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Pregnancy after cancer A genetic risk for the offspring?
 

Pregnancy after cancer A genetic risk for the offspring?

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    Pregnancy after cancer A genetic risk for the offspring? Pregnancy after cancer A genetic risk for the offspring? Document Transcript

    • Pregnancy after cancer A genetic risk for the offspring? Maryse Bonduelle, MD PhD 30-10-2008 Herhaling titel van presentatie 1 Pregnancy after cancer -Is the cancer possibly related to a genetic syndrome? -Is cancer in the parents related to a higher cancer risk for the offspring? -Is the therapy for cancer a genetic risk for the offspring? Herhaling titel van presentatieHeidelberg 2 30-10- 200815/11/ Hereditary cancer syndromes - Appearing in childhood - Appearing in adulthood Herhaling titel van presentatieHeidelberg 3 30-10- 200815/11/
    • Hereditary Cancer Syndromes in Childhood Cancer Syndrome Gene Retinoblastoma RB1 Wilms tumor WT1, others Familial adenomatous polyposis APC Multiple endocrine neoplasia type 2 RET Li-Fraumeni TP53 Von Hippel-Lindau VHL Nevoid basal cell carcinoma PTC Herhaling titel van presentatieHeidelberg 4 30-10- 200815/11/ Nonheritable vs Heritable Retinoblastoma 1/20 000 Feature Nonheritable Heritable Tumor Unilateral Usually bilateral Family history None 20% of cases Average age at dx ~2 years <1 year Increased risk of No Osteosarcoma, second primaries other sarcomas, melanoma, others Herhaling titel van presentatieHeidelberg 5 30-10- 200815/11/ Wilms Tumor 1/ 10 000 children Childhood kidney cancer arising from embryonic cells Occurs in heritable and non-heritable forms Multiple genes involved True familial Wilms tumor rarely observed Sporadic, Bilateral (presumed unilateral heritable) ~5%–7% >90% Familial ~1% Herhaling titel van presentatieHeidelberg 6 30-10- 200815/11/
    • Genetic Heterogeneity in Wilms Tumor Syndromes Locus Syndrome WT1 gene at 11p13 Denys-Drash 11p13 region WAGR 11p15 region Beckwith-Wiedemann Xq26 Simpson-Golabi-Behmel 17q12-21 Familial Wilms 19q13 Familial Wilms Herhaling titel van presentatieHeidelberg 7 30-10- 200815/11/ Hereditary cancer syndromes - Appearing in childhood - Appearing in adulthood Herhaling titel van presentatieHeidelberg 8 30-10- 200815/11/ Hereditary Cancer Syndromes in Adulthood Frequent syndromes with cancer susceptibility – BRCA1/2 genes – HNPCC – FAP – Melanoma – Rare syndromes Indications for predictive testing of cancer genes Herhaling titel van presentatieHeidelberg 9 30-10- 200815/11/
    • Common Familial Cancer Syndromes: Autosomal Dominant Disorders Common 1-10% of these cancers in the general population Hereditary breast/ovarian cancer: BRCA1, BRCA2 Hereditary breast / ovarian cancer accounts for 5 -10% of cases Hereditary colorectal cancer: HNPCC, FAP Hereditary colorectal cancer accounts for 5% of all cases. HNPCC (hereditary nonpolyposis colon cancer) and FAP (familial adenomatous polyposis) account for most of the hereditary cancers. Familial Melanoma, with or without dysplastic nevi: 5 to 7% of patients are from genetically high risk families. Herhaling titel van presentatieHeidelberg 10 30-10- 200815/11/ How Much Breast and Ovarian Cancer is Hereditary? 10%–15% 5%–10% 5%–10% Breast Cancer Ovarian Cancer Sporadic Familial cluster Inherited breast and ovarium Herhaling titel van presentatieHeidelberg 11 30-10- 200815/11/ Causes of Hereditary Susceptibility to Breast Cancer Contribution to Hereditary Gene Breast Cancer BRCA1 20%–40% BRCA2 10%–30% TP53 <1% PTEN <1% Undiscovered genes 30%–70% Herhaling titel van presentatieHeidelberg 12 30-10- 200815/11/
