Heredo-familial Tumors Flashcards
(20 cards)
Germline genetic mutation and gene penetrance?
GERMILINE GENETIC MUTATION: gene change in a body’s reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. Germline
mutations, also called germline variants, are passed on from parents to offspring.
GENE PENETRANCE: gene penetrance measures the proportion of individuals in a population who carry a specific gene and express the related trait.
What is cancer predisposition syndrome?
It is a genetic mutation that increases the chances of developing cancer at an earlier stage compared to the general population. What causes genetic changes ?
Germline mutations, infections from some viruses, smoking, environmental factors.
Hereditary vs familial?
HEREDITARY: is most commonly used when referring to diseases with a known genetic cause, such as a syndrome related to a specific genetic variant.
FAMILILAL: disorders are those which appear to have a genetic component, affecting more family members than would be expected by chance alone.
However, a single genetic cause or explanation is not known.
Hereditary cancer syndromes?
Most diagnoses of cancer are sporadic forms (80-90%), they may involve somatic mutations, spontaneous or induced. Only 5-10% are considered hereditary, but often it’s underdiagnosed.
- arise from mutations that confer elevated susceptibility to cancer .
- typically exhibit autosomal dominant inheritance pattern.
-Common indicators which can aid in their identification: early onset of cancer, the occurrence of multiple tumors in the same individual, a positive family history, and an atypical sex distribution. -
Breast and ovarian cancer predisposition syndrome?
5-10% of Breast Cancer are hereditary and among them, ~ 20% are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes.
- autosomal dominant inheritance.
- pathogenic variants in BRC1/2 are highly penetrant and are associated with a significantly elevated lifetime risk of breast and ovarian cancer.
- Associated to an increased susceptibility to other malignancies: prostate and pancreatic
What to do when BRCA mutation is found?
- intensified screening with MRI after age 30. Or US and mammography every 6 months.
- Bilateral risk reduction mastectomy.
- for ovarian cancer US every 6 months and serum CA125, can also do a risk reducing bilateral salpingo oophorectomy.
Why is BRCA1/2 testing important for oncology patients?
Breast cancer with BRCA1/2 germline variant is more susceptible to platinum-based chemotherapy and PARP inhibitors such as Olaparib and veliparib.
What is li fraumeni syndrome? Implication for oncologic patients?
• Inherited familial predisposition to a wide range of certain, often rare, cancers.
• It is due to germline mutations in the tumor suppressor gene TP53 (highly penetrant).
• Autosomal dominant inheritance.
• Cumulative risk of breast cancer in women of 85% by age 60 (young age), important from an epidemiological point of view.
• The cumulative cancer risk associated with Li-Fraumeni: 50% by the age of 40 years and up to 90% by the age of 60 years.
• Cancers most closely associated: soft tissue sarcoma, osteosarcoma, breast cancer, brain and CNS tumors, adrenocortical carcinoma, acute leukemia.
- Due to the risk of radiation-induced secondary malignancies, a careful decision-making process with regard to risk–benefit ratios on the use of radiotherapy in patients with breast cancer harboring a germline TP53 pathogenic variant is warranted (mainly in those who need adjuvant radiotherapy after mastectomy). Consider the same attention to treatment with chemotherapy, there are treatment-induced tumors.
- The priority should be given to surgical or ablative treatments over radiotherapy.
- Non-genotoxic chemotherapies should be preferred.
Colorectal cancer predisposition syndromes?
30% of all colorectal cancer cases are an inherited form of the disease, but only 5% of cases are associated with highly penetrant inherited mutations and clinical presentations that have been well characterized.
The two main categories of heredity syndromes depend on the presence of polyps :
Poliposys syndromes : Familial adenomatous polyposis, MUTYH associated polyposys, juvenile polyposis syndrome, peutz jeghers syndrome and cowden syndrome.
Non polyposis syndrome : Lynch’s syndrome.
Polyposis syndromes?
FAP : linked to a mutation in APC, which is an oncosupressor. Autosomal dominant and have lifetime risk of colorectal cancer almost 100%. Predominant colorectal phenotype > 100 adenomas and there also extracolic manifestations such as gastric fundic gland polyps, duodenal adenomas, congenital hypertrophy of retinal pigment epithelium.
JUVENILE POLYPOSIS SYNDROME associated to a mutation in SMAD4 or BMPR1A, it confers 36-68% lifetime risk of CRC, with mean age of diagnosis of 45y. It is also associated to upper GI cancers.
PEUTZ-JEGHERS associated to a mutation in STK11 and an increased risk of CRC, breast, pancreatic and gynecological cancers.
