DR. Mojibina

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The availability and acceptability of early invasive diagnostic methods (eg, chorionic villus sampling)

The continued need for second trimester screening for open fetal neural tube defects

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Women with singleton pregnancies underwent: first-trimester combined screening:◦measurement of nuchal translucency◦pregnancy-associated plasma protein A

[PAPP-A]◦ The free beta subunit of human chorionic

gonadotropin (HCG) at 10 weeks 3 days through 13 weeks 6 days of gestation

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maternal age was combined with fetal NT

and maternal serum biochemistry (free β-hCG and pregnancy-associated plasma protein (PAPP-A))

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◦measurement of:alpha-fetoprotein total human chorionic gonadotropinunconjugated estriol inhibin A at 15 through 18 weeks of

gestation

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This is a new technique use of the phenomenon of fetal blood cells gaining

access to maternal circulation through the placental villi

only a very small number of fetal cells enter the maternal circulation in this fashion

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fetus has two major blood proteins: albumin and alpha-fetoprotein (AFP) Since adults typically have only albumin in their blood the MSAFP test can be utilized to determine the levels

of AFP from the fetus

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the gestational age must be known with certainty

the amount of MSAFP increasses with gestational age

the MSAFP can be elevated for a variety of reasons

which are not related to fetal neural tube or abdominal wall defects, so this test is not 100% specific

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a neural tube defect in the fetus:from failure of part of the

embryologic neural tube to close there is a means for escape of more

AFP into the amniotic fluid

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Neural tube defects (NTD): second most prevalent congenital anomaly in the United States

Two factors have played a significant role in the prevention of this disorder in developed countries: ◦Sonographic imaging combined with

amniocentesis for diagnosis of affected fetuses ◦folic acid supplements for prevention of the

disorder

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The frequency of NTDs is increased with exposure to certain environmental factors:◦ drugs (valproic acid, carbamazepine, Folic acid deficiency)◦ diabetes mellitus◦Obesity

Adequate folate is critical for cell division due to its essential role in the synthesis of:◦ nucleic◦ certain amino acids

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the observations that NTDs have a high rate:◦ in monozygotic twins◦ more frequent among first degree relatives◦ more common in females than males

The risk of recurrence for NTDs: approximately 2 to 4

percent when there is one affected sibling

With two affected siblings, the risk is approximately: 10 percent

The risk of NTD according to family history:◦ to be higher in countries such as Ireland where the prevalence if

NTDs is high

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The genetic polymorphisms : mutations in the methylene tetrahydrofolate reductase gene may increase the risk for NTDs Folate is a cofactor for this enzyme which is part of the pathway of homocysteine metabolism in

cells The C677T and the A1298C mutations are associated with

elevated maternal homocysteine concentrations and an increased risk for NTDs in fetuses

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can be accomplished by supplementation of the maternal diet with only 4 mg of folic acid per day

but this vitamin supplement must be taken a month before conception and through the first trimester

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This test is most commonly used as a test for pregnancy

Later in pregnancy: in the middle to late second trimester

the beta-HCG can be used in conjunction with the MSAFP to screen for chromosomal abnormalities, and Down syndrome in particular

An elevated beta-HCG coupled with a decreased MSAFP suggests Down syndrome

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made by the fetal adrenal glands

Estriol tends to be lower when Down syndrome is present

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An increased level of inhibin-A is associated with an increased risk for trisomy 21

A high inhibin-A may be associated with a risk for preterm delivery

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BRCA1 AND BRCA2 GENES

Breast cancer develops in about12 percent of women who live to age 90

a positive family history is reported by 15 to 20 percent of women with breast cancer

Just only 5 to 6 percent of all breast cancers are associated with an inherited gene mutation

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Two major susceptibility genes for breast cancer, BRCA1 and BRCA2

Testing for mutations in these genes, is available

Clinicians and patients must decide when it is appropriate to screen for their presence

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As an essential part of the normal mechanisms that repair double-strand DNA breaks (ionizing radiation and DNA cross linking agents such as cisplatin)

through recombination with undamaged, homologous DNA strands

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Cisplatin is a platinum-based chemotherapy drug

used to treat various types of cancers, such as sarcomas, some carcinomas, lymphomas and germ cell tumors

