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