Genetics and cancers Flashcards
What % of endometrial and ovarian cancers are linked to genetic inherited predisposition?
5% endometrial cancers are attributed to genetic inherited predisposition
10% ovarian cancers
What are the attributes or essential properties of a cancer cell
self-sufficiency in growth signals; insensitivity to antigrowth signals; evasion of apoptosis; limitless replicative potential; sustained angiogenesis; tissue invasion and metastasis; and the development of genomic instability
Standard criteria exist for identifying women at risk of a BRCA mutation
What is it?
early onset breast cancer (less than 45 years old);
two breast primaries in one individual;
breast and ovarian cancer in the same individual;
breast cancer and more than one close blood relative with breast cancer less than age 50 years, or more than one close relative with ovarian cancer at any age, or more than two close relatives with breast cancer at any age;
breast or ovarian cancer at any age and Ashkenazi Jewish ancestry;
a family history of male breast cancer;
ovarian cancer and family history of breast or ovarian cancer; an
women from families that meet the above criteria.
What is important in a FHx for cancers?
How many generations?
What questions to ask?
Maternal and paternal sides of families should be considered independently.
A three-generational history is the standard for determining risk.
Close attention should be paid to the type of cancer, bilaterality, age of diagnosis and history of chemoprevention or risk-reducing surgeries.
Once a mutation has been identified what can we do about it
Combined oral contraceptive pill (COCP) use by women with BRCA mutation has been shown to be associated with a lower risk of ovarian cancer by 50%
No increase in breast Ca
Transvaginal ultrasound and serum CA 125 levels as a means of surveillance are associated with high false-positive rates and show no proven benefit. In fact, it is associated with late-stage presentation in affected women. Currently there are no recommendations for its use.
RR BSO greatly reduces the risk of ovarian cancer and mortality. Risk reduction is estimated to be 85–95 per cent, especially if performed by the age of 40- HRT is ok if no hx breast cancer
Women undergoing RR BSO have an approximately three per cent risk of having a tubo-ovarian malignancy at the time of their surgery
What is the BRCA inheritance pattern
autosomal dominant
What genes are associated with the HBOC syndrome
What other cancers are predisposed to?
Hereditary breast and ovarian cancer syndrome
HBOC syndrome is caused by mutations in the BRCA1 or BRCA2 genes. Autosomal dominant inheritance
Cause 15% of breast and ovarian cancers Also implicated in Fallopian tube Prostate peritoneal Male breast Pancreas
What is the chromosome affected and risk of ovarian and breast cancers from BRCA 1 & 2
BRCA 1
Breast 70%
Ovarian 45%
Chromosome 17q
BRCA 2
Breast 70%
Ovarian 20%
Chromosome 13q
Lynch syndrome
(HNPCC)
What is the cancer risk?
Risk endometrial ca 20-60%
Risk ovarian ca 10%
Earlier onset
Multiple primary cancers
It predisposes to colorectal, as well as hepatobiliary, urinary, small bowel, brain and sebaceous tumours.
How is HNPCC inherited ?
Autosomal dominant
What is the genetic mutation in HNPCC?
It is caused by mutations in multiple genes that produce proteins responsible for mismatch repair, these include: MLH1, MSH2, MSH6 and PMS2.
We identify woman at risk of HNPCC by assessing their genetic risk using the Modified Bethesda Guidelines
They include
Colorectal cancer (CRC) or endometrial cancer diagnosed before age 50;
CRC or endometrial cancer with a synchronous, metachronous or other Lynch-associated malignancy at any age;
CRC characterised by tumour-infiltrating lymphocytes, peritumoral lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern diagnosed before age 50 years;
CRC or endometrial cancer and a first-degree relative diagnosed with CRC, endometrial or a Lynch-associated malignancy diagnosed before age 50 years; or
CRC or endometrial cancer diagnosed at any age with two or more first or second-degree relatives with Lynch-associated malignancies diagnosed at any age.
How to manage woman with HNPCC
Prophylactic hysterectomy and RR BSO should be discussed with women with Lynch syndrome who have completed child bearing.
However, women should be made aware that surgery will significantly reduce, but not eliminate, their risk.
For younger women, COCP, systemic progesterone and progesterone intrauterine devices have been shown to reduce the risk of developing endometrial cancer in the general population.12COCP use is also associated with a reduced risk of ovarian epithelial cancers in low-risk populations.
The American College of Obstetricians and Gynecologists recommends endometrial biopsy starting at age 30–35 years and repeating every one to two years. Women should also keep a menstrual diary and promptly report any abnormal uterine bleeding. Neither ultrasound nor CA 125 levels are recommended for screening for ovarian cancer for reasons discussed above
Peutz-Jeghers syndrome
What is its inheritance ?
What does it put you at risk of?
How common?
autosomal dominant
m=f
1:8000- 1:200 000
Germline mutation in STK`11 on chromosome 19p13.3
pigmented mucocutaneous macules (melanin spots), multiple gastrointestinal polyps and an increased risk of gastrointestinal and non-gastrointestinal cancer.
Melanin spots are present in more than 95 per cent of patients and gastrointestinal hamartomatous polyps are present in most patients. The most common sites of gastrointestinal tract malignancy are the colon and pancreas. The most common site of extraintestinal tract cancer is the breast.
What is the inheritance of cowden syndrome?
How common is it?
What is its mutation?
Rare AD disease 1:200 000
Germline mutations in the PTEN gene (a tumour suppressor gene) located on chromosome 10q23.
