Breast Cancer: Recurrent Genomic Alterations: Difference between revisions

|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''

|[https://omim.org/entry/172420 172420]

|[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=PLCG1 PLCG1]

|sequence variants, amplification, altered expression

|Diseases: sequence alterations recurrent in postradiation angiosarcoma (recurrent p.Arg707Gln mutation). Prognosis: Overexpression predictive of metastases in Luminal A, B breast cancer.

|-

|''PRKD1''

|2

|Gain of function

|sequence variants

|Diseases: TNBC, adenoid cystic carcinoma, ER positive BC. Prognosis: increased gene expression associated with reduced disease free survival (especially in TNBC). Therapy: emerging target (siRNA, miRNA).

|-

|''PTEN''

|1

|Loss of function

|sequence variants, other structural rearrangement, epigenetic modification

|Therapy: AKT inhibitor therapy capivasertib, resistance to trastuzumab (HER2 targeted therapy), increased sensitivity to AKT and mTOR inhibitors; Diseases: hereditary syndromic risk for breast and other cancers (high penetrance); lobular BC, TNBC. Majority (>99%) PTEN mutations detected in tumors are somatic not germline. Prognosis: higher risk of recurrence.

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|''PTPRB''

|3

|Gain of function

|sequence variants

|Diseases: postradiation angiosarcoma; Function: angiogenesis

|-

|''PTPRD''

|2

|Loss of function

|sequence variants, other structural rearrangement, epigenetic modification

|Tumor suppressor gene loss of function alterations in 4% breast cancer

|-

|''RAD50''

|3

|Loss of function

|sequence alteration, other structural rearrangement

|Diseases: limited evidence for hereditary BC (how often sporadic?)

|-

|''RAD51C''

|2

|Loss of function

|sequence variants

|Diseases: Slight increased risk for hereditary BC, primarily ER-negative (odds ratio, 1.93; 95% CI, 1.20 to 3.11 in NEJM 2022 study)

|-

|''RAD51D''

|2

|Loss of function

|sequence variants

|Diseases: Slight increased risk for hereditary BC, primarily ER-negative (odds ratio, 1.80; 95% CI, 1.11 to 2.93 in NEJM 2022 study)

|-

|''RB1''

|2

|Loss of function

|sequence variants, other structural rearrangement

|Therapy: acquired hormone resistance; resistance to CDK4/6 inhibitors. Diseases: TNBC, metastatic BC

|-

|''RECQL''

|2

|Loss of function

|sequence variants

|Diseases: moderate evidence for BC risk.

|-

|''RET''

|1

|Gain of function

|fusion, amplification, altered expression

|Therapy: FDA approved for RET fusion; overexpression associated with endocrine resistance. Diseases: ER-positive BC

|-

|''RICTOR''

|2

|Gain of function

|amplification, altered expression

|Therapy: possibly targetable with mTOR inhibitors; Diseases: TNBC

|-

|''RPS6KB1''

|2

|Gain of function

|amplification, altered expression

|Therapy: amplification or overexpression may predict sensitivity to inhibitors of p70S6K signaling, as well as to inhibitors of upstream signaling, including mTOR and PI3K. Overexpression linked with resistance to radiation treatment.

|-

|''RUNX1''

|3

|Other/Complex

|sequence variants, altered expression, other structural rearrangement

|Diseases: Lobular BC, ER positive luminal BC (tumor suppressor), TNBC (oncogenic via overexpression). Prognosis: higher expression predictive of decreased survival.

|-

|''RUNX3''

|3

|Loss of function

|altered expression, epigenetic modification, other structural rearrangement, sequence variants

|Prognosis: poor survival, correlates with recurrence. RUNX3 functions to inhibit YAP-mediated migration and stemness in breast cancer, together with RUNX1

|-

|''SETD2''

|2

|Loss of function

|sequence variants

|Diseases: recurrent in phyllodes tumor

|2

|Gain of function

|sequence variants

|Diseases: TNBC, ER positive luminal BC, adenoid cystic carcinoma

|3

|Gain of function

|sequence variants, other structural rearrangement, altered expression

|Diseases: invasive ductal carcinoma, adenoid cystic carcinoma. SMARCA5 regulates nucleosome repeat length.

|3

|Loss of function

|sequence variants, altered expression

|Diseases: altered in 1-2% of invasisive breast carcinoma (CBioPortal); recent evidence suggests SPEN acts as a tumor suppressor in ER-positive breast cancer and overexpressed SPEN sensitizes HR-positive breast cancer cells to the effects of tamoxifen; more mutations detected in patients with ER+/PR- breast cancer or detectable MRD

|2

|Loss of function

|sequence variants

|Diseases: syndromic risk for hereditary BC and other cancers (Peutz-Jeghers syndrome) (high penetrance, but most mutations detected in tumors are somatic not germline). Lkb1 activates AMPK and negatively regulates the mTOR pathway in response to cellular energy levels. Therapy: may be responsive to mTOR inhibitors.

|2

|Gain of function

|altered expression

|Diseases: mBC. Trop-2 is protein product of TACSTD2, and is expressed in the majority of breast cancers. Therapy: Trop-2 expression is targeted by antibody-drug conjugate (ADC) sacituzumab govitecan in TNBC and HR+, HER2- mBC previously treated with endocrine therapy, a CDK4/6 inhibitor, and a multiple lines of chemotherapy.

|2

|Gain of function

|sequence variants, amplification, altered expression

|Diseases: ER positive BC, Enriched in special subtypes including neuroendocrine tumors, lobular BC; metastatic breast cancer. Therapy: hormone resistance. TBX3 is one of several estrogen receptor transcriptional regulators also including MYC, CTCF, FOXA1.

|2

|Gain of function

|amplification, sequence variants

|Diseases: phyllodes tumor, more frequent in borderline and malignant tumors (promoter mut); carcinoma (TERT amplification), metaplastic carcinoma (promoter mutation)

|2

|Gain of function

|amplification, sequence variants

|Therapy: responsiveness to anthracycline inhibitors. Prognosis: increased TOP2A expression is an adverse prognostic indicator.

|2

|Loss of function

|sequence variants, other structural rearrangement, altered expression

|20301425; 33471991; 28027327; 32636452; 24803582; 14576853; 30504931

|-

|2

|Other/Complex

|altered expression

|Diseases: BC all types, diagnostic utility in identifying breast origin (IHC marker), including TNBC where it is useful as GATA3 expression is usually absent. TRPS1 is a GATA gene family member and paralog of GATA3. Overexpression is observed in breast cancer and is of uncertain prognostic significance. Therapy: overexpression is linked to multidrug resistance in BC.