11/10- Cancer Genetics Flashcards

Question

What cancer is Philadelphia seen in?

Answer 1

CML- chronic myelogenous leukemia

Answer 2

- Could develop of a specific inhibitor against the BCR-Abl protein - Resulted in improved treatment of Ph+ leukemia (CML and ALL) with improved survival. - Now also used for tumors which have activation of other related kinases, like gastrointestinal stromal tumors (GIST) with activation of c-Kit kinase

Answer 3

- Translocations: ~80% of prostate cancer; most common is androgen responsive TMPRSS2 gene and the ERG oncogene. - Translocation: activation of ALK kinase in anaplastic lymphoma. - Deletions between gene: P2RY8 promoter and exon 1 are fused to CRLF2 coding region (growth factor) in high risk ALL and Down Syndrome-ALL.

Answer 4

Chr 2 inversion -\> EML4-ALK fusion - Inversion event is seen in ~3% of non-small cell lung cancer. - Results in activation of ALK because the EML4 domain aids in heterodimerization

Answer 5

- Early trials supported the use of ALK inhibitors for the treatment of EML4-ALK–positive NSCLC * Crizotinib approved for EML4-ALK rearranged NSCLCs - Targeting of activated ALK may be successful therapeutic approach to diverse tumors types. - Pediatric Phase 1 trial of crizotinib demonstrated activity against tumors with rearranged ALK. * Including ALK translocations, inversions * However, less clear efficacy for tumors with missense mutations

Answer 6

- **JAK2** mutations in high-risk childhood **ALL** and ALL associated with Down syndrome - **ALK** mutations (and amplification) in familial and sporadic **neuroblastoma** - **FLT3** internal tandem duplication **in AML**. - **EGFR** missense mutations in lung cancer associated with sensitivity to tyrosine kinase inhibitors (**gefitinib**) * Secondary somatic mutations V843I or T790M then associated with resistance to same class of drugs

Answer 7

- JAK2 mutations in high-risk childhood ALL and ALL associated with Down syndrome - **ALK** mutations (and amplification) in familial and sporadic **neuroblastoma** - **FLT3** internal tandem duplication in **AML**. - **EGFR** missense mutations in lung cancer associated with sensitivity to t**yrosine kinase inhibitors (gefitinib)** * Secondary somatic mutations V843I or T790M then associated with resistance to same class of drugs

Answer 8

- BRAF (B-raf) gene was found to carry a specific mutation V600E in a substantial percentage of malignant melanoma: * Subsequently identified in many other advanced cancers and pediatric brain tumors. - Targeted trials of BRAF inhibitors led to rapid FDA approval of several drugs for V600E mutated melanoma - Similar mutations at orthologous position in KIT (D\>V) as seen in BRAF in other tumor types.

Answer 9

Function mutations in IDH1/2 in astrocytomas and secondary glioblastoma multiforme. - IDH1/2 also frequently mutated in AML - Functional assays reveals that these are gain of function mutations which alter substrates for chromatin remodeling

Answer 10

- Activation of proto-oncogenes by mutation, amplification and translocation result in increased or altered regulation that fosters tumor cell growth and survival. * Mutations in oncogenes are occasionally inherited - Alterations maybe specific to the type of cancer but same gene often mutated in several different tumors * Resulted in development of many new targeted therapies. - Cancer genome projects seek to identify all such changes to allow for specific and less toxic treatment for a wide variety of cancers

Answer 11

False - For most tumor types, e.g. breast, the inherited fraction fall in the range of 5-10%. - Several rare tumors, adrenocortical carcinoma, retinoblastoma and medullary thyroid cancer have very high inherited fraction (40-60%).

Answer 12

The majority of inherited cancer result from **loss of function (LOF)** mutations in **tumor suppressor genes** - Rare examples of inheriting oncogenic driver mutations The risk of cancer in mutation carriers is high enough to result in specific management guidelines.

