Upload
fay-small
View
214
Download
1
Tags:
Embed Size (px)
Citation preview
What is the link?
Malignant tumours are caused by genetic changes
Hereditary diseases are genetically transmitted
Familial clusters of malignancies
Sporadic/Familial genetic changes
Mutation can be sporadic in 1 somatic cell: epigenetic
Mutation can be present in a germ cell: Germline mutation All cells derived from that cell will
harbour the mutation Can be inherited or new
Familial tumours of the uterine corpus
95% are sporadic5% are familial
Lynch syndromeVariant: Muir-Torre syndrome
Cowden syndromeBRCA1
HNPCC
Hereditary nonpolyposis colorectal cancer syndrome
Lynch Autosomal dominant Germline mutations in mismatch
repair genes Genes that are responsible for correcting
errors (mismatches) during DNA replication
Caretaker genes
Normal function: helps genome to be stable during replication
DNA Mismatch repair genes
Microsatellites: repetitive DNA sequences
Prone to replication errors Normally corrected by Mismatch repair
system
Microsatellite instability
Whenever Mismatch repair genes do not function
Result: microsatellites are no longer “stable” during replication
Hence: Microsatellite Instable MSS, MSI-Low, MSI-High
Are all MSI-High tumours Lynch?
20-25% of all endometrial Ca are MSI-H
75% are sporadic: epigenetic silencing of MLH1 (promotor methylation)
Remaining cases: mostly Lynch associated
Ca 2% of all endometrial cancers! Age dependent: 9% in younger patients
Recognising is important
Patient and family have increased risk for malignancies
Genetic counseling/testing
Gynecologic malignancy is sentinel cancer in 50%
Malignancy in Lynch
Increased risk of multiple malignanciesC
olon
Endometrium
Ovary
Stomach
Urinary tract
Hepatobiliary tract
Small intestine
Brain
How to diagnose Lynch?
Def: germline mutation in DNA mismatch repair genes
Mutation analysis is definitive test Expensive and time consuming Patient consent needed
Screening!
Simple screening: immunohistochemistry
Using Ab against MLH1, PMS2, MSH2, MSH6: detection of MSI-H tumours Sensitivity 91% Specificity 83%
IHC result
Expression can direct mutational analysis
+ staining with all 4 Abs: no further testing
(except if clinical suspicious)
Importance of IHC result
Loss of MSH2 and/or MSH6 is virtually diagnostic for Lynch!
Loss of MLH1 or PMS2 can still be epigenetic (= not because of germline mutation)
Disadvantages of IHC
Interpretation can be problematic 10% of germline mutations remain
undetected by IHC Loss of expression can be
epigenetic= not Lynch, but sporadic
Features of Lynch associated breast Ca
Same age Same type Same grade Same stage Same receptor and HER2 status Same chemotherapy?
Which endometrial Ca should be stained?
< 50 ys Non-endometrioid Ca < 60 ys Lower uterine segment Multicentric or heterogeneity Peritumoral lymphocytes TIL > 42/10 HPF “hard to type” Ca Familial/personal history
Hereditary tumours of ovary and fallopian tube
10% of all ovarian Ca are associated with inherited germline mutations
BRCA1/2 Lynch
Lifetime risk for mutation carriers
BRCA1: 66% BRCA2: 10-20% MLH1/MSH2: 3-12%
Global Western population <2%
BRCA1/BRCA2
Inherited mutations in BRCA1 or BRCA2 genes
BRCA1/BRCA2 act as tumour suppressor genes
Autosomal dominant
Tumour suppressor genes
Normal function: gene encodes for protein involved in control of normal cell cycle
Of each gene are 2 copies in a cell: 2 mutations are needed before the protein will not be encoded properly
2 mutations: 1 in each allele
First: makes cell “vulnerable”
Mutation on second allele: no longer synthesis of normal protein
No longer normal function
What is not associated with BRCA?
Mucinous Ca If high grade/high stage: think of
metastasis first! Low grade serous Borderline serous
BRCA1/2 associated ovarian/tubal Ca
Since high risk of Ca if carrier: prophylactic BSO
At age 35 ys, or after child-bearing is completed
Occult cancers
= Ca in absence of preoperative evidence of malignancy
4-10% of prophylactic BSO
Can measure up to 5 cm
Precursor lesions
Tubal Intraepithelial Carcinoma (TIC)
In 8% of prophyactic BSO
+ for p53 High Ki67 (>50%)
Precursor lesions of TIC
SCOUT p53 signature Proliferative p53 signature
Importance in routine setting unknown
BRCA1/2 and breast cancer
Lifetime risk of breast Ca if carrier: BRCA1: 70% BRCA2: 45%Other risk factors remain important
Histopathologic features of BRCA associated breast Ca
Invasive Ca of no special type (BRCA1)
Grade 3 Triple negative p53 positive Basal CKs positive
Hereditary diffuse gastric cancer
Families with diffuse gastric cancer and lobular Ca breast
Germline mutations of CDH1 gene (E-cadherin)
Diagnostic criteria
≥ 2 cases of diffuse gastric cancer in 1st or 2nd degree relatives, at least 1 diagnosed < age 50
or≥ 3 cases of diffuse gastric cancer in
1st or 2nd degree relatives, regardless of age at diagnosis
Breast cancer in HDGC
Females in HDGC families are at increased risk of breast CaLifetime cumulative risk of 60% by age
80
Most are lobular Ca
Diagnosis?
Lobular Ca breast and gastric diffuse Ca are similar
Metastasis? 2 separate primaries?
Treatment is completely different!
Take home messages
Familial tumours can be encountered every day
High level of suspicion Detection is important for genetic
counseling