Non polyposis syndrome?
Lynch syndrome : 1-3% of all CRC diagnoses, caused by germline inactivation of mismatch repair genes or epithelial cell adhesion molecules. Autosomal dominant inheritance. Increased lifetime risk of CRC (30-73%) and extracolonic malignancies: endometrial (30-51%), ovarian ((4%–15%), gastric (up to 18%), small bowel (3%–5%), urinary tract (2%–20%), pancreatic (4%), brain or cutaneous gland tumors.
3 phenotypes:
• Turcot syndrome: combination of CRC and central nervous system tumors.
• Muir-Torre syndrome: combination of CRC and cutaneous gland tumors.
• Constitutional or biallelic MMR deficiency: individuals who are homozygous or compound
heterozygotes for pathogenic variants in the MMR gene; characterized by cafe´-au-lait spots and childhood-onset tumors.
Why is the detection of hereditary syndromes so important?
For patients without cancer:
• Prevention and early detection of associated cancers by active surveillance can increase survival and improve QoL.
• Possibility of Chemoprevention (e.g. Aspirin in LS patients, non-steroidal anti-inflammatory drugs in FAP patients).
For patients with cancer:
• Different choice for surgical technique (E.g. extended colectomy to consider mainly in Young LS patients).
• Presence of MSI is a demonstrated prognostic factor; remains controversial the predictive
role for CT (Indication for adjuvant CT in stage II CRC patients).
• Further treatment options: Immunotherapy for MMR-deficient patients, especially in case of
advanced CRC.
Gastric cancer predisposition syndromes?
The majority of gastric cancers are sporadic, but a familial clustering is observed in about 10%. 1-3% are hereditary, encompassing the three major syndromes:
1. HEREDITARY DIFFUSE GASTRIC CANCER (HDGC): most common.
2. FAMILIAL INTESTINAL GC (FIGC)
3. GASTRIC ADENOCARCINOMA AND PROXIMAL POLYPOSIS OF THE STOMACH (GAPPS), a rare variant of FAP.
Gastric cancer can develop in the setting of other hereditary cancer syndromes: Li-Fraumeni, FAP, PJS, LS, hereditary breast/ovarian cancer syndrome, MAP and juvenile polyposis.
Hereditary diffuse gastric cancer syndrome?
• Caused by Germline mutation in the cadherin 1 gene (CDH1), which encodes for the cell adhesion protein E-cadherin. Recently, CTNNA1 gene, encoding alfa–E-catenin, has also been implicated.
• Rare, highly penetrant, autosomal dominant.
• Diffuse and poorly differentiated gastric carcinoma infiltrating the stomach wall without forming a mass.
• Cumulative risk of GC up to 70% and 56% for males and females respectively, with a median age of 38 years.
• Other distinctive features: lobular breast cancer (lifetime risk 42%), cleft lip/palate.
GASTRIC ADENOCARCINOMA and PROXIMAL POLYPOSIS of the STOMACH?
Caused by specific point mutations in promoter 1B regions of the APC gene à reduction of APC expression.
• Autosomal dominant pattern of inheritance.
• Phenotype: >100 gland polyps in the gastric body and fundus with antral sparing.
• Increased susceptibility to intestinal gastric type adenocarcinoma due to malignant polyp degeneration, with a lifetime risk of 13-25%.
Pancreatic cancer predisposition syndromes?
• HEREDITARY PANCREATIC CANCER (3%): known syndromes caused by germline mutations (BRCA2). Other conditions that give a higher susceptibility to this cancer: PJS and Hereditary pancreatitis, that are associated with the highest accumulated risk for PC (36% and 18- 53%, respectively).
• FAMILIAL PANCREATIC CANCER (7%): a family clustering (without an identified gene mutation) of pancreatic cancer with at least 2 first-degree relatives without a known hereditary cancer syndrome, the risk of pancreatic cancer increases with the number of affected family members.
In hereditary pancreatic cancer BRCA1/2 have an important role.
Kidney cancer predisposition syndromes?
16%of RCC patients have germline mutation and 5% of RCC are associated to predisposing syndromes.
VHL syndrome : germline mutation in VHL gene, lifetime risk of RCC is 30-40% and also associated with panNETs, pheochromocytoma and hemangioblastomas.
Endocrine cancer predisposition syndromes?
MEN 1: due to supression of MEN1, autosomal dominant, causes a combination of parathyroid tumors, pancreatic islet cell tumors and anterior pituitary tumors.
MEN 2 : mutation in RET oncogene, leading to medullary thyroid carcinoma.
