Hereditary cancer syndromes

Caused by germline mutations affecting specific genes.

High-risk herrditary cancer syndromes have been associated with a 60-100 percent lifetime risk development of colorectal and breast-ovarian cancers.

Account for approximately  10% of all cancers, and roughly 5-10% of all colorectal cancers.
Genes  beyond BRCA 1/2 confer markedly increased risk of breast and/or ovarian cancers: CDH1, PALB 2, PTEN, and TP 53.
These inherited syndromes are associated with a 60-100 percent lifetime risk for development of colorectal cancer, depending upon the genetic syndrome and many also carry an increased risk for multiple extra colonic malignancies.
Most caused by mutations that inactivate particular tumor suppressor genes.
One of these genes is PTEN, which includes a dual-specificity lipid and protein phosphatase.

Generally these disorders is to follow autosomal dominant inheritance.

A few arise from mutations that activate protoncogenes.

Typically patients inherit the mutated allele from 1 parent and a wild-type allele from the other parent.

For most tumor suppressor genes the presence of a wild-type allele is adequate to prevent tumor formation.

For some of these genetic disorders the risk of malignancy past from one generation to the next.

Hereditary breast cancer genes account for 8-10% of ER positive breast cancers: such genes include CHEK2 ,1%, and genes associated with homologous recombination deficiency such as BRCA,12%, BRCA 2, 2%, ATM 0.5-1%, and PALB, 0.5 to 1%.

BRCA1 and BRCA2 are examples of such disorders, and diagnosis may be missed due to lack of diagnosis, incomplete family history, poor communication within families, or the stigma of the diagnosis of cancer.

Mutations in BRCA1, BRCA2, TP53, PTEN, CDH1 and STK11 are high risk mutations that are associated with a more than 5-fold increase in breast cancer risk.

BRCA1 and BRCA2 are the most common of high-risk mutations and confer a greater than 11-fold increase in breast cancer risk.

BRCA1 and BRACA2 associated with a lifetime risk of breast cancer of 66-76% by age 80 years.

Moderate risk mutations associated with breast cancer risk with a 2-5 fold increase include: ATM, CHEK2 and NBM.

ATM, CHEK2 and NBM mutations associated with a lifetime risk of breast cancer of 20-30% and higher if there is a family history of breast cancer.

BRCA1 mutations are disproportionately associated with cancers lacking ER and HER 2, most breast cancers arising in BRCA2, PALB2, CHEK2, and ATM mutation carries are ER positive, mirroring the distribution of sporadic cases.

About 5% of breast cancer patients have a germline BRCA1/2 mutation and about 4.5% of patients have a mutation in another cancer predisposition gene.

In the absence of any known alterations in genetic findings, 25-30% of patients with colorectal and breast-ovarian cancers have a family member with the same diagnosis.

Up to 10% of all G.I. and breast and ovarian cancers are attributed to defined inherited syndromes inncluding: Lynch syndrome, familiar adenomatous polyposis, several hamartomatous polyposis conditions and hereditary breast-ovarian cancer syndromes.



Hereditary breast and ovarian cancer (HBOC) syndrome is most commonly characterized by deleterious germline mutations in BRCA1 and BRCA2. 



HBOC patients are prone to the development of malignant neoplasms in multiple organs including the breast, ovary, and fallopian tube. 



Breast cancers diagnosed in BRCA1-mutation carriers are frequently of a high Nottingham grade and display medullary morphology and a triple-negative and/or a basal-like immunophenotype. 



In contrast, breast cancers in BRCA2-mutation carriers are similar to sporadic luminal-type tumors that are positive for 


Both familial and attenuated FAP is a form of the disease with lower severity, including development of fewer polyps, and overall lower risk of colorectal cancer of 70%.
Both FAP and AFAP are caused by germline mutations in the APC gene.
Testing for the ATC gene should be considered if there are more than 20 adenomas in the colon or rectum,  A known family history of FAP come and more than 10 adenomas on a single colonoscopy.

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