Familial Cancer Syndromes PDF

Familial Cancer Syndromes Mehmet Ali Ergün, MD, PhD, Prof. Department of Medical Genetics  Terminology Cancer – group of disorders having uncontrolled cell growth – genetics x environment – inherited Neoplasm: mass of cells= tumor Tumorigenesis: tumor formation Mali...

Familial Cancer Syndromes Mehmet Ali Ergün, MD, PhD, Prof. Department of Medical Genetics  Terminology Cancer – group of disorders having uncontrolled cell growth – genetics x environment – inherited Neoplasm: mass of cells= tumor Tumorigenesis: tumor formation Malign: neoplasms invade nearby tissues and spread (metastasis) Benign X Malign Cancer development (apoptosis)  Cancer causes: Genetics Cancer genes Somatic cells somatic cells – genes x environment – are not transmitted Germline cells – inherited germline cells – cancer families  Classification of Cancer Genes Tumor suppressor genes – normally inhibit cellular proliferation Oncogenes – activate proliferation DNA repair genes  Oncogenes cancer genes originate from proto-oncogenes – involved in the four basic regulators of normal cell growth growth factors growth factor receptors signal transduction molecules nuclear transcription factors a mutation occurs in a proto-oncogene – become as an oncogene – leads to unregulated cell growth and differentiation  Oncogenes & TSG a single copy of a mutated oncogene is required to contribute to the multistep process of tumor progression tumor suppressor genes are disabled by – deletions – loss-of-function mutations oncogenes are activated by – gain-of-function mutations – gene amplification  Oncogenes & TSG Tumor suppressor genes – exhibit germline mutations that can cause inherited cancer syndromes » Retinoblastoma » Li-Fraumeni syndrome Oncogenes – found in sporadic tumors – germline oncogene mutations that cause inherited cancer syndromes are uncommon  tumor suppressor genes –RB1 –NF1 –TP53  TP53 gene Tumor protein p53 somatic mutations – in >50% of all human tumors – in 70% of colorectal tumors – in 40% of breast tumors – in 60% of lung tumors  Two-hit model of carcinogenesis Knudson mentioned in 1971 after analysis of retinoblastoma inherited retinoblastoma – an affected individual usually has an affected parent – there is a 50% chance of genetic transmission to each of the offspring – bilateral (affecting both eyes)  Two-hit model of carcinogenesis sporadic retinoblastoma – neither parent is affected – there is no additional risk to other progeny – involves only one eye Knudson indicated that at least two mutations may be required to create a retinoblastoma – first mutation alter the retinoblastoma gene in the germline, so it would be present in all cells – second mutation would be an additional event occurring in an already-altered cell  Persons who inherited one hit would require only one additional mutational event in a single retinoblast In sporadic cases, both mutations would have to occur somatically in the developing fetus  Retinoblastoma the most common childhood eye tumor – 1/20,000 children clinical presentation by the age of 5 years  Retinoblastoma 60% caused by somatic mutations – are not transmitted to the affected individual's offspring 40% are caused by inherited mutations  Retinoblastoma RB1 gene is on chromosome 13 inherited retinoblastoma is – multifocal – bilateral  Retinoblastoma a white reflex (leukocoria) can be seen in the right eye  Retinoblastoma 5-year survival rate for retinoblastoma patients is about 95% familial retinoblastoma patients are also susceptible to other types of cancer later in life – osteosarcomas (malignant bone tumors) 15% – soft tissue sarcomas – cutaneous melanomas careful monitoring for subsequent tumors and avoidance of agents such as x-rays  Li-Fraumeni syndrome (LFS) autosomal dominant involves breast and colon carcinomas, soft- tissue sarcomas, osteosarcomas, brain tumors, leukemia, and adrenocortical carcinomas tumors usually develop at early ages multiple primary tumors are commonly seen two-hit model such as retinoblastoma I II MI DM, III HT 4 3 11 Y 2 3 4 5 6 7 8 9 10 1 IV 53 Y V 2 2 2 4 2 VI 34 Y 31 Y 11 