Molecular Genetics - Gynaecological Cancers (VI) Flashcards
3 clinical applications of HPV test?
1) Primary screening
2) Triage of atypical squamous of undetermined significance (ASCUS)
3) Test of cure
Inheritance pattern of BRCA1/2- associated hereditary breast and ovarian cancer
Autosomal dominant
Germline mutation of BRCA1 and BRCA2
Associated diseases and risks of BRCA1/2 positive
Definitively increase lifetime risks of:
- Ovarian cancer
- Fallopian tube cancer (BRCA1 only)
- Breast cancer
- possibly others: melanoma, colorectal, stomach…etc
Histological types of tumors caused by BRCA mutation.
1) High grade Serous Adenocarcinoma
- Ovary, Peritoneum, Fallopian tube, Endometrium
2) Serous Tubal Intraepithelial Carcinoma (STIC)
- Fallopian tube
Describe response of BRCA mutation carriers with BRCA-related cancer to platinum-based chemotherapy and PARP inhibitors
BRCA carrier:
Higher initial response to plat- based chemotherapy
Similar survival rate after 5 and 10 years as non-carriers
good response to PARP inhibitor, improve survival
2 methods to identify BRCA mutation
Sanger sequencing
Next generation sequencing
5 classes of BRCA mutation related to risk of disease progression
Increased risk of disease:
- Pathogenic
- Likely pathogenic
No increased risk of disease:
- Benign
- Likely benign
Unclear
- Variant of Unknown Significance
Difference in results from BRCA blood test and BRCA tumour testing for high grade serious ovarian cancer.
BRCA in blood = germline or somatic mutation
BRCA in tumour = Pathological variant, Variant of unknown significance, Negative
Not clinically important to differentiate germline or somatic > both use PARP anyways
Germline mutation identified for genetic counseling
Which BRCA test can differentiate somatic and germline mutation?
BRCA blood test
Genetic cause of HNPCC?
Inheritance pattern?
Constitutional mutation in 1 of 4 DNA mismatch repair genes: MSH2, MSH6, PMS2, MLH1
Deletion of 3’ EPCAM can extend into MSH2 and result in same phenotype
Autosomal dominant inheritance
Function of Mismatch repair genes?
Consequence if mutated?
MMR genes maintain microsatellite stability
Microsatellite = tract of repetitive DNA motifs that can slip at parental or daughter DNA strand
MMR repairs slippages
Loss of MMR causes microsatellite instability
Cancers associated with HNPCC?
- Colorectal
- Prostate
- Endometrium, ovary
- Stomach, small bowel
- Urinary tract
- Brain
Diagnostic criteria of genetic mutations causing HNPCC?
Germline mutation in MMR genes (MSH2, MSH6, PSM2, MLH1)
EPCAM mutation
Lynch syndrome
3 methods for diagnosis
1) IHC for MMR proteins
2) Microsatellite instability analysis:
- Microsatellite stable (MSS)
- Low MSI (MSI-L)
- High MSI (MSI-H)
3) Next generation sequencing Gene panel testing
Define the MMR screening scheme for Lynch syndrome/ HNPCC
Aberrant MMR seen on IHC
- MSH2/ MSH6 loss of expression from germline MMR mutation + No germline EPCAM mutation = Lynch syndrome
- MLH1/ PSM2 loss of expression + MLH1 promoter methylation = Sporadic mutation
No MLH1 promoter methylation = germline mutation
3 approaches to subtype cervical cancer?
- HPV DNA test by sequencing
- IHC for p16 surrogate marker
- Morphological diagnosis of SCC or adenocarcinoma
3 classes of SCC cervical cancer
SCC, HPV associated
SCC, HPV independent
SCC, NOS (not otherwise specified)
6 classes of adenocarcinoma cervical cancer?
Adenocarcinoma in situ, HPV associated
Adenocarcinoma in situ, HPV independent
Adenocarcinoma, HPV associated
Adenocarcinoma, HPV independent - Gastric type
Adenocarcinoma, HPV independent - Clear cell type
Adenocarcinoma, HPV independent - Mesonephric type
List 4 pure sex-cord tumours and associated genetic factors (2)
- Adult granulosa cell tumor = FOXL2 missense mutation
- Juvenile granulosa cell tumour = n/a
- Sertoli cell tumour = n/a
- Sex cord tumour with annular tubules = Germline SKT11 gene mutation
3 molecular subtypes of Sertoli-Leydig cell tumours
Difference in age group and differentiation
- DICER1 mutant
- Young
- Moderate to poor differentiated - FOXL2 mutant
- Post-menopausal
- Moderate to poor differentiated - DICER/ FOXL2 wild type
- Intermediate age
- Well differentiated
High grade serious ovarian cancer with BRCA1/2 mutation.
Treatment?
PARP inhibitor (Olaparib)
+
Platinum-based chemotherapy
Synergistic lethality
MMR-deficient endometrial cancer +/- metastasis
Treatment?
Immunotherapy
anti-PD-1/ PDL-1 immune checkpoint inhibitors
e.g. Pembrolizumab, anti-PD immune checkpoint inhibitor
(programmed cell death ligant-1)
Default treatment for DNA MMR deficiency solid tumours
Pembrolizumab, anti-PD immune checkpoint inhibitor
US exam reveal cluster of small, grape-like cysts in the Placenta with no fetal tissue growth.
Dx?
Complete Hydatidiform mole
2 types of hydatidiform mole/ Molar pregnancy.
Cause?
Abnormal fertilization of oocyte > placental growth with abnormal/ no fetal growth
- Complete = Abnormal placenta + No fetal development
- Partial = Abnormal placenta + some fetal growth
Difference in chromosome composition of complete (mono or dispermic) vs partial hydatidiform mole.
Complete = Diploid
- Monospermic = empty ovum + 23X from sperm (replicate) = 46XX
- Dispermic = empty ovum + 23X/ Y from 2 sperm = 46XX or 46XY
Partial = Triploid
- Normal ovum + 23X/Y from 2 sperm = 69XXX, 69XXY or 69XYY
Father to mother chromosome ratio in Complete vs partial hydatidiform mole
Complete - Father to mother ratio = 2:0
Partial - Father to mother ratio = 2:1 (extra paternal haploid present)
Genetic test method for hydatidiform mole? (which marker to differentiate complete vs partial HM)
1) P57-KIP2 only expressed in maternal allele
Complete hydatidiform mole has no maternal chromosome = no P57-KIP2 expression
Test = IHC for P57-KIP2 expression in cytology and stromal cells
IHC positive = Partial HM
IHC negative = complete HM
2) Molecular genotyping to d/dx HM
Use of molecular typing to differentiate types of hydatidiform mole?
Molecular genotyping:
- Androgenic diploidy = Complete HM
- Diandric Triploidy = Partial HM
- Biparental Dipoidy = Non-molar/ normal
