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Hereditary tumours to be aware of Gerd JACOMEN Dept. of Pathology 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 sporadic 5% are familial Lynch syndrome Variant: Muir-Torre syndrome Cowden syndrome BRCA1 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 Involved genes MLH1, MSH2, MSH6, PMS2 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% Features that raise suspicion Familial anamnesis Clinical Gross Histology Familial anamnesis Not only gynecologic malignancies Not only females Take your time! Malignancy in Lynch Increased risk of multiple malignancies Colon Endometrium Ovary Stomach Urinary tract Hepatobiliary tract Small intestine Brain Clinical Other malignancies? Age BMI 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) Advantage of IHC as screening Simple Inexpensive Readily available Can direct gene sequencing 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 Breast Cancer and Lynch Breast Cancer Research 2012,14:R90 Breast Cancer Research 2012,14:110 MSI in breast Ca 0-3% in sporadic breast Ca > 50% of breast Ca in Lynch syndrome mutation carriers Features of Lynch associated breast Ca Same Same Same Same Same Same age type grade stage receptor and HER2 status 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 Frequency of BRCA-mutation 0.3% of women is carrier of the mutation 2% of Ashkenazi jews Histology of BRCA associated ovarian Ca Type: Serous Grade: High Stage: Advanced BRCA1 = BRCA2 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 Prophylactic BSO Occult cancers Tubal intraepithelial Ca Occult cancers = Ca in absence of preoperative evidence of malignancy 4-10% of prophylactic BSO Can measure up to 5 cm Where? Most are located at tubal fimbriae Due to oxidative stress at ovulation Prognosis Even little tumours may metastasise Complete staging necessary as for serous Ca ovary Precursor lesions Tubal Intraepithelial Carcinoma (TIC) In 8% of prophyactic BSO + for p53 High Ki67 (>50%) Prognosis Uncertain Some cases may metastasise Chemotherapy not considered necessary Precursor lesions of TIC SCOUT p53 signature Proliferative p53 signature Importance in routine setting unknown p53 signature p53 Ki67 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 Ca Lifetime cumulative risk of 60% by age 80 Most are lobular Ca Gastric biopsy of patient with lobular Ca Atypical cells and signet cells in stroma Diagnosis? Lobular Ca breast and gastric diffuse Ca are similar Metastasis? 2 separate primaries? Treatment is completely different! ER Take home messages Familial tumours can be encountered every day High level of suspicion Detection is important for genetic counseling Take home messages 2 Familial anamnesis Not limited to the same cancer Not limited to gyneco/breast Not limited to female members