESR1	1	Metastatic ER-positive	Hormone therapy resistance
FGFR1-4	2	ER-positive	FGFR inhibitors
FOXA1	2	ER-positive, Luminal subtype, lobular histology
GATA3	2	ER-positive, Luminal subtype
JAK2*	2	TNBC	JAK2 inhibitors, immunotherapy
MAP2K4	2	Metastatic BC
MAP3K1	2	ER-positive, Metastatic BC
MYC*	2
NBN	1	Possible hereditary risk	PARP inhibitors (germline)
NF1	1	Possible hereditary risk	mTOR/PI3K/AKT inhibitors (germline)
NTRK1-3	1		NTRK inhibitors
PALB2	1	Often hereditary risk	PARP inhibitors (germline)
PIK3CA	1	ER-Positive, Luminal subtype	PI3K inhibitors for selected hotspot mutations; acquired hormone resistance
PTEN	2	Loss in lobular BC Possible hereditary risk	mTOR/PI3K/AKT inhibitors; radiation contraindicated
RB1	2	Metastatic BC	Acquired hormone resistance
STK11	1	Possible hereditary risk
TBX3	2	Lobular BC
TOP2A*	2		Anthracycline inhibitors
TP53	1	TNBC, HER2-enriched, Metastatic BC Possible hereditary risk	Radiation contraindicated

* Indicates genes more commonly activated by amplification than by sequence variation

Abbreviations: BC, breast cancer. TNBC, triple negative breast cancer.

Cancer Genomics Consortium Levels of Evidence

Tier	Data Source(s)	Interpretation
1	FDA approved therapies, professional guidelines, multiple large clinical studies	Strong evidence supporting clinical utility of variant(s) for diagnosis, selection of therapies, or predicting disease outcome
2	One large study or multiple case reports	Emerging evidence supporting clinical utility of variant(s)
3	Case reports or expert opinion	Unknown clinical significance
4	Published evidence indicating lack of pathogenicity of variant(s)	Benign or likely benign

Table 3 - Genes with known hereditary risk associations in breast cancer

Gene	Associated Syndrome; Breast Cancer Subtype
ATM	Ataxia telangiectasia syndrome
BARD1	TNBC
BRCA1	BRCA-Related Breast/ Ovarian Cancer Syndrome; TNBC
BRCA2	BRCA-Related Breast/ Ovarian Cancer Syndrome; TNBC
CDH1	Hereditary Diffuse Gastric Cancer and Lobular Breast Cancer
CHEK2	Inherited breast cancer
NBN	Nijmegen Breakage Syndrome
NF1	Neurofibromatosis type 1
PALB2	Fanconi anemia
PTEN	Cowden syndrome
RAD51C	TNBC
RAD51D	TNBC
STK11	Peutz-Jeghers syndrome
TP53	Li-Fraumeni syndrome