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Genetics and Cancer Risk Assessment in the Affected/Unaffected Population/High Risk Clinic Lisa Michels, MSN, APNP Oncology/Hematology/Cancer Genetics Objectives • No disclosures Objectives: • Understand the difference between sporadic, familial and hereditary cancers • Known inheritable cancer syndromes • Characteristics of personal/patient history that may be linked to a cancer syndrome • Genes connected with cancer syndromes • Understanding cancer risk profiling Cancer Occurrence Sporadic: • Cancers that occur by chance • Typically don’t have relatives with the same type of cancer Familial: • cancer likely caused by a combination of genetic and environmental risk factors. • May have one or more relatives with the same type of cancer, but there doesn’t seem to be a specific pattern Hereditary: • Cancer occurs when an altered gene is passed down from parent to child • Typically have relatives with the same type of cancer • May develop more than one cancer • Cancers usually occur at an earlier than average age The Biology of Cancer • Cancer results from abnormal gene expression • DNA stores genetic information as a genetic code which consists of triplets of bases called CODONS. • CODONS-specify the amino acid sequence of a protein. • Mutations may occur during DNA replication and recombination or arise spontaneously. Point Mutations • Silent Point • Missense Point • Nonsense Point Frameshift Mutations • Deletion • Insertion • Deletion and insertion Cancer Syndromes Hereditary Breast and Ovarian Cancer Syndrome – Gene: BRCA 1, BRCA 2 (tumor suppressor gene) – Related cancer types: Female Breast, ovarian, and other cancers, including melanoma, pancreatic, prostate and male Breast cancer Phenotype • Early age-onset breast/ovarian cancer • More tendency for tumors to be triple negative-ER-/PR-/Her2-neu- • More aggressive cancers with: medullary histology, high histologic grade, areas of necrosis, trabecular growth pattern, high S- phase fraction, and high mitotic index Testing Criteria for the Affected • Ashkenazi Jewish decent with breast, ovarian or pancreatic cancer at any age • Known mutation in family • Early age onset breast cancer • Triple negative breast cancer • Two breast cancer primaries in one individual • Ovarian cancer • Male breast cancer • Breast cancer at any age and + Testing Criteria for the Unaffected • A known BRCA mutation in the family • History of 2+ breast primaries in one individual • History of 2+individuals with breast primaries on the same side of the family • History of 1+ ovarian cancer from the same side of the family • 1st or 2nd degree relative with breast cancer under 45 • History of 1+ family member on same side with a combination of breast + • Male breast cancer in the family Li-Fraumeni Syndrome – Gene: TP53(Tumor suppressor gene) – Related cancer types: Breast cancer, soft tissue sarcoma, osteosarcoma (bone cancer), leukemia, brain tumors, adrenocortical carcinoma and other cancers • The risk of developing any invasive cancer (excluding skin cancer) is ~50% by age 30 (1% in the general population) and is 90% by age 70. • Early onset breast cancer accounts for 25% of all the cancers • soft tissue sarcomas (20%), bone sarcoma (15%) glioblastomas (13%). • Other cancers seen in this syndrome include leukemia, lymphoma and adrenocortical carcinoma Diagnosis • Li–Fraumeni syndrome is diagnosed if the following three criteria are met: • the patient has been diagnosed with a sarcoma at a young age (below 45), • a first-degree relative has been diagnosed with any cancer at a young age (below 45), • and another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age. +TP53 mutation Birch criteria and the Eeles criteria Cowden Syndrome Multiple hamartoma syndrome Gene: PTEN (tumor suppressor gene) • Related cancer types: Breast, thyroid, endometrial (uterine lining), and other cancers Characteristic features : • macrocephaly • intestinal hamartomatous polyps • benign skin tumors multiple trichilemmomas, papillomatous papules • acral keratoses • dysplastic gangliocytoma of the cerebellum Lynch Syndrome Hereditary non-polyposis colorectal cancer – Genes: MSH2, MLH1, MSH6, PMS2, EPCAM – Related cancer types: Colorectal, endometrial, ovarian, renal pelvis, pancreatic, small intestine, liver and biliary tract, stomach, brain, and breast cancers • 80% lifetime risk for colon cancer • Two-thirds of these cancers occur in the proximal colon • The mean age of CRC diagnosis is 44 for members of families that meet the Amsterdam criteria. • Women with HNPCC have an 80% lifetime risk of endometrial cancer. • The average age of diagnosis of endometrial cancer is about 46 years. • HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years-old; approximately 30% are diagnosed before age 40 years. • Mean age of diagnosis of gastric cancer is 56 years of age with intestinal-type adenocarcinoma being the most commonly reported pathology. Variants of Lynch • Muir-Torre-features of Lynch with sebaceous gland and keratoacanthamos • Turcot syndrome-hereditary multiple CRC’s and primary brain tumors Founder’s mutation-50% of all Lynch families in Finland De Novo in 30% of cases Familial Adenomatous Polyposis • Gene: APC and MUTYH • Related cancer types: Colorectal cancer, multiple non- malignant colon polyps, and both non-cancerous (benign) and cancerous tumors in the small intestine, brain, stomach, bone, skin, and other tissues • 7% risk by age 21, rising to 87% by age 45 and 93% by age 50 • Attenuated FAP-flawed gene which reduces the body's ability to