Dr Mehrdad Zeinalian MD, MPH, PhD of Molecular Medicine Poursina Hakim Research Institute Dec 2013 Genetic Counseling in Pancreatic Cancer

Introduction The lifetime risk of pancreatic cancer among men and women in the United States is ~1.4%. It is estimated 10% of cases may be due to an underlying hereditary cause. Most family cancer syndromes and genetic conditions are linked to exocrine pancreatic cancer. Exocrine cancers make up 95% of all pancreatic cancers and include pancreatic adenocarcinoma, the most common type. The underlying genetic cause for clusters of pancreatic cancer in many families is still unclear.

Familial risk of pancreatic cancer* First Degree Relatives with Pancreatic Cancer Risk for Developing Pancreatic Cancer 01-2% 14-6% 24-7% % * NSGC Familial Pancreatic Cancer Fact Sheet

Hereditary Pancreatic Cancer Hereditary pancreatic cancer can be divided into three distinct categories: 1) known hereditary cancer syndromes mainly defined by risk for other cancers which include > risk of PC 2) known hereditary disease which causes inflammation of the pancreas leading to > risk of PC 3) familial pancreatic cancer (a clustering of pancreatic cancer in 2 or more first degree relatives) in which the underlying genetic cause is not yet known.

1- Hereditary Cancer Syndromes

Hereditary Breast and Ovarian Cancer (HBOC) BRCA1 and BRCA2 genes; autosomal dominant. Clinical features include significantly increased risks of breast, ovarian, and prostate cancer. The general population prevalence of BRCA1/2 mutations is ~1/800-1/2500 in non- Jewish individuals. BRCA2 mutations are the most common identifiable germline mutation in familial pancreatic cancer. BRCA2 mutations have been identified in ~17-19% of familial pancreatic cancer families (even in the absence of a family history of breast and/or ovarian cancer). BRCA2 mutations are associated with a ~4-8% lifetime risk of PC. The association between BRCA1 mutations and pancreatic Cancer is less clearly defined.

PALB2 (Partner and localizer of BRCA2) gene This new gene encodes a protein that functions in genome maintenance (double strand break repair). This protein binds to and colocalizes with the BRCA2 protein in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. Germline mutations in the PALB2 gene have been identified in ~3-4% of familial pancreatic cancer cases. Mutations in the PALB2 gene are associated with an increased risk of pancreatic and female breast cancers. The exact cancer risks associated with PALB2 mutations are not well defined at this time.

Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) FAMMM is due to germ-line mutation in CDKN2A (p16) gene. CDKN2A plays an important role in cell cycle regulation and acts as a tumor suppressor. Autosomal dominant. Clinical features include multiple skin nevi, increased risk of melanoma including melanoma at an earlier than average age and multiple primary melanomas, and an increased risk of pancreatic cancer. CDKN2A mutations are associated with a ~10-19% risk of PC.

Lynch Syndrome/ Hereditary Non- polyposis Colorectal Cancer (HNPCC) Due to defect in Mismatch repair genes (MLH1, MSH2, MSH6, PMS2) Autosomal dominant Clinical features include significantly increased risk of colon, uterine, ovarian, other gastrointestinal, and urinary tract cancers and sebaceous adenomas and carcinomas. The incidence of Lynch syndrome in the general population is ~1/200-1/1000. Association of PC with HNPCC is less clear but recent data suggest a ~3.7% lifetime risk.

Peutz-Jeghers Syndrome (PJS) Due to germ-line mutations in STK11 (Serine/threonine kinase 11 ) gene Autosomal dominant The incidence of PJS is ~1/25,000-1/280,000. Clinical features include hamartomatous polyps throughout the gastrointestinal tract, distinctive mucocutaneous hyperpigmented macules of the lips, mouth, buccal mucosa, hands, and feet, and increased risk of intestinal and extraintestinal tumors and cancers (e.g. colorectal, breast, gynecologic, gastric). Patients with PJS have a lifetime risk of ~11-36% to develop PC.

Familial adenomatous polyposis (FAP) It is an inherited condition due to APC gene germ-line mutations. APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumors. Autosomal dominant Clinical features include numerous polyps form mainly in the epithelium of the colon with the incidence rate of malignancy near 100, when left untreated. An increased risk of thyroid (~2%), small bowel (5-10%), pancreatic (~2%), and stomach cancers (~0.5%), brain tumors (<1%) and hepatoblastoma (~1.6%)

Li-Fraumeni Syndrome (LFS) LFS is caused by an germ-line mutation in “TP53” gene. Autosomal dominant TP53 gene is responsible for initiating DNA repair mechanisms and/or apoptosis upon detection of DNA damage; so it has been described as "the guardian of the genome" The frequency of new (de novo) TP53 mutations is estimated to be at least 7% and may be as high as 20%. persons with Li–Fraumeni syndrome have an approximately 25-fold increased risk of developing a malignant tumor by age 50 than the population average. They are at risk for a wide range of malignancies, with particularly high occurrences of breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, bone sarcomas, pancreatic, and adrenal cortical carcinoma.

