Hereditary Cancer: BRCA and Lynch Syndrome

Germline versus somatic

Hereditary cancer syndromes come from germline pathogenic variants present in every cell from conception. Tumors develop when the second copy is lost or inactivated in a cell (the “two-hit” model for tumor suppressors). Germline testing uses blood or saliva; finding a variant changes screening, surgery, therapy, and testing for relatives.

BRCA1 and BRCA2

BRCA1 and BRCA2 repair DNA double-strand breaks by homologous recombination. Pathogenic germline variants greatly raise the risk of breast and ovarian cancer, and of prostate and pancreatic cancer. Inheritance is autosomal dominant: men and women carry and transmit variants, and each child of a carrier has a 50% chance of inheriting it ¹.

• Ashkenazi Jewish ancestry is a risk-assessment criterion ¹; three founder variants (BRCA1 c.68_69delAG and c.5266dupC, BRCA2 c.5946delT, long known as 185delAG, 5382insC, and 6174delT) account for most BRCA variants in that population, so targeted founder testing was once common.
• Testing is now usually full sequencing plus deletion/duplication analysis of BRCA1/2 within a multigene panel, since large rearrangements are missed by sequencing alone.
• PARP inhibitors (olaparib, talazoparib, rucaparib) exploit the repair defect; BRACAnalysis CDx is a companion diagnostic for them ^{2 1}.

Lynch syndrome

Lynch syndrome is the most common hereditary colorectal cancer syndrome, also raising the risk of endometrial, ovarian, gastric, urinary tract, and other cancers. It’s caused by germline pathogenic variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2, or deletions in EPCAM, the gene upstream of MSH2, which silence MSH2 ³. It’s autosomal dominant ³.

Without mismatch repair, errors in repetitive DNA accumulate, so Lynch tumors are microsatellite unstable (MSI-high) and lose expression of the affected MMR protein.

Screening tumors for Lynch

Many centers screen every new colorectal cancer for MMR deficiency by immunohistochemistry for the four MMR proteins or by MSI testing ³. The pattern of protein loss points to the gene:

MLH1 and PMS2 travel together (as do MSH2 and MSH6), because PMS2 and MSH6 are unstable without their partners.

The sporadic trap: most MSI-high colorectal cancers with MLH1 loss aren’t Lynch syndrome. They come from hypermethylation of the MLH1 promoter, an acquired change common in older patients, and they often carry BRAF V600E, which is essentially absent in Lynch tumors ³. So MLH1 loss is followed by BRAF V600E or MLH1 promoter methylation testing; if either is present, the cancer is likely sporadic. If neither, germline testing follows.

Familial adenomatous polyposis

FAP comes from germline APC variants and causes hundreds to thousands of colorectal polyps, with near-certain colorectal cancer without colectomy ³. Other syndromes include Li-Fraumeni (TP53) and MUTYH-associated polyposis (autosomal recessive).

Classifying germline variants

Germline variants are classified in five tiers under the ACMG/AMP standards, using weighted evidence (population frequency, computational predictions, functional studies, segregation in families) ⁴:

1. Pathogenic
2. Likely pathogenic
3. Uncertain significance (VUS)
4. Likely benign
5. Benign

Pathogenic and likely pathogenic variants guide management. A VUS doesn’t: care is based on personal and family history, and many VUS are later reclassified, most often to benign. Labs reclassify as evidence accumulates and should have a process for notifying clinicians.

This differs from the four-tier somatic system in the previous lesson; don’t mix the two.

What to take from this

BRCA1/2 and Lynch syndrome are autosomal dominant with a 50% transmission risk. BRCA testing means full sequencing plus deletion/duplication analysis, and PARP inhibitors exploit the repair defect. Lynch syndrome comes from MLH1, MSH2, MSH6, PMS2, or EPCAM; tumors are MSI-high with matching MMR protein loss. MLH1 loss with BRAF V600E or MLH1 promoter methylation is usually sporadic. Germline variants are classified pathogenic, likely pathogenic, VUS, likely benign, or benign, and a VUS shouldn’t drive clinical decisions.