    • BRCA1-Associated Cancers: Lifetime Risk Breast cancer 50%-85% (often early age at onset) Second primary breast cancer 40%-60% Ovarian cancer 15%-45% Possible increased risk of other cancers (eg, prostate, colon) Herhaling titel van presentatieHeidelberg 13 30-10- 200815/11/ BRCA2-Associated Cancers: Lifetime Risk breast cancer (50%-85%) male breast cancer ovarian cancer (6%) (10%-20%) Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown) Herhaling titel van presentatieHeidelberg 14 30-10- 200815/11/ Comparing Breast Cancer Risk Estimates in BRCA Mutation Carriers 100 BRCA1+ carriers (BCLC) 80 Breast cancer risk 60 BRCA1+ carriers (%) (Ashkenazi Jews) 40 20 General population 0 40 50 60 70 80 Easton DF et al. Am J Hum Genet 56:265, 1995 Age Struewing JP et al. N Engl J Med 336:1401, 1997
    • Other Genetic Conditions Associated With Increased Breast Cancer Risk Syndrome Gene Mutation Li-Fraumeni TP53 Cowden PTEN Muir-Torre MSH2, MLH1 Peutz-Jeghers STK11 Herhaling titel van presentatieHeidelberg 16 30-10- 200815/11/ Hereditary colorectal cancer: HNPCC, FAP Hereditary colorectal cancer accounts for 5% of all cases • HNPCC hereditary non-polyposis colon cancer • FAP familial adenomatous polyposis account for most of these hereditary cancers HNPCC is much more common than FAP Herhaling titel van presentatieHeidelberg 17 30-10- 200815/11/ Hereditary colorectal cancer: HNPCC, FAP HNPCC Specific genes involved – MLH1, MSH2, PMS1, PMS2, and MSH6. Average age of diagnosis is 45 years – 2/3 occur in the right colon Lifetime risk of colorectal cancer is at least 80%. Endometrial adenocarcinoma in 30 - 60% of women Other gastrointestinal cancers – stomach, small bowel, and gallbladder) Genito-urinary cancers – kidney, ureter, and bladder) Ovarian cancer Herhaling titel van presentatieHeidelberg 18 30-10- 200815/11/
    • Hereditary colorectal cancer: HNPCC, FAP FAP: APC gene (adenomatous polyposis coli) accounts for 1% of colon cancer – mutations in APC gene on chromosome 5q21 Adenomatous polyps (>100) occur in the colon in more than 90% of gene carriers by age 20. Prevention prophylactic colectomy – Flexible sigmoidoscopy is recommended every one to two years, beginning at age 10 – 12 years. – Prophylactic colectomy Herhaling titel van presentatieHeidelberg 19 30-10- 200815/11/ Other genes in relation to intestinal cancer Hereditary Predominant Gene Syndrome Pattern Cancer Tumor suppressor genes APC FAP Dominant Colon, intestine, etc. AXIN2 Attenuated Polyposis Dominant Colon TP53 (p53) Li-Fraumeni Dominant Multiple (including colon) STK11 Peutz-Jeghers Dominant Multiple (including intestine) PTEN Cowden Dominant Multiple (including intestine) BMPR1A Juvenile Polyposis Dominant Gastrointestinal SMAD4 (DPC4) Juvenile Polyposis Dominant Gastrointestinal Herhaling titel van presentatieHeidelberg 20 30-10- 200815/11/ Repair/Stability genes hMLH1, hMSH2,hMSH6 Lynch syndrome Dominant Multiple (including PMS2 colon, uterus, and others) MYH (MutYH) Attenuated Recessive Colon Polyposis BLM Bloom Recessive Multiple (including colon) Oncogenes KIT Familial GI GI stromal tumors Stromal Tumor PDGFRA Familial GI GI stromal tumors Stromal Tumor Adapted from Vogelstein et al. Herhaling titel van presentatieHeidelberg 21 30-10- 200815/11/
