W8LECT - GENETICS OF BIOLOGICAL PROCESSES Flashcards

Question

I. GENETICS OF DEVELOPMENT - Governing molecules I. 17. What are the features of Homeobox genes?

Answer 1

1. Hox genes (homeobox sequence) 2. 60 AA, helix-turn-helix structure proteins 3. Positional information – longitudinal axis 4. Max. 13 box 5. Spatial colinearity

Answer 2

1. Coding triplet repeats 2. Polyalanine disorder

Answer 3

- Lower hedgehog singing results in cyclopia. - Interactions between morphogens and HOX genes: mutations in SHH and HOXD: holoprosencephaly.

Answer 4

the course of an individual’s life

Answer 5

abnormal crossing-over during male gametogenesis (meiosis I)

Answer 6

1. 46 XX male - SRY is transferred to chromosome 2. 46 XY female - SRY is lost from Y chromosome

Answer 7

1. X-linked recessive hereditary disease 2. XY genotype 3. normal serum testosterone level 4. female external sexual characteristics 5. sterile 6. testosterone receptor mutation

Answer 8

1. Anosmia (lack of sensing smell) 2. hypogonadotrop- hypogonadism 3. Delayed puberty 4. Treated with hormone replacement therapy

Answer 9

1. Mutations in KAL1 gene (among others) 2. X chromosome, PAR1 3. Encodes a cell adhesion protein which has a role in neuronal migration 4. Part of these stem cells migrate to the olfactory nerve, another part to the hypothalamus during development. 5. No gonadotropin-releasing hormone (GHRH): failure in gonadal differentiation

Answer 10

- CYP21A2 mutation - male genitals in the case of girl babies,in male babies, an enlarged penis, slow rate of weight gain, weight loss, dehydration (dehydration), male pattern hair and deep voice (virilisation) in female patients)

Answer 11

1. In our lives, there is about 40% chance of developing cancer of any type 2. Tumors are in only <10% of Mendelian inheritance, but the GENOTYPE (genetic background) AFFECTS OUR OVERALL CANCER RISK (complex trait/disease). 3. A multi-stage process; characterized by accumulation of somatic mutations, derived from one cell (clonality).

Answer 12

- On average, each cancer genome carries four or five driver mutations, which provide cancer cells with a selective advantage. - Only 5% of tumors studied had no identified driver aberrations. - Many cancers exhibited hallmarks of genomic catastrophes called chromoplexy (17.8% of tumours) and chromothripsis (22.3%), which result in major structural changes to the genome.

Answer 13

A change in the DNA sequence that can be inherited from either parent

Answer 14

- A change in the DNA sequence in cells other than sperm or egg - The mutation is present in the cancer cell and its offspring, but not in the patient’s healthy cells

Answer 15

- Most cancer is the result of acquired, or somatic, mutations that occur in a cell. - Cancers that occur because of somatic mutations are referred to as sporadic cancers. - Somatic mutations are often caused by environmental and lifestyle - Cancers caused by germline mutations are called hereditary cancers and account for 5-10% of all cancers.

Answer 16

- Cancers that occur because of somatic mutations

Answer 17

Cancers caused by germline mutations are called hereditary cancers and account for 5-10% of all cancers.

Answer 18

- Multistep carcinogenesis, a series of successive mutations, some of which contribute to tumour growth/persistence (evolutionary advantage => these are driver mutations (x) - Other sequence changes occur randomly, but play no role in tumour evolution (passanger mutations)

Answer 19

- Germline mutations are inherited and present in all cells of the body - Tumor formation can affect multiple organs (tumor syndromes) - The first step of multistep tumor formation is already given, less time is needed +) usually appears at a younger age +) but it is 'only' a predisposition, the occurrence of further mutations is not a matter of course: inherited variation often influences the type of mutations that occur later +) often a distinctive 'final' mutation spectrum and distinctive pathological/biological presentation - the possibility of individual therapy

Answer 20

1. Only 5 –10% of cancer cases have a clear hereditary component 2. e.g. BRCA1 and BRCA2 in breast cancer 3. Even in those cases where susceptibility is clearly inherited, somatic changes are required for cancer to develop

Answer 21

1. Driver mutation: confers a selective growth advantage 2. Passenger mutation: has no effect on the fitness of a clone

Answer 22

FALSE! => The majority of cancer is caused by somatic mutations.

