Breast Cancer: Recurrent Genomic Alterations: Difference between revisions

|3

|Loss of function

|sequence variants

|Diseases: refuted evidence for hereditary BC (but definitive evidence for ovarian cancer). HRD. Therapy: PARP inhibitor (preclinical use)

|-

|C19MC

|3

|Other/Complex

|sequence variants, amplification, other structural rearrangement

|Diseases: ER positive BC, metastatic BC. Prognosis: uncertain; associated with improved survival but cooperates with PIK3A to promote tumor progression

|-

|''CCN6''

|2

|Loss of function

|sequence variants, other structural rearrangement

|Diseases: metaplastic BC, basal- like or claudin low TNBC

|-

|''CCND1''

|2

|Gain of function

|amplification

|Diseases: ER positive BC, luminal B subtype; Therapy: CDK4/6 inhibitor in ER-positive HER2-negative BC w/ CCND1 amplification; Prognosis: amplification associated with poor long term prognosis.

|-

|''CCND3''

|3

|Gain of function

|amplification, sequence variants

|Diseases: all subtypes; one study (25927147) indicates higher frequency in metaplastic BC

|-

|''CCNE1''

|2

|Gain of function

|amplification, altered expression, sequence variants

|Disease: metastatic BC; overexpression associated with poor prognosis; Therapy: resistance to CDK4/6 inhibitors. Additionally, CCNE1 amplification or activating mutations may be sensitive to inhibitors of Cdk2, the protein that Cyclin E1 binds and activates. Other potential therapies include combined Cdk and Akt or PI3K inhibitors, and Wee1 inhibitors.

|-

|''CD274''

|1

|Gain of function

|altered expression, amplification

|Encodes PD-L1. Diseases: metastatic TNBC; associated with TILs; Prognosis: elevated PD-L1 expression favorable. Treatment: PD-L1 expression predicts sensitivity to PD-L1 blockade; 2 FDA approved IHC assays for mTNBC - Roche VENTANA (SP142) for Tecentriq (atezolizumab) and Agilent (22C3) pharmDx assay for KEYTRUDA (pembrolizumab). Amplification currently of uncertain significance.

|-

|''CDH1''

|1

|Loss of function

|sequence variants, other structural rearrangement, altered expression

|Diseases: invasive lobular carcinoma, luminal A molecular subtype; constitutional variants associated with hereditary breast & gastric cancer (high penetrance) (OMIM * 192090). However, most CDH1 loss of function mutations detected in ILC are somatic not germline (0.3% germline in one study 31263054).

|-

|''CDK12''

|2

|Loss of function

|sequence variants

|Diseases: TNBC, adenoid cystic carcinoma; Therapy: CDK12/CDK13 inhibitors induce BRCAness phenotype (preclinical) via synthetic lethality in combination with PARP inhibitors

|-

|''CDK13''

|2

|Loss of function

|sequence variants

|Diseases: TNBC, adenoid cystic carcinoma; Therapy: CDK12/CDK13 inhibitors induce BRCAness phenotype (preclinical)

|-

|''CDK4''

|2

|Gain of function

|amplification, sequence variants

|Therapy: CDK4/6 inhibitors to ER-positive HER2-negative BC in pre-menopausal women

|-

|''CDK6''

|2

|Gain of function

|amplification, sequence variants, other structural rearrangement

|Therapy: CDK4/6 inhibitors to ER-positive HER2-negative BC in pre-menopausal women; amp can be resistance mechanism to CDK4/6 therapy

|-

|''CDKN1B''

|2

|Loss of function

|sequence variants, other structural rearrangement

|Disease associations: ER positive (luminal) BC. Prognosis: mutations associated with tumor aggressiveness. Germline mutations breast, prostate, and small intestinal neuroendocrine tumors

|-

|''CDKN2A''

|2

|Loss of function

|sequence variants, other structural rearrangement, epigenetic modification

|Disease associations: metastatic BC. Treatment: CDK4/6 inhibitor in ER-positive HER2-negative BC w/ loss of CDKN2A. Prognosis: mutation associated with poor outcome

|-

|''CHD4''

|3

|Gain of function

|sequence variants

|Disease associations: ER positive (luminal) BC. Poor prognostic indicator.

|-

|''CHEK2''

|1

|Loss of function

|sequence variants

|Disease associations: constitutional pathogenic variants associated with hereditary BC (moderate penetrance); especially ER positive BC. Loss of remaining CHEK2 allele is associated with chromosomal instability but not HRD. c.1100delC germline a/w 2-3x increased risk for BC in women and 10x increased risk in men. (odds ratio, 2.13; 95% CI, 1.60 to 2.84 in 2022 NEJM study)

|-

|''CREBBP''

|2

|Loss of function

|sequence variants, amplification

|Diseases: all subtypes, especially associated with adenoid cystic carcinoma and neuroendocrine tumors. CREBBP is a gene in the chromatin modification / remodeling pathway.

|-

|''CTCF''

|3

|Loss of function

|sequence variants, altered expression

|Disease associations: ER positive BC, enriched in metastatic breast cancer. Associated with aberrant DNA methylation patterns. Therapy: hormone resistance.

|-

|''CTLA4''

|2

|Other/Complex

|altered expression

|Diseases: BC, positive correlation with immune cell infiltration. Therapy: Overexpression targetable with anti-CTLA4 antibody therapy. Prognosis: favorable with overexpression.

|-

|''CTNNA1''

|2

|Loss of function

|sequence variants

|Disease associations: Inactivating mutations (somatic or germline) in a subset of ILC. Germline pathogenic variants associated with hereditary diffuse gastric and lobular breast cancer syndrome; constitutional CTNNA1 variants are found in a minority of patients with familial ILC negative for CDH1 variants.

|-

|''CTNNB1''

|2

|Gain of function

|sequence variants, altered expression

|Diseases: ILC, TNBC including acinic cell carcinoma, metaplastic carcinoma (absent or aberrant beta catenin expression); desmoid-type fibromatosis of the breast. Targeted anti-WNT signaling therapies being investigated in clinical trials.

|-

|''CTNND1''

|2

|Loss of function

|altered expression, other structural rearrangement

|Diseases: Inactivating alterations / aberrant expression in a subset of ILC with retained CDH1 gene expression. Diffuse cytoplasmic staining of CTNND1 (p120) by IHC, instead of expected membranous staining, is another marker of ILC.

|-

|''CTTN''

|2

|Gain of function

|amplification, altered expression

|Therapy implications: CYP19A1 (encoding aromatase) gene amplification increases aromatase activity and leads to resistance to endocrine therapy. Diseases: ER positive BC, metastatic

|-

|''EGFR''