THE GENOMIC LANDSCAPE OF BREAST CANCERS FOLLOWING PREGNANCY
TP53 mutations more common cancers following early pregnancy
The effects of parity and age at first pregnancy on the risk of breast cancer have been known for decades. In general parity increases risk in the first decade after pregnancy and then a marked reduction in risk thereafter, more pronounced with earlier age at first pregnancy. A recent study from Belgium attempts to shed light on the genomic makeup for breast cancers following pregnancy and the relationship to age and parity. Three hundred thirteen patients were available who developed primary breast cancer and in whom whole genome studies, RNA sequencing and tumor infiltrating lymphocytes (TIL) were available. In addition, parity, age at first pregnancy and molecular subtypes were available for study.
The authors first looked at the incidence of breast cancer driver genes. In this cohort of patients, only 2 genes were found frequently mutated, PIK3CA (found in ~40% HR+ breast cancers) and TP53. Early age at first pregnancy (≤ 25 years old) was associated with a higher frequency of TP53 mutations (50%) as well as a higher incidence of MYC amplification. The co-occurrence of TP53 mutations and MYC amplification was independently associated with young age at first pregnancy. This is consistent with studies on the MYC oncogene in the pan-cancer data. On the contrary, there was no difference between mutations in BRCA1/2 (“BRCAness”) between older and younger age at first pregnancy.
Since prior reports have suggested that pregnancy cancer protection may be anti-tumor immunity, the authors also measured TILs and found no difference in early and late pregnancies. Interestingly, they looked at 49 patients diagnosed with breast cancer up to 10 years postpartum and compared them to 17 nulliparous patients. Though somewhat counterintuitive they found that pregnancy-associated breast cancers occurred at a younger age than nulliparous patients and a higher frequency of triple negative patients. Might this reflect the increased breast cancer risk found in the first decade after pregnancy? Compared to nulliparous patients pregnancy associated tumors had significantly higher levels of TILs.
The authors also documented as have others that young age at first pregnancy is associated with a marked reduction in luminal cancer subtypes. As others have found, breast cancers of late parous patients resemble breast cancers from nulliparous women. The authors also hypothesize that the higher frequency of TP53-mutant breast cancers in early parous women might be explained by the possibility that early pregnancy might protect less effectively against TP53-mutant precancerous lesions.
The authors concluded that their findings have highlighted a previously unknown link between reproductive factors and “ the genomic landscape of subsequent breast tumors.”