2. Hereditary Diseases Associated with an Increased Risk of Pancreatic Cancer

Hereditary Pancreatitis (HP) Primarily due to mutations in the PRSS1 (Trypsin-1, cationic trypsinogen) gene. Trypsin-1 is the main isoform of trypsinogen secreted by pancreas. Autosomal dominant. Clinical features include recurrent pancreatitis, often beginning in the teenage years, and leading to chronic pancreatitis in late adolescence to early adulthood % lifetime risk of PC. Smoking is associated with a further increase in risk and younger age of onset of PC. Rare and accounts for a small percentage of pancreatic cancer cases (In Europe, its prevalence is estimated to be 3 to 6 per million individuals).

Cystic Fibrosis (CF) Due to mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. CFTR is an ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes. Autosomal recessive Characterized by chronic obstructive lung disease and pancreatic insufficiency. Median age at diagnosis is 6-8 months; however, age at diagnosis varies widely. Patients with CF may have an increased risk of pancreatic cancer and may be diagnosed at very young ages (cases have been reported in individuals in their teens to twenties). Incidence of CF is 1 in 2,500 newborn, with calculated carrier frequency of 1 in 25.

Referral for Genetic Counseling It should be considered for individuals with a personal and/or family history that includes any of the following risk factors: 1) Multiple cases of pancreatic cancer on the same side of the family. 2) A combination of related cancers on the same side of the family (e.g. pancreatic/breast/ovarian, pancreatic/melanoma, or pancreatic/colon/uterine/ovarian). 3) Multiple related primary cancers in one individual (e.g. pancreatic/ melanoma, pancreatic/breast). 4) Ashkenazi Jewish ancestry and pancreatic cancer. 5) Pancreatic cancer and multiple and/or early onset gastrointestinal polyps including more than 15 gastrointestinal polyps or more than 5 hamartomatous polyps.

Screening for Individuals at Increased Risk Routine population screening for pancreatic cancer is not of practical use. Some data suggest that screening may prove valuable in individuals at high risk by detecting lesions at an earlier, treatable stage. The optimal screening method for pancreatic cancer is still unclear. Consideration of screening, particularly in the setting of a research protocol, is recommended for individuals with a greater than 10-fold increased risk to develop pancreatic cancer beginning at age or years younger than the youngest relative with pancreatic cancer or at age 30 for individuals with PJS.

Screening should be considered for individuals meeting the following criteria: 1) Diagnosis of PJS or hereditary pancreatitis. 2) A known BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, or PMS2 mutation and one or more first or second degree relatives with pancreatic cancer. 3) A family history of 2 or more relatives with pancreatic cancer on the same side of the family including at least one first degree relative of the individual having screening.

References 1. SEER Stat Fact Sheets: Pancreas. Retrieved August 9, 2011 from 2. Greer JB, Lynch HT, and Brand RE (2009). Hereditary pancreatic cancer: A clinical perspective. Best Practice and Research Clinical Gastroenterology 23: Gover S and Syngal S (2010). Hereditary pancreatic cancer. Gastroenterology.139: Reider H and Bartsch DK (2004). Familial pancreatic cancer. Familial Cancer 3: Petrucelli N et al (2011) BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. 6. Retrieved August 16, 2011 from 7. Murphy KM et al (2002). Evaluation of candidate genes MAP2K4, MADH4, ACVR1B,and BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%. Cancer Research 62: Habbe N et al (2006). Familial pancreatic cancer syndromes. Endocrinology and Metabolism Clinics of North America 35: Advances: Cancer Genetic Counseling. Yale Cancer Center. Oct 2011

کرایتریاهای کلی ارجاع جهت مشاوره ژنتیک سرطان ابتلای فرد یا حداقل یکی از بستگان نزدیک وی به یکی از انواع سرطان یا پولیپ گوارشی در سن کمتر از 50 سال ابتلای یکی از بستگان نزدیک فرد به سرطان های تخمدان و لوزالمعده در هر سنی بروز انواع بسیار نادر سرطان در خانواده بروز سرطان های مشابه در چند نفر از افراد فامیل ( در بستگان پدری یا مادری ) بروز بیش از یک نوع سرطان در هر یک از اعضای خانواده اثبات وجود یک جهش ژنی شناخته شده مرتبط با سرطان در خانواده وجود سرطان و یا پولیپ در کولون سمت راست

شماره تماس مرکز مشاوره و تشخیص ژنتیک سرطان مؤسسه پورسینای حکیم : دکتر زینلیان

Thanks a lot for your attention