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Diagnostic Molecular Pathology > 22 Prostate cancer > Flashcards

22 Prostate cancer Flashcards

1
Q

What is the most common non-cutaneous malignancy in men in USA?

A

Prostate cancer

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2
Q

What are the prognosis of prostate cancer?

A

1) High Cure Rates for Local and Regional Prostate Cancers: 80% to 85% of cases at detected in local and regional stages: Stage I, II, and III;

2) Stage IV prostate cancer:
– nonlocalized or recur and progress after primary treatment;
– poor prognosis;
– nearly all metastatic prostate cancer become resistant to anti-androgen therapies, i.e. metastatic castration-resistant prostate cancer

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3
Q

Metastatic castration-resistant prostate cancer

A

1) Prostate cancer has spread to lymph nodes or other parts of the body, such as the bones;

2) Increased prostate-specific antigen (PSA) level;

3) Low in testosterone level;

4) aka CRPC

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4
Q

What is neuroendocrine prostate cancer (NEPC)?

A

1) An aggressive histologic subtype of prostate cancer:
– can be de novo small cell carcinoma of the prostate;
– Most commonly arises in later stages of prostate cancer as a mechanism of treatment resistance.

2) The poor prognosis of NEPC is attributed in part to late diagnosis and a lack of effective therapeutic agents.

3) Has unique clinical and molecular features

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5
Q

What is the widely used biomarker/test for early detection of prostate cancer currently?

A

serum PSA

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6
Q

Gold standard of prostate cancer diagnosis?

A

Pathological examination of core biopsy tissue

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7
Q

How is prostate cancer graded?

A

Gleason grading system:

1) score of 2-10;

2) higher score, more aggressive

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8
Q

How is localized prostate cancer treated?

A

1) radical prostatectomy;

2) radiation therapy

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9
Q

What are molecular testing targets for prostate cancer?

A

1) Prostate-specific kallikreins;
2) ETS gene rearrangements;
3) PTEN deletion;
4) Long noncoding RNA;
5) Germline mutations

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10
Q

Describe Kallikreins

A

1) a large family of related serine proteases
2) diverse roles
3) found in many tissues including prostate and breast
4) Kallikreins are predominantly localized to the cytoplasm of glandular epithelial cells
5) can be detect in secreted fluid

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11
Q

Kallikreins highly expressed in prostate

A

1) PSA is encoded by KLK3 gene;
2) human kallikrein 2 (aka. hK2) is encoded by KLK2

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12
Q

PSA and hK2 are regulated by which signaling pathway?

A

androgen signaling pathway

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13
Q

How are PSA and hK2 processed to become its active form?

A

1) PSA and hK2 are produced as preproenzymes;
2) the preproenzymes are posttranslational modified to become catalytically active:
– preproenzyme signal sequence is proteolytically cleaved;
– N-terminal activation domain is then released

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14
Q

How is preproenzyme of PSA processed to become its active form?

A

PreproPSA is processed by a signal peptidase into the proPSA, which is then enzymatically cleaved by trypsin-like protease (including hK2) to yield active PSA.

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15
Q

What is truncated proPSA?

A

1) A subset of proPSA is truncated into a stable, catalytically inactive form: i.e [-2]proPSA;

2) it is not further processed to active PSA;

3) In seminal fluid, a proportion of active PSA are proteolytically inactivated by different proteases.

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16
Q

How is active PSA inactived?

A

by proteases

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17
Q

Are PSA molecules in peripheral blood free PSAs?

A

1) vast majority of active PSA molecules are bound to protease inhibitors, e.g. alpha-1 antitrypsin: Bound PSA are complexed PSA (cPSA).

2) the reminder of PSA, including both inactive PSA and proPSA forms, circulating unbound as free PSA.

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18
Q

What are the free PSA forms?

A

1) multichain PSA;

2) nicked PSA;

3) PSA that is not attached to other proteins is called free PSA because it circulates freely in the blood;

4) Intact PSA is free PSA;

5) [-2]proPSA is another form of PSA

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19
Q

what is % free PSA

A

Percent-free PSA is a ratio that compares the amount of free PSA to the total PSA level.

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20
Q

What is total PSA

A

1) The total PSA level includes the amount of both free and bound PSA in the blood.

2) aka. tPSA

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21
Q

what is the normal rang of free PSA?

