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''

|fusion, amplification, sequence variants

|ER+ metastatic tumors resistant to ER-targeted theapies, resistance to CDK4/6 inhibitors, resistance to HER2 targeted therapies

|-

|''FGFR3''

|3

|Gain of function

|altered expression

|Diseases: ER/PR-negative and triple-negative breast cancers; overexpression associated with higher grade tumors and poor prognosis. Therapy: clinically approved targeted therapy is available for ovarian cancer. Clinical trials ongoing for breast cancer.

|-

|''FOXA1''

|2

|Gain of function

|sequence variants, amplification

|Diseases: ER positive BC, Enriched in special subtypes including neuroendocrine tumors, lobular BC. Therapy: associated with endocrine therapy resistance. Expression is associated with Less favorable outcome in non-luminal tumors (unlike in luminal tumors) namely in molecular apocrine tumors that are AR+

|-

|''GATA3''

|2

|Other/Complex

|sequence variants

|Diseases: ER positive BC; luminal; endocrine resistant mBC. Frameshift mutations predominate; most mutations impact exons 5 or 6 and impact the second ZF domain or carboxy terminus.Mutations in GATA3 in ctDNA in metastatic cancer is associated with changes in MDM2 pathways and potential vulnerability to MDM2 inhibition.

|-

|''GNAS''

|3

|Gain of function

|sequence variants, amplification

|Disease: Fibrous Dysplasia (hereditary GNAS mut), familial male breast cancers [overexpression results in elevated proliferation and migration]. Mutation in Adenomyoepithelioma, low grade metaplastic carcinoma (fibromatosis like MC and low-grade adenosqumous carcinoma) , Juvenile papillomatosis, mucinous cytadenocarcinoma

|-

|''GPS2''

|3

|Loss of function

|sequence variants, other structural rearrangement

|Diseases: ER positive (luminal) BC.

|-

|''HGF''

|2

|Gain of function

|amplification, altered expression, sequence variants

|Diseases: TNBC basal-like subtype. Therapy: activating mutations confer sensitivity to HGF or MET inhibition and are associated with resistance to EGFR family tyrosine kinase inhibitors including trastuzumab. Prognosis: HGF activation is a poor prognostic indicator.

|-

|''HRAS''

|2

|Gain of function

|amplification, sequence variants

|Diseases: postradiation angiosarcoma; metaplastic carcinoma; Q61 hotspot mutation in adenomyoepithelioma (ER-negative), may be targatable (MEK inhibitors)

|-

|''IDH2''

|1

|Gain of function

|sequence variants

|Diseases: Tall cell carcinoma with reverse polarity / solid papillary carcinoma with reverse polarity. Mutations identified in breast cancers from Arabic descent. Wild type (wt) IDH2 maybe potentially targetable in TNBC.

|-

|''JAK2''

|2

|Gain of function

|sequence variants, amplification

|Diseases: enriched in TNBC; Therapy: potential sensitivity to JAK2 inhibitors or Immune checkpoint inhibitors

|-

|''KDM6A''

|3

|Loss of function

|sequence variants, other structural rearrangement

|Diseases: Enriched in solid basaloid subtype of adenoid cystic carcinoma and metaplastic BC. KDM6A and KDM6B are H3K27me3-demethylases involved in post-translational modifications of histones; context-dependent modulation of tumor cell transition between epithelial and mesenchymal states. Mostly a role for loss of function but the mechanism is complex.

|-

|''KDR''

|2

|Other/Complex

|sequence variants, amplification

|Diseases: postradiation and primary angiosarcoma. In primary angiosarcoma , indicator of worse prognosis. Formerly named VEGFR2.

|-

|''KMT2B''

|3

|Loss of function

|sequence variants, other structural rearrangement, altered expression

|Diseases: all subtypes; enriched in metaplastic BC (referred to as MLL2 gene).

|-

|''KMT2C''

|2

|Loss of function

|sequence variants, fusion

|Diseases: enriched in special subtypes including solid basaloid subtype of adenoid cystic carcinoma, metaplastic BC, basal- like or claudin low TNBC, mucinous carcinoma; metastatic breast cancers, neuroendocrine neoplasms

|-

|''KMT2D''

|2

|Loss of function

|sequence variants

|Diseases: enriched in solid basaloid subtype of adenoid cystic carcinoma, phyllodes tumor; metaplastic BC. NOTCH activation downregulates p63. Germline: Kabuki syndrome

|-

|''KRAS''

|3

|Gain of function

|amplification, sequence variants

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

|-

|''LRP1B''

|3

|Other/Complex

|sequence variants, amplification, other structural rearrangement

|Observed in ~4.3% of breast cancers (CBioPortal), Nuclear LRP1B is assoc w/ poor patient prognosis, but patients with mutation LRP1B have favorable outcomes to immune checkpoint inhibitors in multiple cancers

|-

|''MAF''

|3

|Gain of function

|amplification

|Diseases: associated with bone metastases from larger, high-grade breast cancers. Bisphosphonates (Zoledronic acid) possible clinical use therapeutic, per AZURE and NSABP-B34 clinical trials.