Answer 23

- Many protein-coding driver mutations occur in single-site ‘hotspots’. - The most frequently mutated sites were well- studied hotspots in cancer genes

Answer 24

- In colorectal adenocarcinoma, for example, it were find APC mutations to have the highest odds of occurring early, followed by KRAS, loss of 17p and TP53, and SMAD4 - Whole-genome duplications occur after tumors have accumulated several driver mutations, and many chromosomal gains and losses are typically late.

Answer 25

1. Oncogenes 2. Tumor suppressor genes 3. Mutator genes

Answer 26

Dominant mutations, usually somatic

Answer 27

recessive mutation in cellular level, but they often result in a dominantly inherited predisposition

Answer 28

- play a role in DNA repair, germline and somatic mutations. - Dominantly inherited predisposition or AR tumorigenic syndrome may be caused

Answer 29

- a gain-of-funtion mutation of a proto-oncogene, which leads to an oncogene or - a loss-of-function mutation of a tumor suppressor gene. => The loss-of-function mutations are more common than the gain of function mutations, even if both alleles are mutated.

Answer 30

1. Proto-oncogene - Def.: genes that regulate cell division => Normal cell division 2. Ocogene - Def: mutated or over-expressed proton-oncogene => Uncontrolled cell division leading to tumor formation

Answer 31

- Mutations in the Ras genes (Hras, Nras, Kras) are the most frequent oncogenic mutations - Gly12Val point mutation in the Ras genes → the ability of the active Ras protein to hydrolyze GTP decreases → signalling is continuously active, independently of the external ligands → proliferation ↑

Answer 32

- The main cause tumor suppression is the LOH = loss of heterozygosity. - The most common mutations in tumors affect: +) the RAS oncogene +) the P53 tumor suppressor gene (they occur in > 60% of all cancers).

Answer 33

- The tumor suppressor p53 is found mutated in roughly 60% of human cancers! - Inheritance of one mutant p53 allele results in the Li-Fraumeni syndrome, in which a rare form of cancer develops in several tissues - Tumors arise when the 2nd allele is mutated, so the trait is inherited as autosomal recessive

Answer 34

- Retinoblastoma is the most common eye tumor in children; surgery and radiation is effective (90% - 2 forms of Retinoblastoma: unilateral and bilateral.

Answer 35

- Unilateral, sporadic retinoblastoma develops in children with no family history

Answer 36

Bilateral, hereditary retinoblastoma is the paradigm of Alfred Knudson’s two- hit mutation model, stating two mutations are required for RB development

Answer 37

- Cancer is caused by mutations, so factors that increase mutation rate will increase cancer rate. - Many environmental factors (carcinogens) also cause DNA damage or mutations, that can lead to cancer

Answer 38

BRCA1 and BRCA2

Answer 39

- Philadelphia chromosome = t(9;22) - BRC-ABL fusion – increased tyrosine-kinase activity - CML and ALL - Medication: Gleevec (Imatinib)

Answer 40

1. Epigenetic inactivation 2. Epigenetic depression

Answer 41

- Oncogenes – e.g. IGF2 (insulin-like growth factor = somatomedin A) - In normal cells only the paternal allele is expressed. - In colon cancer the maternal allele is expressed, as well. - relationship between oncogenes and epigenetics

Answer 42

DNA oncoviruses (e.g. human papilloma virus (HPV) typically cause cancer by inactivating p53 and Rb, thereby inhibiting the function of these tumor suppressors.

Answer 43

HPV: infects the mucosa and underlying progenitor cells. Depending on the subtype of the virus cervix or head and neck cancer risk increases.

Answer 44

Tumour heterogeneity : - existence of subpopulations of cells, with distinct genotypes and phenotypes - divergent biological behaviours, within a primary tumor and its metastases, or between tumours of the same histopathological subtype (intra- and inter- tumour, respectively).