A

1) Free PSA levels are often higher in those with non-cancerous conditions of the prostate and lower in those with prostate cancer.

2) A percent-free PSA above 25% is considered normal.

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22
Q

At what level of total PSA, the doctor will test for blood free PSA?

A

between 4 and 10

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23
Q

What is the abnormal % free PSA in blood?

A

1) Some doctors recommend that if you have a percent-free PSA of 18% or less, you should have a prostate biopsy.

2) Other doctors recommend having a biopsy if the percent-free PSA is around 12% or less.

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24
Q

what is intact PSA?

A

1) Intact PSA is an uncleaved form of PSA, and it is similar to native PSA except it is enzymatically inactive.

2) There are no differences in iPSA levels in men with or without cancer, but the ratio of this marker to fPSA was significantly higher in men with cancer.

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25
Q

What is the level of total PSA, % free PSA, and ratio of intact PSA to free PSA in normal patient in comparison to prostate cancer patient?

A

1) Total PSA is low;

2) % free PSA is high (10-30%);

3) ratio of intact PSA to free PSA is low

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26
Q

What is the level of total PSA, % free PSA, and ratio of intact PSA to free PSA in prostate cancer patient?

A

1) Total PSA is high;

2) % free PSA is decreased;

3) ratio of intact PSA to free PSA is high:
intact PSA includes proPSA such as [-2]proPSA

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27
Q

ETS gene rearrangements in prostate cancer

A

1) fusions of androgen-responsive genes and ETS family proto-oncogenic transcription factors such as ERG;
2) recurrent ETS gene fusions found in 50% of human prostate cancers

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28
Q

What is the most prevalent ETS gene fusion in prostate cancer?

A

1) TMPRSS2 : ERG;

2) it results from an intrachromosomal rearrangement of chromosome 21.

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29
Q

Describe TMPRSS2 : ERG fusion (aka T2E)

A

1) joins the androgen signaling responsive elements in the TMPRSS2 5’-untranslated region to the protein-coding exons of the ERG transcript.
2) basically, ERG oncoprotein is under the control of androgenic regulation.
3) leads to ERG overexpression.

30
Q

TMPRSS2 stands for?

A

1) transmembrane protease serine 2;

2) TMPRSS2 is prostate specific;

3) Androgen responsive

31
Q

ERG stands for?

A

1) ETS-related gene;

2) it is a v-ets erythroblastosis virus E26 oncogene homolog;

3) 55% prostate cancer has ERG overexpression, mainly due to the TMPRSS2 : ERG fusion.

32
Q

What ERG encodes?

A

ERG is an oncogene that encodes a member of the erythroblast transformation-specific family of transcription factors

33
Q

What is ERG function in a cell?

A

a key regulator of cell proliferation, differentiation, angiogenesis, inflammation and apoptosis

34
Q

At what stages of prostate cancer, TMPRSS2 : ERG fusion present?

A

in both early- and late-stage prostate cancer (castration-resistant prostate cancer, CRPC)

35
Q

Besides TMPRSS2 : ERG gene arrangement, what gene mutation is the most common recurrent in prostate cancer?

A

PTEN deletion

36
Q

What is PTEN?

A

1) a tumor suppressor gene;
2) encodes a protein and lipid phosphatase that negatively regulates the PI3K signaling pathway;
3) PTEN stands for phosphatase and TENsin homolog deleted on chromosome 10

37
Q

What’s the effect PTEN deletion in prostate cancer?

A

1) dysregulation of PI3K signaling, leading to increased proliferation and decreased apoptosis.

2) PTEN deletion and ETS gene rearrangement may synergize to promote prostate cancer.

3) PTEN deletion observed more in patients with ETS gene rearrangement than without ETS gene rearrangement.

4) PTEN deletion is associated with advanced prostate cancer as well as a decreased time to biochemical recurrence. (recurrent earlier).

38
Q

Which long noncoding RNA (lncRNA) have been implicated in prostate cancer?

A

1) PCAT-1 and PCAT29 have novel oncogenic or tumor-suppressor roles in prostate cancer progression;

2) SChLAP1 antagonizes the SWI/SNF chromatin-modifying complex, promotes tumor cell invasion and metastasis;

3) SChLAP1 is strongly associated with aggressive, lethal prostate cancer;

4) PCA3 is a sensitive and specific biomarker for prostate cancer detection (assessed in urine)

39
Q

Which long noncoding RNA (lncRNA) have been implicated in prostate cancer?