    • Familial Melanoma, with or without dysplastic naevi: Genes involved – CMM1, CMM2, (CDKN2), CDK4. Approximately 5 to 7% of patients are from genetically high risk families. – They are characterized by invasive melanoma in at least two first degree relatives. – Some have 10 to 100 moles on upper trunk and limbs. Prevention – Monthly skin exams, twice yearly dermatologic evaluation and early excision of suspicious lesions Herhaling titel van presentatieHeidelberg 22 30-10- 200815/11/ Uncommon hereditary cancers Basal cell nevus syndrome Neurofibromatosis type 1 Carney syndrome Neurofibromatosis type 2 Osteochondromatosis Paraganglioma Chordoma Peutz-Jeghers syndrome Cowden syndrome Prostate cancer, familial Esophageal cancer with tylosis Retinoblastoma Gastric cancer, familial Tuberous sclerosis Renal cancer, familial von Hippel-Lindau disease Li-Fraumeni syndrome Wilms' tumor Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Gene frequency is often unknown Cancers are uncommon in the general population Herhaling titel van presentatieHeidelberg 23 30-10- 200815/11/ Group 1 - Genetic test result will change medical care and is standard management Examples Gene Familial adenomatous polyposis APC Multiple endocrine neoplasia 2 RET Multiple endocrine neoplasia 1 MEN1 Retinoblastoma RB1 Von Hippel-Lindau disease VHL Herhaling titel van presentatieHeidelberg Modified from ASCO Statement. J Clin Oncol 14:1730, 1996 24 30-10- 200815/11/
    • Group 2 - Possible medical benefit in the identification of a germline mutation Examples Gene(s) Hereditary nonpolyposis MLH1,MSH2, MSH6, colorectal cancer PMS1, PMS2 Hereditary breast and BRCA1, BRCA2 ovarian cancer Li-Fraumeni syndrome TP53 Cowden syndrome PTEN Modified from ASCO Statement. J Clin Oncol 14:1730, 1996 Herhaling titel van presentatieHeidelberg 25 30-10- 200815/11/ MEN 1 and MEN 2 Are Distinct Hereditary Cancer Syndromes MEN 1 MEN 2 Anterior pituitary Thyroid C-cells Parathyroid Parathyroid Adrenal cortex Adrenal medulla Pancreatic islets Germline Germline mutations in MEN1 mutations chr 11 in RET, chr 10 Herhaling titel van presentatieHeidelberg 26 30-10- 200815/11/ Von Hippel-Lindau Disease Autosomal dominant inheritance VHL gene maps to chromosome 3p25.5 Multiple tumor types – renal cell carcinoma – retinal angioma – cerebellar hemangioblastoma – pheochromocytoma – pancreatic cysts, islet cell tumors – epididymal cystadenoma Herhaling titel van presentatieHeidelberg 27 30-10- 200815/11/
    • Li-Fraumeni Syndrome Rare autosomal dominant syndrome Early onset of bone and soft tissue sarcomas, breast cancer, brain cancer, leukemia, adrenocortical carcinoma, and other tumors Multiple primary tumors TP53 germline mutations associated with most cases Testing in children and adults raises important ethical and psycho-social issues Herhaling titel van presentatieHeidelberg 28 30-10- 200815/11/ Pregnancy after cancer -Is the cancer possibly related to a genetic syndrome? -Is cancer in the parents related to a higher cancer risk for the offspring? -Is the therapy for cancer a genetic risk for the offspring? Herhaling titel van presentatieHeidelberg 29 30-10- 200815/11/ Familial risk in common cancers1 Cancer in probands risk in offspring (15-53y) • high FHR2 >5 – Thyroid cancer FHR 10.7; CI 95% 6.9-16.6 – Testicular cancer FHR 5.4; CI 95% 2.6-11.3 • intermediate FHR 2-5 – Colon, rectal, lung, breast, cervical, uterine, ovary, skin • low FHR <2 - stomach, renal , nervous system, lymphoma, leukemia 1Hemminki 2FHR familial hazard ratio et al. Int J Cancer 1998 Herhaling titel van presentatieHeidelberg 30 30-10- 200815/11/
