Adobe Systems Hereditary cancer syndromes Jakub Trizuljak aVLKG7X1c Klinická genetika - cvičení Adobe Systems Název předmětu (kód předmětu) (např. První pomoc - cvičení (VLPO011c)) Výstupy z učení ̶Student se naučí rozpoznat akutní život ohrožující stavy u diabetiků. ̶ ̶Student se naučí základní principy první pomoci u diabetiků. ̶ ̶ Basic Dogmas of Oncology Genetic information DNA -> RNA Molecular structure of protein Biochemical function of protein Symptoms (Phenotype) Aberrant gene expression is a key step in the initiation, promotion and progression of the tumor III) Biological correlates of gene expression are identifiable I) Cancer is a genetic disease II) Carcinogenesis is a multistep process Carcinogenesis is a multistep process involving alterations in at least two distinct classes of genes Hereditary cancer syndromes Hereditary cancer syndromes Hereditary cancer syndromes Hereditary cancer syndromes Hereditary cancer syndromes Hereditary breast and ovarian cancer: HBOC Breast cancer ●the most frequent malignant cancer in female patients from Czech Republic ●rising incidence, declining mortality ●5-10% of all breast carcinomas are hereditary Ovarian cancer ●ovarian, fallopian and primary peritoneal tumors make up to 15% of all malignant cancers in women ●Czech Republic is on the čth palce in Europe in incidence ●mortality is relatively high !!! ●early tumors have good prognosis, however most cancers are diagnosed in stage III or IV BRCA1 / BRCA2 ●germline BRCA1/2 mutations cause increased risk of malignancy ●lifelong risk of breast cancer is 40-87% / 18-88% ●breast cancer risk until 40 years is19% for BRCA1 mutation carriers, 12% for BRCA2 mutation carriers ●lifelong risk of ovarian cancer is 22-65% / 10-35% ●increased risk of other malignancies (endometrial cancer, cervix cancer, colorectal carcinoma, prostate and stomach cancer) BRCA1/2 DNA cell pathways Level of ●DNA repair ●cell cycle ●apoptosis PARP inhibitors Olaparib (Lynparza) Other candidate genes ●There are further candidate genes increasing risko of hereditary breast and ovarian cancer ●ATM, APC, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 ●Gene panels: CZECANCA: CZEch CAncer paNel for Clinical Application BRONCO- Brno ONCOlogical panel ●more than 300 genes associated with cancer susceptibility BRCA1/2 mutation screening ●NGS – next generation sequencing ●MLPA analysis of large mutations or deletions ●comparison of detected mutations in databases, in silico prediction Example pedigree ●AD mode of inheritance ●ccurence of breast / ovarian cancer in younger pts. ●occurence of neoplasms in every generation ●Occurence of other malignancies ●asymptomatic carriers! (incomplete penetrance) 1 6 Ca ovaria 53 let Ca prsu 56 let Ca ovaria 47l. Ca prsu 52l. Ca plic fumator +80 let Dissemin. Ca prostaty BRCA1 BRCA1 Empiric assessment of cancer risk - Claus model Individual risk ●assessment based on family history, age of onset in relative and character of found mutation ●molecular genetic investigation is indicated by clinical geneticist ●ossibility of preimplantation genetic diagnostics Useful links: http://www.omim.org http://arup.utah.edu/database/BRCA/ http://cancer.sanger.ac.uk/cosmic criteria for genetic testing - sporadic form ●fallopian / ovarian / primary peritoneal cancer in any age ●triple negative breast cancer (ER, PR, HER2 neg.) ˂60 years, medullary carcinoma almost always consistent with TNBC ●unilateral breast cancer ˂45 years (˂50 if no family history known) ●two primary breast cancers, first ˂50 years or both ˂60 years ●breast and pancreas cancer duplicity in any age ●male breast cancer in any age According to NCCN, NICE, ESMO, SLGG criteria for genetic testing – familial form 3 relatives ●At least 3 direct relatives (including the proband ) with breast cancer in any age 2 relatives ●2 direct relatives (including the proband) with breast cancer, at least one diagnosed ˂50 years, or both ˂60 years ●Proband with breast cancer of any age and a direct relative with ovarian cancer, triple-negative breast cancer or medullar