A

1) PCAT-1 and PCAT29

2) SChLAP1

3) PCA3

40
Q

What are the germline mutations identified in prostate cancer?

A

HOXB13;
BRCA1;
BRCA2

41
Q

HOXB13 encodes which protein?

A

1) HOXB13 encodes a homeobox transcription factor;
2) HOXB13 plays central roles in prostate gland development

42
Q

Which HOXB13 mutation is associated with a significantly increased risk of early-onset prostate cancer?

A

HOXB13 G84E

43
Q

Prostate cancer with HOXB13 G84E mutation have a low frequency in what gene alteration?

A

1) ERG gene rearrangement;
2) high rate of SPINK1 overexpression

44
Q

Role of BRCA1 and BRCA2 in prostate cancer

A

Germline mutations of BRCA1 and BRCA2 are associated with an increased risk of prostate cancer and may predispose to aggressive disease.

45
Q

Function of BRCA1 and BRCA2

A

1) BRCA1 and BRCA2 are tumor-suppressor genes;
2) Roles in multiple intracellular processes, including DNA damage repair, translational regulation, and chromatin remodeling

46
Q

Rare potentially targetable alterations in prostate cancer

A

1) Gene rearrangements involving BRAF or RAF1;
2) BRAF V600E;
3) an androgen-driven SLC45A3 : FGFR2 fusion;
4) IDH1 R132H;

Note: These mutations often seen in tumors lack of ETS fusions.

47
Q

How to detect prostate-specific kallikreins (PSA and hK2)

A

1) peripheral blood or urine;
2) immunoassays (ie, enzyme-linked immunosorbent assay);
3) monoclonal antibodies provide specificity for hK2 and the various PSA isoforms.

48
Q

How to detect ETS gene rearrangements such as TMPRSS2 : ERG in prostate cancer?

A

1) RT qPCR after whole transcriptome amplification;
2) transcription-mediated amplification (TMA);
3) FISH;
4) IHC with a monoclonal ERG antibody;
5) ISH (in situ hybridization) - detect ETS gene rearrangements in tissue;
6) qRT-PCR
7) RNAseq

49
Q

How to detect PTEN deletion in prostate cancer

A

1) interphase FISH;
2) IHC for PTEN expression

50
Q

How to detect lnRNA PCA3?

A

1) transcription-mediated amplification (TMA);
2) PCA3 and SChLAP1 can be detected using RNA-based ISH assay

51
Q

Germline mutations detections

A

1) Sanger;
2) allele-specific PCR;
3) single-strand conformation polymorphism;
4) melting point analysis;
5) targeted NGS

52
Q

Does elevated PSA mean prostate cancer?

A

No.

1) Could be prostatitis and benign prostate hyperplasia;

2) Thus PSA testing is sensitive but not specific

53
Q

What is NEPC?

A

1) small cell carcinoma of the prostate
2) Neuroendocrine prostate cancer
3) dependence on androgen receptor (AR) signaling is lost as tumors progress from a prostate adenocarcinoma to a NEPC histology, typically manifest by downregulation of AR, PSA, and PSMA expression in tumors.

54
Q

How is NEPC diagnosed?

A

1) based on anatomic location: located at the prostatic base/bladder neck;
2) could be prostate or bladder origin;
3) FISH or IHC showed ERG gene arrangement in more than 50% of NEPC but not in bladder small cell carcinoma.

55
Q

If a patient prostate tissue has ERG gene rearrangement, is the prostate the primary cancer origin site?

A

Yes

56
Q

Can a negative ERG gene rearrangement exclude a diagnosis of prostate cancer?

A

No

57
Q

What is the CofirmMDx assay used for prostate cancer?

A

1) used in patients with negative biopsy for whom prostate cancer is strongly suspected;
2) ConfirmMDx detects methylation of multiple genes, including APC and GSTP1;
3) Hypermethylation of APC and GSTP1 is significantly more frequent in prostate caner than benign prostatic tissue.

58
Q

Why is FISH a preferred method to detect ERG gene rearrangement?

A

Androgen signaling may be dysregulated in NEPC or metastatic prostate cancer, ERG protein expression might be false negative with IHC.