    • Familial risk in common cancers1 Cancer in probands < 50y increased risk for the children of • breast, renal, skin (melanoma), nervous system, thyroid, endocrine gland in young persons <40y • colon, rectal, ovarian but not at young age 1Hemminki et al. Int J Cancer 1998 Herhaling titel van presentatieHeidelberg 31 30-10- 200815/11/ Pregnancy after cancer -Is the cancer possibly related to a genetic syndrome? -Is cancer in the parents related to a higher cancer risk for the offspring? -Is the therapy for cancer a genetic risk for the offspring? Herhaling titel van presentatieHeidelberg 32 30-10- 200815/11/ Cancer therapy in parents • Chemotherapy and radiotherapy can be mutagenic to animal and human germ cells (most data derived from animal studies) • Damage to germ cells might influence fertilization, increase rate of abortion and cause malformation in men previously exposed to cancer treatments • Chemotherapy and radiotherapy during pregnancy can be teratogenic to the offspring Herhaling titel van presentatieHeidelberg 33 30-10- 200815/11/
    • Cancer therapy in parents • In human often multiple drug administration • Most data indicate that radiotherapy and chemotherapy are mutagenic • to female and male germ cells at various stages of maturation • Monitoring of human offspring indicates no increase in foetal chromosomal or congenital anomalies • How to explain discrepancy? Herhaling titel van presentatieHeidelberg 34 30-10- 200815/11/ No increase in foetal chromosomal or congenital anomalies? How to explain discrepancy? • Mutated spermatozoa may not be able to fertilize the oocyte • If fertilization occurs dominant lethal mutations may result in undetected miscarriage • Correction mechanism ?? (Host et al. 2000) - in the oocyte to correct for chromosomal anomalies in sperm - to correct mutations in the oocyte • Trend to decreased frequency of chromosomal anomalies long time after chemotherapy - Removal of the damaged sperm cells? Herhaling titel van presentatieHeidelberg 35 30-10- 200815/11/ Cancer therapy in parents Combined chemotherapy • MOPP chromosomal non-dysjunction 3 y after therapy mutagenic non correctable effects (Brandriff 1994) • BEP in testicular cancer chromosomal aneuploidy detected with FISH (Martin et al. 1999) • NOVP FOR Hodgkin patients transient sperm aneuploidy with FISH no increase after 9 months (Martin et al. 1995) • Large doses can overwhelm repair mechanisms explanation for differences in long term effects Herhaling titel van presentatieHeidelberg 36 30-10- 200815/11/
    • Cancer therapy in parents Male cancer patients • ICSI with semen from recovered patients (after chemo or radiotherapy) - No increase in malformation observed • ICSI can bypass natural selection process Caution if ejaculates used for IVF/ICSI Herhaling titel van presentatieHeidelberg 37 30-10- 200815/11/ Cancer therapy in parents Former female cancer patients • No increase in congenital anomalies or miscarriage • If IVF shorter span between chemo and pregnancy - Graafian follicle 6 months of growth - Safe period before oocyte retrieval and IVF? Monitoring of chromosomal aberration and birth defects Herhaling titel van presentatieHeidelberg 38 30-10- 200815/11/ Conclusions • Cancer susceptibility syndromes are monogenic disease - high recurrence risk - mostly autosomal dominant - penetrance and age of onset variable - Ex. BRCA, HNPCC, FAP, NF1 etc PGD possible Herhaling titel van presentatieHeidelberg 39 30-10- 200815/11/
    • Conclusions • In familial cancer Long–life surveillance in offspring • After treatment of oncological problems in father or mother Prenatal surveillance – Karyotype; Ultrasound Herhaling titel van presentatieHeidelberg 40 30-10- 200815/11/