Genetics and Cancer Risk Assessment in the Affected/Unaffected Population/High Risk Clinic

Lisa Michels, MSN, APNP /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 • 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 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 • DNA stores genetic information as a genetic code which consists of triplets of bases called CODONS. • CODONS-specify the amino acid sequence of a . • 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 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, 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 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, , 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), (cancer of the ), osteosarcoma, melanoma, and soft tissue sarcoma • 45% are inheritable • More likely to be bilateral • May be associated with pinealoblastoma-known as trilateral 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 and • 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 with at least one first-degree relative who has one of the three main MEN 1 tumors Von Hippel-Lindau Syndrome – Gene: VHL – Related cancer types: Kidney cancer and multiple noncancerous tumors, including pheochromocytoma • tumors of the central nervous system (CNS) are benign hemangioblastomas. • Hemangioblastomas may develop in the brain, the retina of the eyes, and other areas of the nervous system. • Over 90% penetrance by the age of 65. • Age at diagnosis varies from infancy to age 60-70 years, with an average patient age at clinical diagnosis of 26 years.

Purpose of High Risk Clinic

• To identify individuals and families at increased risk for developing cancer • To help patients and families better understand and manage their cancer risk • To provide appropriate medical and genetic information for use in early detection, prevention, and improved cancer management High Risk “Clinic” • About 10% of a mammography screening population will be appropriate for risk profiling and possible genetic testing • Currently techs do an assessment and have been educated on a + screen • Patients are offered an opportunity to meet with NP for genetic counseling, high risk profiling and genetic testing. • Appointments usually 60 minutes • Most insurances covering appointment, but testing may be different • Patients younger than mammography screening age or men can be referred by PCP Cancer-Risk Assessment • Why patient seeking this service • past medical/surgical history • Current health status, including lifestyle issues • Assess dietary, hormonal, environmental and other cancer-risk factors • Family medical/surgical history • Pedigree • Physical exam-head circumference, dermatological findings-café au lait spots, nodules, eye abnormalities • Risk for developing cancers and probability of having a mutation • Psychosocial issues • Explain autosomal-dominant patterns of inheritance • Confidentiality of genetic information • Alternatives to testing • Risks and benefits to gene testing • Handouts Pre-test Education and Counseling

• Discuss type of genetic test, cost, accuracy, how performed and potential test results • Information regarding polices for storage and release of test results • Review how patient would like to obtain results- phone call or office visit • Disclosing test results to family members • Review and obtain written consent • Obtain insurance information • Drawing of blood or obtaining buccal sample Post-test Counseling

• Assess response to results • Discuss what results mean to patient’s own risk of developing cancer • What do results mean to family • Review medical follow-up recommendations • Available resources for additional information, psychological support or counseling. Probability/Empiric Risk Tools

Mutation Probability Models: • Couch • Penn II • Myriad Prevelance tables Mutation Pobability and Risk Assessment Models: • BRCAPRO • Tyrer-Cuzick-incorporate personal risk factors including age of menarche, age of 1st live birth, breast biopsies, BMI, age at menopause and HRT • BOADICEA Risk Assessment Models: • Gail-like Tyrer-Cuzick-BMI, age at menopause and HRT • Claus Gene Panels

• BRCA1/2 Ashkenazi Founder Mutation Panel • BRCA1 and BRCA2 Sequencing and Deletion Duplication Analysis • Breast Cancer High Risk Panel-BRCA1, BRCA2, CDH1, PTEN, STK11, TP53 • Breast/Ovarian Cancer Panel-ATM, BARD1, BRCA1, BRCA2, BR1P1, CDH1, CHEK2, EPCAM, FANCC, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53, XRCC2 • Lynch/Colorectal High Risk-APC, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2 • Pancreatic Cancer Panel-APC, ATM, BRCA1, BRCA2, CDK4, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53, VHL, XRCC2 • Biggest panel-CancerNext 49genes-Ambry Genetics Questions?

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