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works by crosslinking across DNA inter-strands making it impossible for rapidly dividing cells to

duplicate their DNA for cell division (mitosis) The damaged DNA sets off DNA repair mechanisms

which fails to work so in turn activate cell death processes (apoptosis)

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The reason why BRCA mutations predispose mainly to breast and ovarian cancers is unclear

intact BRCA1 represents a barrier to transcriptional activation of the estrogen receptor

that functional inactivation could lead to altered hormonal regulation of mammary and ovarian epithelial proliferation

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Cancer risk with a high penetrance

women who have inherited mutations

the lifetime risk of breast cancer is between 65 and 85 percent by age 70

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Ovarian cancer is also linked to the presence of BRCA mutations

the lifetime risk of ovarian cancer: ◦ between 45 and 50 percent in women who have a deleterious

BRCA1 mutation◦ and 15 to 25 percent for those with a BRCA2 mutation

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prostate cancer male breast cancer pancreatic cancer Although the risk of male breast cancer and pancreatic

cancer may be under 10 percent the risk of prostate cancer in BRCA2 carriers may be as

high as 35 to 40 percent

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The gene Locus for BRCA1: 17q21a large gene24 exons encoding a 220 kD 1863 amino acidsTwo recognizable motifs

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BRCA2 (13q12.3)was identified by Wooster et al. in 1995 It encodes for 384 kD nuclear protein3418 amino acidsBRCA2 bears no homology to any known

tumour supressor genescontains 27 exons spread over 70 kb of genomic DNA

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Degree of relatedness to affected relatives Number of affected relatives The age of the relative(s) when breast cancer occurred Laterality of the disease in affected relatives Whether there is a family history of ovarian cancer

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Screening for colorectal cancer

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Colorectal cancer (CRC) is ◦ a common◦ Lethal◦ preventable disease

It is infrequent before age 40 the incidence rises progressively to 3.7/1000 per year

by age 80

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Before deciding how to screen: clinicians should decide whether the individual patient is at

average or increased risk based on his or her medical and family history A few simple questions are all that is necessary: Have you ever had colorectal cancer or an adenomatous polyp Have you had inflammatory bowel disease (Crohn disease) Has a family member had colorectal cancer or an adenomatous

polyp If so, how many was it a first-degree relative (parent, sibling, or child) and at what age was the cancer or polyp first diagnosed

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an inflammatory bowel diseasecauses inflammation of the

gastrointestinal tract in both men and women

persistent diarrhea, abdominal pain, fever, and at times rectal bleeding

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Patients at highest risk with familial syndromes (HNPCC, FAP)

should be screened for CRC with colonoscopy at frequent specified intervals

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a first-degree relative with colon cancer or adenomatous polyp diagnosed at age <60 years or two first-degree relatives diagnosed at any age should be advised to have screening colonoscopy

starting at age 40 years or 10 years younger than the earliest diagnosis in

their family whichever comes first, and repeated every five years

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•Hereditary nonpolyposis colorectal cancer (HNPCC)•the most common of the well-defined colorectal cancer syndromes•accounting for at least 2% of the total colorectal cancer •carrying a greater than 80% lifetime risk of cancer

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can be detected in approximately 90% of tumors from individuals with Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

MSI is also reported in approximately 15% of sporadic colorectal carcinomas

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responsible for the MSI of the HNPCC tumors In contrast to the classical tumor suppressor pathway the mismatch-repair gene tumor pathway accumulates

mutations in genes involved in tumorigenesis

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can be accomplished by appropriate clinical cancer screening of HNPCC patients with mutations in mismatch repair (MMR) genes

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In individuals with cancer mutation detection can be accomplished relatively

efficiently by germline mutation analysis of individuals (blood) whose cancers show microsatellite instability (MSI)

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Among 378 adenoma patients six (1.6%) had at least one MSI adenoma Five out of the six patients (83%) had a germline MMR gene

mutation MSI analysis is a useful method of prescreening colorectal

adenoma patients for HNPCC

Microsatellite Instability in Adenomas as a Marker for Hereditary Nonpolyposis Colorectal Cancer

Anu Loukola et al. American Journal of Pathology. 1999;155:1849-1853

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Cells deficient for both alleles of a mismatch repair gene, leading to somatic mutations

which can be demonstrated by analyzing microsatellite sequences in the tumor DNA

These sequences display frequent somatic deletions and insertions, often referred to as microsatellite instability (MSI).