Answer 13

Patients with inherited chromosomal abnormalities may have an increased risk of **developing cancer** - **Trisomy 21** results in ~20 fold increase in **leukemia** and also shifts the myeloid: lymphoid ratio to 40:60. * Not an increased risk of solid tumors in adults with DS - Girls with mosaic **Turner syndrome** or gonadal dysgenesis at increased risk for **gonadoblastoma**. * Correlates with presence of Y chromosome - Children who survive **trisomy 18** have a very high rate of developing **Wilms tumor.**

Answer 14

- Transient myeloid proliferation (TMP) * May or may not evolve into leukemia is seen in infants. * Somatic GATA1 mutations found in TMP cells - JAK2 missense mutations and CRLF2 activation due to intrachromosomal deletion found in DS-ALL

Answer 15

This is the second class of genes which are commonly found to be mutated in sporadic human cancers as well as in families with an inherited predisposition to cancer. - Early on they were referred to as anti-oncogenes The normal function of these genes is to suppress tumor formation by several mechanisms including regulating the cell cycle, maintaining genomic stability, or maintaining normal tissue architecture.

Answer 16

Many dominant cancer disorders result from inheriting **deleterious mutations in tumor suppressor genes (TSG)**

Answer 17

- Inhibit proliferation (often by regulating proto-oncogene activity - Down regulate the cell cycle - Repair DNA - DNA damage checkpoints

Answer 18

**1. Cell fusion experiments**. The transformed or “cancer” phenotype could be suppressed by fusion between malignant cells and normal cells. **2. Inherited forms of cancer**. First hypothesized by Knudson (PNAS (1971) (68:820) based on analysis of the inheritance of retinoblastoma.

Answer 19

- May be difficult to see until certain lighting conditions. - Parents may comment on abnormal pupil that isn’t obvious in exam room lights. - Need to be suspicious.

Answer 20

- Childhood eye cancer which can be seen in absence of family history (sporadic) or inherited in an autosomal dominant manner. - Patients with a family history of Rb are much more likely to have bilateral tumors. * Appeared to have earlier age of diagnosis - Knudson reviewed 48 cases of Rb and applied statistical analysis which showed that it fit a model of only two events or “hits” being required for tumor formation

Answer 21

- Only 20% of patients with bilateral Rb have a +FH - With 80% are de novo RB1 mutations with -FH. - If you inherit a RB1 LOF mutation there is 90% likelihood of developing RB. - Some mutations with lower RB risk including missense and splice site.

Answer 22

Inactivation of both copies of a TSG is required to develop cancer. - Both inactivation events can occur somatically during development of childhood (unilateral tumor) OR - Inherit a single mutation in a TSG and then somatically acquires loss/inactivation of the second normal copy of the gene to develop tumor (more likely to be bilateral). - At cellular (somatic) level these genes are recessive because both copies of the gene are lost in tumors. - Autosomal dominant inheritance of susceptibility to cancer. - Mutations are nonsense, frameshift, deletions and methylation of promoter – opposite of what you see in oncogenes

Answer 23

2nd hit can cause **loss of heterozygosity**

Answer 24

Hereditary form of RB due to nonsense mutation

Answer 25

Sporadic Rb due to somatic mutation/methylation

Answer 26

Long term survivors of bilateral Rb have a very high rate of **second malignancies** - Bone and soft tissue sarcomas are the most common second primary cancer in childhood. - Radiation therapy significantly increases the risk of malignancy, particularly for sarcomas. - Recent study suggest 68% risk of second primary malignancy through ~age 50 with epithelial tumors, e.g. lung cancer common in adult RB1 mutation carriers

Answer 27

- Childhood tumor with high “heritable fraction”. In tumor, both copies of RB1 gene are inactivated. * First mutation often point mutation or local event * Second hit often larger event that causes loss of wild type gene or silencing by methylation - Can inherit one mutation and have 2nd hit. * More likely to be bilateral or multifocal. * Can have positive family history with AD pattern or result from de novo mutation in egg or sperm (80% of cases). * At-risk for a cluster of tumors types - Genetic testing for RB1 mutation allows differentiation of hereditable cases * Allows identification of siblings or offspring at risk. * Mutation carriers undergo extensive screening for RB

Answer 28

* Affect multiple generations with cancer * Transmission of cancer predisposition through both mothers and fathers. * Can be due to de novo mutations with no FH. * Age of onset of cancers often earlier then for general population * Bilateral or multiple primary tumors are common * There is often a clustering or increased risk of a few tumors types within the family. * There is incomplete penetrance so that not all mutations carriers develop cancer.

