Genetoc Aspect of Cancer

8/13/2019 Genetoc Aspect of Cancer

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Volgograd State MedUniversityMedical Genetics

TOPIC: GENETIC ASPECTS OF CANCER

PRESENTED BY: CHIA YIK LUEI

GROUP : 29, GENERAL MEDICINE


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Introduction

The etiology of cancer is multifactorial, with genetic,environmental, medical, and lifestyle factors interacting to prgiven malignancy.

Knowledge of cancer genetics is rapidly improving ourunderstanding of cancer biology, helping to identify at-risk

individuals, furthering the ability to characterize malignanciesestablishing treatment tailored to the molecular fingerprint odisease, and leading to the development of new therapeuticmodalities.


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Role of medical genetics in onco

Genetic information provides a means of identifying people who have an incancer. Sources of genetic information include biologic samples of DNA, infofrom a persons family of disease, findings from physical examinations, and

Family history may identify people with a modest to moderately increased may serve as the first step in the identification of an inherited cancer predisconfers a very high lifetime risk of cancer.

For an increasing number of diseases, DNA-based testing can be used to idemutation as the cause of inherited risk and to determine whether family meinherited the disease-related mutation.


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Role of gene mutations in cance

Mutations can have harmful, beneficial, neutral, or uncertain effects on heinherited as autosomal dominant, autosomal recessive, or X-linked traits.

if the mutation is autosomal recessive, the health effect of the mutation iswhen two copies of the mutated gene are inheritedmutation carriers, wrelatively common in the general population.

Many cancer-predisposing traits are inherited in an autosomal dominant fthe cancer susceptibility occurs when only one copy of the altered gene is


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Familial Cancer Susceptibility

Syndrome


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Theory of Familial CancerSusceptibilty Syndrome

Clustering of cancer in families is not uncommon and may be due toshared environmental exposures and/or inherited genetic factors,including complex interactions between the two.

Most known hereditary cancer susceptibility genes are rare anhigh penetrance (the proportion of individuals carrying a givea that also express its associated trait)


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However, such genes likely account for only a small proportion of cawith a larger proportion due to common variation in one or several lpenetrance genes that interact with other genes or environmental fa(e.g., tobacco smoke, alcohol).


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Feat res of hereditar cancer incl de the


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Features of hereditary cancer include thefollowing:

IN THE INDIVIDUAL PATIENT:

Multiple primary tumors in the same organ.

Multiple primary tumors in different organs.

Bilateral primary tumors in paired organs.

Multifocality within a single organ (e.g., multiple tumors in the same breast, all of whichhave risen from one original tumor).

Younger-than-usual age at tumor diagnosis.

Tumors with rare histology.

Tumors occurring in the sex not usually affected (e.g., breast cancer in men).

Tumors associated with other genetic traits. Tumors associated with congenital defects.

Tumors associated with an inherited precursor lesion.

Tumors associated with another rare disease.

Tumors associated with cutaneous lesions known to be related to cancer susceptibilitydisorders (e.g., the genodermatoses).


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IN THE PATIENTS FAMILY:

o

One first degree relative with the same or a related tumor and one of the individfeatures listed.

o Two or more first-degree relatives with tumors of the same site.

o Two or more first-degree relatives with tumor types belonging to a known familia

cancer syndrome.

o Two or more first-degree relatives with rare tumors.

o

Three or more relatives in two generations with tumors of the same site oretiologically related sites.

Th f di i


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Themes for discussions:I. Familial breast/ovarian cancer

Li-fraumeni syndrome

Cowden syndrome

II. Familial colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC)

Familial adenomatous polyposis (FAP) and

attenuated FAP

MYH-associated polyposis (MAP)

Peutz-Jeghers syndrome (PJS)

III. Familial prostate cancer

Hereditary prostate cancer syndromes

IV. Leukemia/Lymphoma

Bloom syndrome Ataxia-telangiectasia

Fanconi anemia

Down syndrome

V. Familial Pediatric cancers

Retinoblastoma

Wilms tumour


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Familial breast/ovarian can


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Most breast and ovarian cancer is sporadic, Several breast and ovarsusceptibility genes have been identified to date, most of which areautosomal dominantmanner.

Approximately 5% is due to germline mutation in BRCA1 (17q) or B

Carrying a BRCA1 mutation confers a lifetime risk of developing brea80% and ovarian cancer of 30-40%.

Mutation in BRCA2 are much less likely to cause ovarian cancer , bubreast cancer.


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Li-fraumeni syndrome

Li-Fraumeni syndrome (LFS) is a rare cancer predisposition scharacterized by pre-menopausal breast cancer, sarcoma (soand bone), leukemia and adrenocortical carcinoma.