Y 17 Y 11 Y Colon Ca Stomach Ca Breast Ca Larynx Ca Lung Ca Endometrium Ca Brain Ca  Li-Fraumeni syndrome (LFS) an abnormal TP53 gene – 50% develop invasive cancer by 30 years of age – > 90% develop invasive cancer by age 70 years TP53 mutations account for 75% of LFS cases another tumor suppressor gene, CHEK2  Familial adenomatous polyposis (FAP) also called adenomatous polyposis coli (APC) is relatively rare – affects 1/10,000 -20,000 account for 100 polyps) penetrance of FAP is virtually 100% a positive family history – ca risk doubles if a first-degree relative is affected Familial adenomatous polyposis (FAP)  Familial Adenomatous Polyposis gene (APC) APC, localized to 5q tumor suppressor gene  APC Germline mutations in the APC gene are identified in family members affected with FAP 1/3 of cases are new mutations in APC  MUTYH encodes a DNA repair protein can result FAP in 10-20% cases – that no APC mutation is detected  prevention an annual colonoscopy starting at 12 years of age use of nonsteroidal anti-inflammatory drugs causes some degree of polyp regression  other ca increased risks of other cancers – gastric cancer (50% of colon tumors – occur relatively in late period SMAD4 mutations – tumor suppressor gene  Hereditary Nonpolyposis Colon Cancer (HNPCC) HNPCC or Lynch syndrome a second form of inherited colon cancer 1- 5% of all colorectal ca autosomal dominant, high-penetrance cancer syndrome a lifetime colorectal cancer risk of 70-90% in heterozygotes  Hereditary Nonpolyposis Colon Cancer (HNPCC) the risk of endometrial cancer is 50% the risk of ovarian cancer is 5-10% small bowel, stomach, brain, pancreas, renal pelvis, ureter ca are seen no polyposis/ small number of polyps  Hereditary Nonpolyposis Colon Cancer (HNPCC) 40-60% of HNPCC cases caused by MSH2 gene mutations 25-30% of cases caused by MLH1 gene mutations PMS2 and MSH6, have a small percentage – DNA mismatch repair genes  Inherited Breast Cancer lifetime prevalence is 1/8-1/12 risk of developing breast cancer doubles – if a first-degree relative is affected BRCA1, BRCA2 major genes  only 1-3% of all breast cancers can be attributed to inherited mutations in – BRCA1 or BRCA2 early-onset and bilateral breast ca – inherited mutations are common  BRCA2 mutations – increased risk of ovarian ca (10-20% lifetime prevalence) about 6% of males who inherit a BRCA2 mutation – develop breast cancer – this represents a 70-fold increase over the risk in the general male population  women who inherit a mutation in BRCA1 – experience a >60% lifetime risk of developing breast ca women who inherit a mutation in BRCA2 – experience a >60% lifetime risk of developing breast ca  BRCA1 and BRCA2 – participate in an important DNA repair pathway – their inactivation results in incorrect DNA repair and – genomic instability  Breast ca genes BRCA1 and BRCA2 mutations are the most common other tumor suppressor genes – CHEK2 – TP53 – PTEN – ATM  clinical course of breast ca among patients – with BRCA1 or BRCA2 mutations is not different from that of other breast cancer patients  Risk reducing oophorectomy – reduces ovarian ca risk by 90% – reduces breast ca risk by 50% Risk reducing bilateral mastectomy – in BRCA1 and BRCA2 carriers – reduces the risk of breast ca by 90%  Familial Melanoma Result from increased exposure to ultraviolet radiation the risk of developing melanoma increases by a factor of 2 – when a first-degree relative is affected the risk increases to 6.5 – when the first-degree relative is affected before 50 years of age 5-10% of melanoma cases occur in inherited, familial forms  CDKN2A CDKN2A gene – the cause of familial melanoma – tumor suppressor gene mutations in this gene are involved in 10- 40% of familial melanoma cases  RET a proto-oncogene can cause inherited cancer syndromes patients with sporadic medullary thyroid carcinomas – advised to undergo genetic testing for RET – 1-7% of these patients have germline RET mutations and thus familial, rather than sporadic prophylactic thyroidectomy – < 6 years of age is recommended for children who inherit a disease-causing mutation – thyroidectomy