Answer 29

- TP53 is the gene - p53 is the protein product (?)

Answer 30

- One of the most frequently mutated tumor suppressor genes found in human tumors (like the Ras of oncogenes) - The vast majority of TP53 mutations are **somatic** mutations in the tumor sample: * point mutations often missense mutations that inactivate important protein domains. * Second copy of the gene can be inactivated by LOH events. These mutations can be inherited to cause Li Fraumeni cancer syndrome with a very high risk of a wide variety of tumors

Answer 31

• The study of cells mutant in TP53 demonstrates that p53 is a checkpoint protein and controls apoptosis . * Cells mutant in p53 lose checkpoint function and enter S phase and M phase despite DNA damage. * Cells with DNA damage that cannot be repaired fail to induce apoptosis * Overall results in mutations, DNA amplification and aneuploidy at a high rate in p53 deficient cells. * “Guardian of the Genome”

Answer 32

Li Fraumeni syndrome was first described based on children with sarcomas who come from families with early breast cancer. – There was apparent autosomal dominant inheritance of overall cancer susceptibility. – Germline TP53 mutations are found in \>80% of Li Fraumeni families. – Overall, germline TP53 mutations are found in ~5-15% of children presenting with sarcomas

Answer 33

* **Sarcomas** – both soft tissue and osteosarcoma in children and adults (not Ewing’s sarcoma). * **Breast cancer** – most common malignancy in LFS families overall with average age of onset ~ 31. * **Leukemias and lymphomas** – in both children and adults, particularly childhood hypodiploid ALL. * **Adrenocortical carcinoma** – in children, otherwise a very rare malignancy. Any child with ACC should have a genetics evaluation. * **Brain tumors** – in both children and adults * Choroid plexus carcinomas frequently due to inherited TP53 mutations • **Other common malignancies** are also seen more frequently including lung and colon cancer.

Answer 34

* EARLY (begin at age 18-21) breast cancer screening with MRI essential. * Colonoscopy beginning at age 25. * Surveillance guidelines in children including: whole body MRI, brain MRI, abdominal ultrasound and serum studies for ACC reported to decrease mortality * Further research is underway to assess the impact of instituting screening guidelines on mortality. * No treatments developed to date that successfully target TP53 mutant tumors once developed

Answer 35

**1/8** women will develop breast cancer in her lifetime

Answer 36

**5-10%** of breast cancer results from inheritance of mutation in cancer susceptibility gene

Answer 37

• **Her2/c-ERBB2 receptor** - oncogene is frequently **amplified** and overexpressed. * Amplification correlates with sensitivity to trastuzumab/Herseptin. * **Ras** - **point mutations** are common. * **MYCC/c-myc** - oncogene is frequently **amplified** but not used for treatment decisions. * **TP53** - is frequently **lost**. * **RB1** - is frequently **lost**. * **Estrogen receptor/progesterone receptor** are not typically mutated but genes **over-expressed**.

Answer 38

* **Breast-Ovarian Families** – _BRCA1\>BRCA2._ * **Li-Fraumeni** – Avg age of onset - 32 in TP53 carriers * **Peutz-Jeghers Syndrome** (_STK11_) –32% by age 60. * **Cowden’s syndrome** – _PTEN_ mutations assoc. with thyroid cancer, hamartomas, skin lesions. * **Hereditary diffuse gastric cancer and lobular breast cancer** – _CDH1_ mutations. * New genes – PALB2 (Breast and pancreatic ca) * Moderate risk genes RR~2.0 for breast cancer * CHEK2 (1100delC founder), BRIP1 * Ataxia telangiectasia (ATM) heterozygous mutation carriers