|-

|''MAML2''

|1

|Gain of function

|fusion

|Diseases: mucoepidermoid carcinoma of the breast

|-

|''MAP2K4''

|3

|Loss of function

|sequence variants, other structural rearrangement

|Preclinical study suggests sensitivity to MEK and ERK inhibitors

|-

|''MAP3K1''

|3

|Loss of function

|sequence variants, other structural rearrangement

|Mutations associated with luminal A subtype BC; potential sensitivity to MEK inhibitors

|-

|''MDM2''

|2

|Gain of function

|amplification

|Diagnosis: amplified in 5% (cBioPortal) to 13% (PMID:30237864) breast cancers; TP53 inactivator. Therapies: resistance to chemotherapy and radiotherapy; MDM2 inhibitors in development

|-

|''MDM4''

|2

|Gain of function

|amplification

|Diseases: Inflammatory BC, potential therapeutic target

|-

|''MED12''

|2

|Gain of function

|sequence variants

|Diseases: fibroadenoma, juvenile fibroadenoma, phyllodes tumor

|-

|''MIB1''

|2

|Other/Complex

|altered expression

|Diagnosis: Ki67 (MIB1 protein product) expression usually performed with ER, PR, and HER2 on a diagnostic biopsy. Therapy: Ki-67 >10% at 2 weeks after initiating endocrine therapy suggests a possible need for additional chemotherapy (POETIC trial). Prognosis: Ki-67 >10% correlates with poorer survival. Magee Equations can be used as a surrogate for Oncotype Dx to predict recurrence (<nowiki>https://path.upmc.edu/onlineTools/mageeequations.html</nowiki>).

|-

|''MSH6''

|2

|Loss of function

|sequence variants, altered expression

|Hereditary: Slightly increased risk of breast cancer (odds ratio, 1.96; 95% CI, 1.15 to 3.33 in 2022 NEJM study)

|-

|''MTOR''

|2

|Gain of function

|sequence variants

|Diseases: TNBC, acinic cell carcinoma, [adenoid cystic carcinoma??]

|-

|''MYB''

|1

|Gain of function

|fusion, other structural rearrangement, amplification

|Diseases: Adenoid cystic carcinoma (''MYB''::''NFIB'' is most common fusion)

|-

|''MYBL1''

|1

|Gain of function

|fusion, other structural rearrangement

|Diseases: TNBC, adenoid cystic carcinoma

|-

|''MYC''

|2

|Gain of function

|amplification, altered expression

|Diseases: ER positive BC, TNBC, invasive micropapillary carcinoma, postradiation angiosarcoma. Prognostic: Amp is associated with higher grade, increased risk of relapse and mortality; Therapy: hormone resistance; resistance to CDK4/6 inhibitors

|-

|''NCOR1''

|2

|Loss of function

|sequence variants, other structural rearrangement

|Diseases: ER positive (luminal) BC; metastatic breast cancers

|-

|''NECTIN4''

|2

|Gain of function

|amplification, altered expression

|Therapy: potential marker for off label use of antibody drug conjugate therapy (EV). NECTIN4 encodes a cell adhesion molecule expressed in >50% invasive ductal carcinoma.

|-

|''NF1''

|2

|Other/Complex

|sequence variants, other structural rearrangement, amplification

|Therapy: endocrine resistance. LoF mutations may be targetable with inhibitors of MAPK pathway components, including MEK inhibitors. Diseases: Metastatic BC. hereditary syndrome with risk for breast & other cancers; risk is primarily associated with missense and nonsense mutations rather than whole gene deletions, suggesting a gain of function mechanism. Risk is modest (odds ratio, 1.76; 95% CI, 0.96 to 3.21 in 2022 NEJM study)

|-

|''NFIB''

|1

|Gain of function

|fusion, rearrangement

|Diseases: adenoid cystic carcinoma MYB partner in MYB-NFIB fusion, triple negative BC

|-

|''NOTCH1''

|2

|Gain of function

|sequence variants, amplification

|Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma. Therapy: inactivating mutations potentially targetable with LGK974, a porcupine inhibitor currently in clinical trials. NOTCH activation downregulates p63. Reduced Notch1 expression associates with increased paclitaxel sensitivity.