breast cancer, male breast cancer, pancreatic cancer or high/grade primary metastatic prostate cancer Predictive testing of a known familial mutation above 18 yrs According to NCCN, NICE, ESMO, SLGG Recommended screening of mutation carriers ●breast self-investigation since 18 years ●clinical breast investigation by a specialist twice a year since 25 years or 10 years earlier than the first occurence of breast/ovarian cancer in relatives ●25-29 let: MRI and ultrasound, twice a years ●30-65 let: MRI a mammography, twice a year ●gynecological investigation twice a year including transvaginal ultrasound ●further investigations (onkomarkers, screening for other malignancies, eg. gastroscopy, colonoscopy) Prophylactic surgery ●bilateral prophylactic adnexectomy, at best in the age of 35-40 years in mutation carriers or immediately in elderly patients, possibility of hysterectomy is always considered (especially in BRCA1 mutation carriers) ●bilateral prophylactic mastectomy at any time the patients asks, after consultation with oncologist and complex preventive investigations Further considerations ●chemoprevention – Tamoxifen Tamoxifen use can protect i BRCA2 mutation carriers, but not in BRCA1 carriers: King et al., 2001 ●Tamoxifen increases survival by 1.8 years and quality adjusted survival by 2,7 years: Grann et al., 2002 ● ●role of oral contraceptives? Low dose COC possibly protects against ovarian cancer in BRCA1/2 carriers but its role in breast cancer is uncertain (probably no increased risk) ● ●reprodukční rozhodnutí The best protection is an early detection! October is the breast cancer awareness month Adobe Systems Hereditary nonpolypous colorectal carcinoma (NPCC) Lynch syndrome Prof. Henry T. Lynch, MD. *1928 - ‘Hereditary factors in cancer: study of two large midwestern kindreds’, Arch. Intern. Med., 1966 Research of several families with colorectal and other cancers in US states Michigan and Nebraska Adobe Systems Lynch syndrome lthe most frequent congenital predisposition to colorectal cancer lhigh penetrance, AD mode of inheritance lapproximately 2-5% of all colorectal cancers l28-75% risk of colorectal cancer in men, 24-52% risk of colorectal cancer in women lRisk of other tumors: endometrial cancer, ovarian cancer in women, gastric cancer, urinary tract cancers, hepatobilary cancers, cancer of small intestine, brain tumors Adobe Systems Lynch syndrome Adobe Systems Adobe Systems 8 Gastric Ca 62 yrs +67 yrs Gastric Ca disseminated. adenocarcinoma unknown origin 62 yrs Gastric Ca MSH6 Example pedigree Adobe Systems MLH1, MSH2, MSH6 and PMS2 genes •mismatch repair genes • •system responsible for genetic stability in prokaryotes and eukaryotes • •recognition of mismatch nucleotides, excision and repair by DNA polymerases Adobe Systems Indikation for mutation screening MLH1, MSH2, MSH6, PMS2 Amsterdam criteria I/II •at least three family members with colorectal carcinoma (or other tumor in HNPCC spectrum), one of thgem is a first degree relative to the other two •at least two generations affected •at least one patient younger than 50 years at the time of diagnosis •the tumor has been verified by pathologist •familiar adenomatous polyposis excluded Adobe Systems Dispenzarization of asymptomatic mutation carriers •total clinical examination by specialist once per year •coloscopy once per 2 years, starting at 20 years, or 10 years earlier than onset of cancer in the youngest affected relative •in women: gynaecological examination once per year, starting at 18 years, transvaginal USG + CA125 1/year starting at 20, 2/year starting at 35 •aspiration biopsy of endometrium 1/year starting at 30 •USG of the abdomen 1/year starting at 30 •urine stick and sediment examination 1/year starting at 30 •gastroscopy 1/3-4 years starting at 35 •further examinations according to the family history and considerations of the attending clinician Adobe Systems Familial adenomatous polyposis Menzel, 1721: Multiple colorectal polypous lesions Corvisart, 1824: Hypertrofic features in a sample of a 22-year old man with more