Answer 39

**BRCA1 = 17q21** * Gene identified by linkage analysis of large families * BRCA1 encodes a protein which is involved in the **response to DNA damage.** * Cancer risk associated with i**nactivating mutations** including frameshifts, nonsense or splicing. * Rare missense changes in important domains are also associated with increased cancer risk. * Hundreds of benign or uncertain missense changes can be identified by sequencing tests. Somatic BRCA1 mutations in sporadic breast cancer are rare, although sometimes seen in ovariant ca

Answer 40

**BRCA2 = 13q12.3** * Pedigrees look similar to BRCA1 so generally test both together although some differences. * Carrying a mutation in BRCA2 predisposes both **women and men to breast cancer.** * Lifetime risk for male breast cancer is 6%. * Risk of **ovarian cancer is lower then for BRCA1** mutations but still substantially increased compared to general population. * Increased risk of **other solid tumors** including **pancreatic** cancer, although absolute lifetime risk for PancrCA is still only 1-2%.

Answer 41

– **Two** specific mutations in **BRCA1** (185delAG and 5382insC) and **one** in **BRCA2** (6174delT). * In total, carrier frequency of 2.4% among Ashkenazi Jewish individuals for all three mutations. * Thus, start genetic testing with these three mutations. If negative for founder mutations we recommend full sequence mutation analysis for those families with a substantial risk of breast/ovarian cancer.

Answer 42

• VUS reported in **~5%** of BRCA1/2 genetic tests. * **Predominantly missense** mutations in regions of the protein without known function. * A variety of approaches including conservation, segregation with cancer and population studies are utilized to try and determine the significance. * It is **important to not over-interpret** VUS as most are benign (even if very rare). • Since Supreme Court decision in 2013 many more US labs offering BRCA1/2 testing. * Different laboratories may report out same VUS differently based on their own criteria. • As you increase the number of genes tested the likelihood of VUS increases rapidly.

Answer 43

* Both BRCA1/BRCA2 proteins are involved in the response to DNA damage. * The ATM protein phosporylates them. * BRCA1 Interacts with Rad51 DNA repair protein in homologous recombination. * BRCA2 interacts with Rad52 and PALB2 (partner and localizer of BRCA2) to be localized to the sites of DNA damage * Thus, it isn’t surprising that mutation in many of these genes results in inherited breast cancer risk

Answer 44

Despite the increased risk for melanoma and pancreatic cancer.. no guidelines for screening

Answer 45

* Early surveillance starting age 25 with breast exams and MRI imaging. * No proven ovarian cancer screening methods * CA125 serum marker and transvaginal ultrasound recommended only if oopherectomy refused. • Chemoprevention: * **Tamoxifen and raloxifene** reduce breast cancer risk in the general population but it is **less clear** their efficacy in mutation carriers. * **OCP’s** may **reduce ovarian** cancer risk (but may have breast cancer risk) * More research is needed on appropriate chemoprevention.

Answer 46

**Prophylactic bilateral salpingo-oopherectomy** decreases OVCA rate by 90%. - Recommended for **all BRCA1/2 carriers** –Also significantly reduces subsequent breast cancer risk. – Very important to remove fallopian tubes – Recommend prophylactic oopherectomy when women complete childbearing (ages 35-40) **Prophylactic mastectomy** – reduces the risk of subsequent breast cancer. – Need to counsel women that it is major surgery but many women from highly affected families consider this a reasonable option for them.

Answer 47

* BRCA1/BRCA2 breast and ovarian cancers respond to therapies directed towards defective DNA repair. * **PARP** (poly ADP ribose polymerase) is a back-up repair pathway for tumors that are defective in homologous recombination mediated by BRCA1/2. * FDA approval of **Olaparib** for **ovarian cancers which contain BRCA1/BRCA2** mutations (2014) * Platinum resistant OVCA may result from back mutation of the BRCA2 gene to wildtype * Early evidence **Olaparib** may work in **BRCA** mutant metastatic **prostate cancer**

Answer 48

* Family history still remains the best tool to identify women that are at significantly elevated risk. * Pre and post-test counseling are essential to clinic process: * Particularly with regard to possible test results • Women mutation carriers have a number of options to decrease cancer-related morbidity and mortality. * Early and increased surveillance * Chemoprevention * Prophylactic surgery – particularly BPO • BRCA1/2 mutations are **not found** in all high-risk families. * Panels of multiple breast cancer genes are now available (BRCA1/2, PALB2, STK11, PTEN, TP53, ….) * This includes less penetrant genes where guidelines for mutation positive women have not been developed.