|-

|''NOTCH2''

|2

|Gain of function

|sequence variants, amplification

|Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma. NOTCH activation downregulates p63.

|-

|''NOTCH3''

|2

|Gain of function

|sequence variants, amplification

|Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma. NOTCH activation downregulates p63.

|-

|''NOTCH4''

|2

|Gain of function

|sequence variants, amplification

|Diseases: Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma.

|-

|''NPM1''

|3

|Gain of function

|amplification, expression

|occurs in ~1% of breast invasive carcinoma, primarily TNBC, mechanism = upregulation of NPM1 expression; poor prognosis, drug resistance in vitro

|-

|''NRAS''

|3

|Gain of function

|amplification, sequence variants

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

|-

|''NRG1''

|1

|Gain of function

|fusion

|Therapy: Targetable alteration (FDA-approved therapy for NSCLC and pancreatic cancer). NRG1 encodes multiple isoforms of Nrg1, known as Neuregulin 1 or heregulin, that function as activating ligands for the ErbB3 and ErbB4 receptor tyrosine kinases, causing ERBB3 heterodimerization and downstream signaling of MAPK, PI3K pathways. In addition, NRG1 can function as a tumor suppressor (pro-apoptotic) and some structural rearrangements are inactivating (PMID: 33413557).

|-

|''NSD1''

|3

|Loss of function

|sequence variants

|occurs in ~1% of breast cancer; essential for anti-estrogen sensitivity to breast cancer; silencing of NSD1 causes resistance to tamoxifen

|-

|''NTRK1''

|1

|Gain of function

|amplification, sequence variants, fusion

|Therapy: TRK inhibitors for fusions (including pan-Trk inhibitors larotrectinib, entrectinib, and repotrectinib); kinase domain mutations confer resistance to certain TRK inhibitors

|-

|''NTRK2''

|1

|Gain of function

|amplification, sequence variants, fusion

|Therapy: TRK inhibitors for fusions (including pan-Trk inhibitors larotrectinib, entrectinib, and repotrectinib); kinase domain mutations confer resistance to certain TRK inhibitors

|-

|''NTRK3''

|1

|Gain of function

|fusion, amplification, sequence variants

|Therapy: TRK inhibitors for fusions (including pan-Trk inhibitors larotrectinib, entrectinib, and repotrectinib); kinase domain mutations confer resistance to certain TRK inhibitors

|-

|''NUP93''

|3

|Gain of function

|amplification, sequence variants, altered expression

|Diseases: TNBC, claudin-low subtype, alterations are rare. Prognosis: in vitro evidence for association with disease progression in TNBC

|-

|''PALB2''

|1

|Loss of function

|sequence variants, other structural rearrangement

|Diseases: hereditary BC (high penetrance), ovarian cancer risk. HRD.

|-

|''PBRM1''

|2

|Loss of function

|sequence variants, other structural rearrangement

|occurs in ~1-2% of metastatic breast cancer; synthetic lethality with PARP inhibitors, sensitizing for immunotherapy

|-

|''PDCD1LG2''

|2

|Gain of function

|amplification

|Diseases: enriched in TNBC; Therapy: potential sensitivity to Immune checkpoint inhibitors. PD-L2 (CD273) is the gene product. (part of 9p24.1 amp)

|-

|''PDGFRA''

|3

|Gain of function

|sequence variants, amplification, other structural rearrangement, fusion

|~1-2% breast carcinoma, associated with mesenchymal type TNBC, emerging therapeutic target, associated with aggressive disease

|-

|''PDGFRB''

|3

|Gain of function

|amplification, sequence variants

|inhibition of tumorigeneisis in BRCA1 deficienct BC cells in preclinical model

|-

|''PGR''

|2

|Gain of function

|sequence variants, altered expression

|Diseases: expressed in HR positive breast cancer. Sequence alterations in ligand binding domain (most commonly Y890C) are implicated in hormone resistance (post hormone therapy treatment)

|-

|''PIK3CA''

|1

|Gain of function

|sequence variants

|Therapy: FDA approved (PI3K inhibitor alpelisib & AKT inhibitor capivasertib); acquired hormone resistance. Diseases: ER-positive BC, including micropapillary, proliferative lesions and invasive cancer precursors. Also in radial scars, codon 1047 most common, 64% overall. Absent in mucinous carcinoma (PMID: 22705004).

|-

|''PIK3R1''

|2

|Loss of function

|sequence variants

|Diseases: metaplastic BC, basal- like or claudin low TNBC. Loss of function increases PI3K signaling and activates Akt. PI3K/Akt/mTOR inhibitors may be effective (clinical trials ongoing).

|-

|''PLCG1''

|3

|Gain of function

|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.

|-

|''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.