Editing Breast cancer genetics

== Epidemiology ==

* Associated with 5-10% of all breast cancers, but 25% of cases in women <30yo
* Overall rare (BRCA found in 0.1% of USA population, and up to 1% of Ashkenazi Jews)
* Estimate individual risk of carrying mutation with <nowiki>https://canrisk.org/canrisk_tool/</nowiki>

== List of syndromes and associated lifetime cancer risk ==

* TP53 - 85%
* BRCA 1 and 2 - 70%
* PALB - 55%
* ATM - 50%
* PJS - 45%
* Cowden syndrome - 40%
* CDH1 - 35%
* NF1 - 30%
* CHEK2 - 30%

== '''Specific genes''' ==

=== '''BRCA''' ===

** Breast CAncer genes
** Lifetime breast cancer risk 70% for both
** Overall mortality rates are similar to sporadic breast cancer of same type
** Tumour suppressor genes which encode proteins that repair dsDNA breaks - Homologous Recombination (HR)
** Leads to cells with loss of HR repair and therefore general genetic instability. BRCA-mutated cells accumulate other mutations in critical genes, including p53. 
*** BRCA1 is also involved with cell-cycle checkpoint regulation, preventing cells with damaged DNA from dividing
** The genetic risk is transmitted in heterozygotic state, with a second hit occurring and subsequent complete loss of function. Therefore autosomal dominant.
** There is also a higher risk of DCIS at a younger age than in the general population
** '''BRCA1'''
*** Accounts for about 40% of familial breast cancer
*** Chromosome 17
*** Associated with basal type triple negative cancer, often high-grade (20% of patients with triple negative have BRCA1); however 38% of cancers are other phenotypes
*** 45% lifetime risk of ovarian cancer for carriers - do the oophorectomy by 40
*** Male breast cancer risk 0.2-1.2%
** '''BRCA2'''
*** Accounts for 30% of familial breast cancers
*** Chromosome 13
*** Cancer risks
**** Hormone-sensitive breast cancer
***** Mostly luminal A or B
**** Ovarian/endometrial cancer 20%
***** Do the oophorectomy by 45
**** Male breast cancer (2-7%)
**** Melanoma
**** Pancreatic cancer 2-5%
**** Prostate cancer 30%
** '''Treatment options'''
*** Intense surveillance - MRI encouraged
**** PBS approved MRI annually from age 25 for all BRCA carriers - on the first scan, find and mark the fibroadenomas
**** Baseline mammogram at age 35, then start doing them annually from 40yo
*** Chemoprevention - efficacy unclear, especially with BRCA1, however likely worthwhile especially pre-menopausal, based on retrospective data
*** Breast cancer treatment differences
**** Recommend mastectomy as opposed to BCS + radiotherapy, due to high risk of local recurrence
*** Contralateral prophylactic mastectomy
**** Risk of cancer on the other side is about 25%
**** CPM generally offered to prevent this
*** Bilateral prophylactic mastectomy - highly effective
**** Salpingo-oophorectomy reduces risk of ovarian cancers from 5.8% to 1.1%, and also reduces breast cancer-specific mortality
**** Overall chance of dying of breast cancer is about 10% if no risk-reducing surgery
**** Once that's done, no formal surveillance but keep an eye on it

=== TP53 ===

** Accounts for 70% of Li Fraumeni syndrome
** High risk of breast cancer especially for <30yo women
** High risk of brain tumours, sarcomas and other malignancies
** See separate topic

=== Ataxia telangiectasia (ATM) ===

** Moderate-risk: 2-3x

=== CHEK2 ===

** Moderate-risk: 15-40%
** Chromosome 22

=== PALB2 ===

** 4-7x risk

=== CDH1 ===

** Mutated e-cadherin (same as DHGC)
** Always lobular cancer
** See separate topic

=== BARD1 ===

=== RAD51C and RAD51D ===

** Preponderance of triple negative cancers

=== PTEN ===


== Indications for genetic testing (based on eviQ Australian guidelines) ==

* Manchester Score can be used to evaluate who gets government funding through PBS - need a score >10, but can also use eviQ criteria
* Known breast/ovarian cancer genetic susceptibility in the family
* Triple negative diagnosed <60yo
* Individual characteristics:
** Male breast cancer
** Breast cancer and Jewish ancestry
** Two primary breast cancers in the same person, where the first occurred at <60yo
** Breast cancer and another associated cancer in the same person at any age (pancreatic, ovarian, prostate)
** Breast cancer diagnosed <=40yo
** Lobular breast cancer AND diffuse-type gastric cancer (in the same person or in the same family)
** Breast cancer diagnosed <50yo with limited family structure or knowledge
** Breast cancer and a personal or family history suggestive of:
*** PJS
*** PTEN hamartoma syndrome
*** Li-Fraumeni
*** NF1
* Family characteristics
** Two first or second-degree relatives with breast or ovarian cancer on the same side of the family, AND:
*** Additional relatives
*** Breast cancer diagnosed <50yo
*** >1 primary breast cancer in the same person
*** Breast and ovarian cancer in the same person
*** Jewish ancestry
*** Male breast cancer
*** Pancreatic cancer
*** High-grade (Gleason 7) or metastatic prostate cancer


iPrevent familial risk assessment tool is the recommended way to assess familial risk in Australia
[[Category:Breast]]