HNPCC patients form adenomas at a slightly but not strikingly increased rate as compared with the general population

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The frequency of the MSI is 80 to 95% in HNPCC cancers

10 to 15% in sporadic colorectal cancers

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The presence of the factor V mutation can cause an increased risk of venous thrombosis

Individuals heterozygous for the Factor V Leiden (FacV) mutation :◦ carry an eight-fold greater risk for thrombosis◦while homozygosity confers an estimated ninety-fold

increased risk

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The most extensively studied biomarker of inflammation in cardiovascular diseases

serum C-reactive protein (CRP)

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Elevated serum CRP was a strong independent risk factor for cardiovascular disease

added to the predictive value of other factors, such as serum total cholesterol

Elevated serum CRP was a stronger predictor of cardiovascular events than LDL cholesterol (LDL-C) At eight years

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Although mortality from coronary heart disease (CHD) has fallen substantially over the past three decades

it remains the leading cause of death in adults

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risk factors for CHD, including:◦Hypertension◦Hypercholesterolemia◦Smoking◦a family history of premature CHD◦and diabetes mellitus

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The Association Between Apolipoprotein E

Polymorphism and Cardiovascular Risk Factors

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the allelic and genotypic frequencies related to apolipoprotein E (ApoE) polymorphism

association of the genotypes with risk factors

and cardiovascular morbidity in population

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the gene amplification technique through the polymerase chain reaction-restriction fragment length polymorphism

(PCR-RFLP) and cleavage with the restriction enzyme Hha I to identify the ApoE genotypes The most

frequent Individuals with the E3E4 had a mean age greater than

those with the E3E3

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Cystic fibrosis: Prenatal genetic screening

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Cystic fibrosis (CF) is a chronic pulmonary and exocrine pancreatic disease the most common monogenic disorder in

Caucasians of Northern European classic form it is marked by abnormal sweat

chloride levels chronic pulmonary disease pancreatic insufficiency liver disease and obstructive azoospermia in males

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an autosomal recessive disease with a carrier rate of 1 in 22 to 25 in Caucasian

Americans of Northern European background the most common mutation in this group is called

F508 and accounts for 75 percent of all CF cases

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The key to all CF screening is knowing which mutations to test for

knowledge of the most common CF mutations in individuals of different heritages

Native Americans are at increased risk of CF (carrier frequency 1 in 31

Jewish heritage (carrier rates ranging from 1 in 24 to 1 in 29 if the patient's ancestors originated in Greece, Bulgaria, or Libya)

to 1 in 90 if the ancestors originated in Iran or Iraq)

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The diagnosis and treatment is complicated: not everyone who is homozygous for the CF mutation has the

classic form of the disease Some individuals have an atypical presentation:◦pulmonary disease associated with pancreatic

sufficiency have only isolated features of the disease:◦ pancreatitis◦liver disease◦nasal polyps◦ congenital bilateral absence of the vas deferens

(CBAVD)

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hemoglobinopathies as two general types: ◦the thalassemias◦decreased globin chain production

hemoglobin variants (eg, sickle cell anemia and its variants, hemoglobin C disease)

chronic, debilitating, and often fatal new therapies:◦including hydroxyurea (XMNI, mRNA>active)◦hematopoietic cell transplantation◦ gene therapy

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Family history of a relative with a hemoglobinopathy or thalassemia

couples from extended families living in endemic areas consanguineous marriages are common, may be at

highest risk Ethnic background:◦ at low risk for hemoglobinopathies are

northern Europeans◦Japanese◦ Native Americans

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mean corpuscular volume (MCV) <80 femtoliters (fL), MCH< 28

in the absence of iron deficiency (alpha or beta thalassemia) Hemoglobin electrophoresis: this test will identify carriers:◦ hemoglobin variants ◦ beta thalassemia

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