Answer 49

(Recall, in breast cancer, BRCA1/2 or first hit commonly inherited)

Answer 50

**Normal epithelium** - Mutation/loss of **APC** (tumor suppressor gene) **Adenoma**; **milid** dysplasia - Mutation (gain of function) of **KRAS** (oncogene) **Adenoma**; **moderate** dysplasia - Mutation/loss of function of **DCC** (tumor suppressore gene) **Adenoma**; **severe** dysplasia - Mutation/loss of **p53** (tumor suppressor gene) **Carcinoma**

Answer 51

* **Autosomal dominant** disorder due to mutations in **APC** with very high penetrance for polyps and colorectal cancer * Adenomatous colonic polyps begin in childhood to adolescence. * Nearly **100%** lifetime **colorectal cancer** risk with 50% risk by age 33. * **Extracolonic** features often referred to as **Gardner** Syndrome. There is a **rare autosomal recessive disorder (MUTYH)** which gives a similar adenomatous polyposis condition

Answer 52

• **Desmoid tumors** – often abdominal. * Painful and can be difficult to treat. * **Osteomas** of the jaw, skull, or other bones * **Epidermoid cysts** on face or trunk * **Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)** – present at birth, asymptomatic but useful clinically. * **Pediatric hepatoblastoma** (~0.5-1% risk) * **Thyroid cancer** (1% risk) * **Medulloblastoma** (\<1% risk)

Answer 53

– ~ 80% truncating mutations in the APC gene. – Small number of deleterious missense mutations. – Deletions (5-10%). * About 15-30% of people diagnosed with FAP result from de novo mutation and are the first person in the family. * In sporadic (non-hereditary) colorectal cancer – 80% show abnormalities of the APC gene. * In both cases tumors show “second hits” with loss of heterozygosity of APC.

Answer 54

- Beta-catenin sits in cytoplasm - Can go to nucleus and activate myc - Normal role of APC is to phosphorylate and degrade beta-catenin; get over-activity of beta-catenin and increased myc

Answer 55

Begin testing with an affected member to identify specific mutation (“private” or “familial”) in family. * Next at-risk family members are tested for that specific mutation. * If no mutation identified in the affected member then consider other genes (MUTYH) and screening of all offspring

Answer 56

* Begin yearly **colonoscopy** between ages **8-12** for surveillance for polyps. * **Prophylactic colectomy** during the teen-age years. * If rectal epithelium is left in place (depending on surgery type) then lifelong surveillance for rectal ca. * Adults should have upper endoscopy every 2-3 years due to increased risk of small intestinal tumors. * Surveillance for hepatoblastoma in young children is controversial but being started. * Chemoprevention studies with celecoxib suggests delays/decreases onset of polyps but effectiveness in reducing cancer risk is not proven.

Answer 57

Aka **Lynch syndrome** **Autosomal dominant** – Increase in **colorectal** cancer, **uterine** cancer, **ureteral** cancer and some other solid tumors including **ovarian** and **pancreatic** cancer. – Stage for stage, the colon cancer is less malignant than in sporadic colon cancer or FAP with greater immune response. – Recently shown to respond better to tumor immunology treatment approaches.

Answer 58

• Results from inheriting a **mutation in one of four genes encoding mismatch repair (MMR) proteins**: * **MSH2, MLH1, MSH6 and PMS2.** * Analysis of tumors revealed expansion and contraction of dinucleotide repeats consistent with defective mismatch repair – termed **microsatellite instablity (MSI)** * Immunohistochemistry reveals absence of the MMR protein in the tumor sample. * In addition, **15-20% of sporadic** colon cancers also show **silencing of MLH1 by methylation** not mutation.