LFS is associated with a high lifetime risk of developing canc

Individuals with LFS have a 50% chance of developing any ty

cancer before age 30 and a 90% chance by age 70.

The risk of cancer is particularly high in females with LFS, coto males.


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Cowden syndrome

Cowden syndrome is an autosomal dominant disorder, charby multiple hamartomas (benign malformations of tissues tresemble tumours) and an increased risk of female breast cthyroid cancer (non-medullary) and endometrial cancer.

The lifetime risk of cancer associated with Cowden syndromhighest for breast cancer, estimated to be as high as 85%, wrisk by age 50.

may also increase the likelihood of developing other cancergastrointestinal malignancies.


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Familial colorectal cancer


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Familial colorectal cancer

An individuals relative risk of colorectal is related to the degree of family history. They arrefer to genetic clinic, if:

-Two affected 1stdegree relatives aged less than 70 years old;

-One affected 1stdegree relative aged less than 45 years old at diagnosis;

-Three close relatives affected with average age at onset less than 60 years old;

-Potential family history of hereditary non-polyposis colorectal cancer (HNPCC);

-Familial adenomatous polyposis (FAP).


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Hereditary non-polyposis coloreccancer (HNPCC)

Also known as Lynch syndrome.the most common type of hereditary colorectal cancer caused by germline least one of four genes involved in mismatch repair.

majority of HNPCC cases are caused by mutations in the MLH1 and MSH2 g

HNPCC is characterized by early onset of colorectal cancer (mean diagnosis

predisposition for multiple colorectal tumours, a predominance of proximalsided) tumours and predisposition for poorly differentiated tumours.

HNPCC is also associated with an increased risk of several other cancers, incthe endometrium, ovary, stomach, small intestine, hepatobiliary tract, uppebrain and skin.


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Familial adenomatous polyposis(FAP) and attenuated FAP

are autosomal dominant disorders characterized by the developmentof precancerous polyps in the colon.

It is due to germline mutations in the APC gene.

If left untreated, individuals with classical FAP have almost a 100% chadeveloping colorectal cancer in their lifetime, with an average age at d

39.Lifetime colorectal cancer risk is slightly lower in people with attenuat(approximately 70% by age 80) and the average age of diagnosis is 10later than in classical FAP.


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Peutz-Jeghers syndrome (PJS)is a rare genetic disorder characterized by

multiple gastrointestinal hamartomouspolyps, hyperpigmentation of the lips andbuccal mucosa, and an increased risk ofseveral gastrointestinal and extraintestinalcancers.

10-20% lifetime risk of colorectal cancerand has been shown due to germline

mutations in STK11, a serine threoninekinase (locus: 19p14).

Individuals with PJS have a high lifetimerisk of developing cancers, the majority ofthem gastrointestinal.


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Familial Prostate Cancer


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Approximately 5% of those with prostate cancer have a famhistory , which the genetic basis is multifactorial.

There is modestly elevated lifetime risk of prostate cancer ocarriers of BRCA1 and BRCA2 mutations.

Similar to breast and ovarian cancer, an estimated 5%10%

prostate cancer diagnoses are attributed to inherited genetor susceptibility genes.


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Hereditary prostate cancersyndromesSeveral prostate cancer susceptibility loci have been identifilinkage analyses, including hereditary prostate cancer (HPC)PCAP, HPCX, CAPB, HPC20, 8p and 8q.


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Leukemia/LymphomaThese disorders primarily involve genes involved in DNA repair, cell cycle regulation

promotion of apoptosis or cell proliferation.


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Bloom syndromeBloom syndrome is a rare autosomal

recessive disorder characterized by ashort stature, but primarily normalbody proportions, hypersensitivity tothe sun on the face resulting in abutterfly rash, sterility in males orreduced fertility in females, and

immunodeficiency.


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Ataxia-telangiectasiais a rare autosomal recessivedisorder characterized bycerebellar ataxia that beginsearly in childhood and progressesover time, and telangiectasias(small blood vessels near the

surface of the skin) on areas ofthe skin exposed to sun and theconjunctiva.


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Fanconi Anemiaa rare autosomal recessivedisease, caused by mutations inup to 15 genes involved in DNArepair/stability.

characterized by physicalabnormalities (e.g., short stature,

deformities of the limbs andextremities), bone marrowfailure and increased cancersusceptibility.


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Familial Pediatric Cance


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Retinoblastomais a malignant tumour of theretina in the eye that occurs earlyin childhood, with the majority ofcases diagnosed before age 5.

It occurs when there aredeleterious mutations to both

copies of the RB1 gene


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Wilms Tumoura childhood malignancy of thekidney cell progenitors thatusually occurs before age 5.

involving germline mutations tothe WT1 gene (chromosome11p13).


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Genetoc Aspect of Cancer

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