protect against the risk of aged cells becoming cancerous-lifetime risk 70% Characteristics • CHRPE-congenital hypertrophy of the retinal pigment epithelium • Multiple polyps manifest higher in the colon than usual-ascending colon, proximal to the splenic flexure or in the gastric or duodenal tracts Characteristics cont. • jaw cysts • Sebaceous cysts • osteomas (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner's syndrome Criteria for Testing APC: • Personal history of >10 adenomas • Personal history of a desmoid tumor • Known deleterious APC mutation in family MUTYH: • Personal history of >10 adenomas • Individual meeting criteria for SPS-serrated polyposis syndrome with at least some adenomas • Known deleterious MUTYH mutation in the family Phenotype: • Presence of 100+ polyps or fewer if younger age • CHRPE, osteomas, desmoids, epidermoid cysts, duodenal and other small bowel adenomas, gastric fundic gland polyps. Increased risk for medulloblastoma, papillary carinoma of the thyroid <2%, hepatoblastoma (1-2% usually <5 years of age, pancreatic cancers<1%, gastric cancers <1% and duodenal cancers 4-12% Hamartomatous Colon Syndromes Peutz-Jeghers-STK11 • Polyps throughout GI tract • Peri-oral melanin pigmentation in 95% • Overall cancer risk is 93% by age 65 • Diagnostic criteria(2 oF 3): small bowel polyposis, pigmented macules oF buccal mucosa, lips Fingers or toes or a relative with PJ Associated cancers: colon, pancreas, stomach, small intestines, esophagus, breast, ovarian, lung, cervical Uterine and testes Juvenile Polyposis Genes:SMAD4 and BMPR1A Juvenile polyps mainly in the colon • Symptomatic presentations • <30 years, benign complications • >30 malignant complications • Colon cancer 50-fold increased risK • Upper GI cancers: may occur (stomach, pancreas, small bowel) • Multiple Congenital anomalies • No sKin findings Retinoblastoma – Gene: RB1 – Related cancer types: Eye cancer (cancer of the retina), pinealoma (cancer of the pineal gland), osteosarcoma, melanoma, and soft tissue sarcoma • 45% are inheritable • More likely to be bilateral • May be associated with pinealoblastoma-known as trilateral retinoblastoma Neurofibromatosis • Genes: Nf1 and Nf2 • NF1, also called von Recklinghausen NF or peripheral NF, is characterized by multiple café au lait spots and neurofibromas on or under the skin. • Enlargement and deformation of bones and scoliosis may also occur. • Occasionally, tumors may develop in the brain, on cranial nerves, or on the spinal cord. • More than 50% of people with NF1 also have learning disabilities • NF2, also called bilateral acoustic NF (BAN), is much less common than NF1 and is characterized by multiple tumors on the cranial and spinal nerves. • Tumors that affect both of the auditory nerves and hearing loss beginning in the teens or early twenties are generally the first symptom of NF2. Diagnosis Criteria: • Physical examination • Medical history • Family history • X-rays • Computerized tomography (CT) scans • Magnetic resonance imaging (MRI) • Biopsy of neurofibromas • Eye tests • Tests for particular symptoms, such as hearing or balance tests • Genetic testing (available for families with documented cases of NF1 and NF2); Multiple Endocrine Neoplasia Type 1 (Wermer syndrome) The 3-P’s – Gene: MEN1 – Related cancer types: Pancreatic endocrine tumors and (usually benign) parathyroid and pituitary gland tumors Type 2 – Gene: RET – Related cancer types: parathyroid tumors, medullary thyroid cancer and pheochromocytoma • MEN1 gene mutations can be identified in 70-95% of MEN1 patients • in about 20% of familial isolated hyperparathyroidism cases • 50% of patients develop signs and symptoms by 20 years of age and more than 95% have symptoms by 40 years of age Clinical Criteria: • Two of the three main tumor types must be present (parathyroid, pancreatic, pituitary) • An index MEN 1 case
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  • The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome

    The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome

    Asadi S and Aranian MR, J Hematol Hemother 5: 008 Journal of Hematology & Hemotherapy Review Article The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome Asadi S* and Aranian MR Division of Medical Genetics and Molecular Pathology Research, Harvard University, Boston Children’s Hospital, Iran Abstract *Corresponding author: Shahin Asadi, Division of Medical Genetics and Molecular Pathology Research, Harvard University, Boston Children’s Hospital, Iran, Tel: +98 Fibrodysplasia Ossificans Progressiva (FOP) is a severely dis- 9379923364; E-mail: [email protected] abling heritable disorder of connective tissue characterized by con- genital malformations of the great toes and progressive heterotopic Received Date: February 7, 2020 ossification that forms qualitatively normal bone in characteristic ex- Accepted Date: February 17, 2020 traskeletal sites. Classic FOP is caused by a recurrent activating mu- tation (617G>A; R206H) in the gene ACVR1 (ALK2) encoding Activin Published Date: February 24, 2020 A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous Citation: Asadi S, Aranian MR (2020) The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome. J Hematol ACVR1 missense mutations in conserved amino acids. Hemother 5: 008. Keywords: ACVR1; BMPR1A; BMPR1B; BMPR2; BMP4; Genetics Copyright: © 2020 Asadi S, et al. This is an open-access article distributed under the mutations, Stone man syndrome terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source Overview of Stone Man Syndrome are credited.