Answer 59

– **Autosomal dominant inheritance of one inactivating mutation in MMR gene** * Normal cells still have one working copy and are MMR proficient (only see MSI in the tumor) – **Loss of the second copy** of the MMR gene as the tumor develops. Alternatively, somatic methylation of both MLH1 promoters is common in sporadic CRC * Results in the tumor cell being mismatch repair defective since both copies are inactive with MSI

Answer 60

- Your first hit coud be mutation of methylation - From there, could have 2nd hit of LOH or methylation - Two hits could be any combo: * Mutation + LOH * Mutation + methylation * Methylation + LOH * Biallelic methylation - If Lynch syndrome, this whole thing would start already with 1 mutated gene

Answer 61

~70% lifetime risk of CRC and endometrial cancer. – Prophylactic colectomy **not** typically performed **Colonoscopy every 1-2 years** beginning at age **25** – Clear evidence that screening prolongs survival. Women require annual evaluation for endometrial cancer and surveillance for ovarian cancer. **Multiple primary** cancer diagnoses are **common**. Recent work suggests that treatment of Lynch syndrome cancers with **immunotherapy** will be **successful**. – New attempt to make cancer vaccine for LS

Answer 62

**_80-85% of CRC demonstrate mutation in APC._** – **1%** due to **germline APC** mutation (**FAP**) – Early event at the initiation of polyp formation. – 2' mutations in Ras and chromosome instability. **_~15% of CRC - microsatellite instability or hypermutated_** – Most common event **silencing** of both copies of the MLH1 **promoter** by methylation. – **2-3%** due to **germline MMR** mutations (**HNPCC**) – Rare somatic mutation in DNA repair genes – These patients may **not** respond to **5-Fluoro-uracil** treatment as well as APC cancers.

Answer 63

• Typically **very rare** disorders * More common in consanguineous families and specific ethnic groups. * Medical problems tends to be more **severe** and begin in **childhood**. * Affected child inherits one copy of the mutant allele from each parent. * Parents (obligate carriers) are generally healthy with little to no clinical features of the disorder (although many exceptions).

Answer 64

Autosomal **recessive** disorder * Starting at **~ age 1** patients demonstrate: easy sunburn, photophobia, photosensitivity and freckling. * Premature **skin changes** with wrinkling, solar keratoses, telangiectasias. * 50 year earlier onset and **1000x** relative risk of benign and malignant **skin cancers**. * **5%** develop **melanoma**

Answer 65

Approximately 18% of patients with XP have a **neurologic phenotype**: – Sensorineural deafness – Segmental demyelination – Ataxia – Choreoathetosis – Spasticity – Supranuclear opthalmoplegia Neurologic findings reflects severe NER defect. Hypothesized due to **lack of repair of oxidative damage in postmitotic neurons.**

Answer 66

Frequency: - US: 1/1million - Japan: 1/100,000

Answer 67

UV sensitivity is the result of all cells having mutations in both copies of repair genes (deficiency state). – cells from patients show sensitivity to UV light and skin cancer risk due to loss of global nucleotide excision repair (NER). Cellular phenotypes can be used for diagnosis and to determine the number of genes involved in the disorder through complementation analysis.

Answer 68

Diagnosis is based on functional studies of UV response of fibroblasts from skin biopsy. AVOIDANCE OF ALL UV EXPOSURE. – Children live indoors. – Special camps for children with XP have outdoor playtime at night. – Special light bulbs, opaque clothing etc. – Conservative management of skin lesions to try and avoid dysfiguring surgery.

Answer 69

Simplifies the genetic testing process: – Requires less family history and pathology information. – Increased likelihood of VUS results May provide “surprising results” with regard to pathogenic mutations despite the family history not being “classic”: – Definitely occurring with regard to TP53 mutation results from hereditary cancer panels Panels often include genes for which there is limited information with regard pathogenicity or surveillance.

11/10- Cancer Genetics Flashcards

(99 cards)