than 20 „protrusions“ of colon ascendens Lockhart-Mummery, Dukes, 1925, Lancet: „Cancer and heredity“ Endoscopic findings in APC Adobe Systems Familial adenomatous polyposis •occurence of more than 100 adenomatous polyps of large intestine (or less in younger age) •onset of polyp formation around 15 years, at 35 years in 95% of patients •high risk of colorectal carcinoma, often multiple carcinomas, at a very early age •penetrance of the disease near 100% until 50 years!!! •APC gene – classical/attenuated form (AD), MUTYH gene (MYH-asociated polyposis) (AR) •other associated malignacies (desmoid tumors, hepatoblastoma) • • • Adobe Systems Macroscopic pathological sample of the large intestine affected by APC Adobe Systems APC gene •tumor-supressor gene •Wnt/ beta-katenin signal pathway inhibition • •plays a role in cell adhesion, migration, chromosome segregation, apoptosis and neural differentiation Adobe Systems Indication for APC mutation screening •all forms of diffuse intestinal adenomatous polyposis •predictive testing can be performed at any age , even in children! •If there is a clinical suspicion for APC, all first degree relatives should undergo colonoscopy during the investigation og clinical (parents, siblings, in children aged 10-15 years sigmoideoscopy) • Adobe Systems Dispensarisation of APC gene mutation carriers •sigmoideoscopy every 1-2 years, starting at 10-12 years, colonoscopy after formation of first polyps •If severe degree of polyposis is discovered, total colectomy or proctocolectomy is considered •gastroduodenoscopy starting at 25 years, according to clinical degree •USG investigation of abdomen 1/year in the first 10 years – heaptoblastoma screening •further investigations depending on family history Adobe Systems Li-Fraumeni syndrome Joseph F., Fraumeni, Jr., MD. *1933 - Frederick Pei Li, MD. 1940 - 2015 „Sarcomas of soft tissues, breast cancer and other neoplasms. A new familial syndrome?“ Ann Intern Med 1969 Adobe Systems Li-Fraumeni syndrome •rare autosomal dominant cancer predisposition syndrome, 50% of individuals is affected by 40 years, up to 90% by 60 years of age •77% of malignancies belongs to these six types: breast cancer, sarkomas of soft tissues, osteosarcomas, brain tumors, adrenocortical carcinoma, and leukemias •increased frequency of other malignancies •classical LFS (TP53 gene mutations) Li-Fraumeni-like syndrom (CHEK2 gene mutations) Adobe Systems TP53 gene •„guardian of genome“ •transcription factor responding to different forms of cellular stress •regulates target genes, inducing cell cycle arrest, apoptosis, DNA repair,, cell senescence and changes in metabolism •regulated by a list of up- and downstream genes • Adobe Systems short arm of chromosome 17 Adobe Systems TP53 mutation screening criteria (modified Li-Fraumeni syndrome criteria by Chompret) •proband with a tumor of the LFS spectrum under 46 years plus at least one first- or second degree rleative with a LFS-associated tumor •proband with multiple tu,mors, out of which at least two belong to the LFS-associated tumors, first of which was diagnosed under 46 years •Proband with adrenocortical carcinoma or a patient with breast cancer diagnosed under 36 years, without a BRCA1 or BRCA2 gene mutation, regardless of family history Adobe Systems Selected dysmorphic syndromes associated with increased risk of malignancies Syndrome Asociované neoplazie Gene Fanconi anemia Sotos syndrom Ataxia teleangiectasia ATM FANCA, FANCC, FANCD and other NSD1 chronic lymfocytic leukemia, lymphomas of childhood hematological malignancies (MDS, leukemias) leukemias, lymphomas Nijmegen Breakage Syndrome NBS lymphomas (Burkitt lymphoma, DLBCL), breast cancer Bloom syndrome BLM Non-Hodgin lymphomas, breast cancer Adobe Systems Sotos syndrome Adobe Systems Nijmegen Breakage Syndrome Adobe Systems Bloom syndrome Figure 1 Figure 4 Adobe Systems Obligate carriers Affected patients Tested individuals Colorectal Ca Kidney Ca Breast Ca Lung Ca Bone tumor ? ? Recurrent lymphoma Lékařská fakulta Masarykovy univerzity 2021 Adobe Systems