59
Q

what is PSMA?

A

1) Prostate-Specific Membrane Antigen;
2) PSMA is a largely prostate-specific transmembrane protein expressed 100- to 1,000-fold higher in prostatic adenocarcinoma than in the benign prostate.
3) Of importance, PSMA expression is increased on androgen deprivation and is highest in high-grade and castration-resistant prostate cancer (CRPC)

60
Q

What is [-2]proPSA?

A

1) One of the promising serum biomarkers is proPSA.

2) proPSA is a pre-mature form of PSA.

3) The molecules are fractions of free PSA, and [-2]proPSA contains 2 amino acids as N-terminus pro-peptides of PSA.

4) Studies have shown the possibilities of using [-2] proPSA-related indices like the Prostate Health Index and %2PSA as tumor markers for diagnosis.

5) [-2]proPSA-related indices have improved specificity compared to commonly used PSA and free PSA to detect prostate cancer, while maintaining high-level sensitivity.

61
Q

What are the prostate-specific antigen (PSA) can be found in serum?

A

1) Free PSA, intact PSA, [-2]proPSA;
2) complexed PSA (bound PSA);
3) hK2 (KLK2 is the gene encodes hK2) - a related enzyme

62
Q

What biomarker can be found in urine for prostate cancer?

A

prostate cancer specific transcripts:
1) PCA3, which is a lncRNA;
2) TMPRSS2:ERG gene fusion

63
Q

Basal cell markers used in prostate cancer IHC?

A

1) In recent period, basal cell markers high molecular weight cytokeratin (HMWCK), P63 and prostate biomarker AMACR have been used as adjuvant to morphology in diagnostically challenging cases with a very high sensitivity and specificity.

2) HMWCK, P63, AMACR

64
Q

what is AMACR?

A

1) Alpha-methylacyl-CoA racemase, aka P504S;

2) A molecular biomarker for prostate cancer;

3) The expression of AMACR/P504S has also been observed in high-grade prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer.

65
Q

What is PIN4 staining for prostate diagnosis?

A

PIN4 consists of a cocktail of three antibodies, including AMACR(P504S), p63, and high molecular weight cytokeratin.
It is a triple stain that is useful in distinguishing prostatic adenocarcinoma (variable AMACR/P504S red cytoplasmic staining with a lack of basal cell p63+HMWK brown staining) from the benign mimickers (with preserved basal cell brown staining of p63+HMWK and generally lack of red cytoplasmic staining of AMACR/P504S).

66
Q

what is PARP1?

A

Poly(ADP-ribose) polymerase 1

67
Q

Function of PARP1?

A

1) a chromatin associated enzyme with role in multiple intracellular processes;
2) involved in DNA damage response pathway;
3) inhibition of PARP1 induces DNA damage mediated cellular apoptosis;
4) inhibition of PARP1 sensitizes tumor cells to radiotherapy and platinum-based alkylating agents.

68
Q

Role of PARP1 in prostate cancer treatment

A

1) In ETS-positive prostate cancer, PARP1 physically interacts with ETS protein;

2) PARP1 is required for ETS-mediated transcription;

3) PARP1 inhibitor reduces ETS-mediated cellular proliferation

69
Q

Role of BRCA1 and BRCA2 in prostate cancer treatment

A

1) BRCA1 and BRCA2 mutations sensitize treatment with PARP1 inhibitor since BRCA1 and 2 impact DNA damage response via inhibition of homologous recombination;

2) BRCA1 and 2 mutations lead to an accumulation of DNA double-stranded breaks;

3) BRCA1 and 2 mutations are not common in prostate cancer, thus people with these mutations benefits from PARP1 inhibition

70
Q

lncRNA PCAT-1 in the regulation of BRCA expression?

A

1) PCAT-1 represses BRCA expression in prostate cancer cell lines (BRCAness phenotype);

2) increased sensitivity to PARP1 inhibitor;

3) PCAT-1 can be a biomarker for the predicting response to PARP1 inhibitors in prostate cancer

71
Q

Potential prostate cancer targeted therapies

A

1) PARP1 inhibitors;
2) PTEN deletion–>dysregulation of PI3K signaling pathway;
3) RAF family (BRAF, RAF1);
4) FGFR2;
5) IDH1

Diagnostic Molecular Pathology (12 decks)

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