Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma

Abstract

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.

Consenso mexicano de linfoma de Hodgkin

“…La respuesta global objetiva fue del 75% con RC en el 34% de los pacientes. La mediana de SLP fue de 5.6 meses en pacientes con respuesta global objetiva y de 20.5 meses en RC 15,22,23 .…”

“…Seguimiento a 40 años, la incidencia acumulada de cáncer mamario en esta población es del 30-40%. Esta elevada incidencia es similar a la de las portadoras de mutaciones BCRA1/2 23 .…”

“…Se considera que el riesgo de cáncer mamario por RT en LH es modificado por dosis de RT y volumen radiado, la edad al momento de la exposición a RT, e inversamente proporcional al riesgo de cáncer, además de que también la menopausia prematura inducida por los agentes alquilantes del tratamiento del LH está presente 22,23 .…”

“…Asimismo, en el breast cancer PRS el riesgo fue 4 veces mayor en los pacientes dentro del decil más alto en comparación al más bajo. Por lo tanto, la susceptibilidad a cáncer mamario en las supervivientes de LH estaría influenciada por factores genéticos inherentes a las pacientes 23 .…”

Closing the survivorship gap in children and adolescents with Hodgkin lymphoma

“…Understanding those risks in survivors can be assimilated into individualizing future front‐line therapy for HL. Recently a breast cancer polygenic risk score (BC‐PRS), consisting of 77 single nucleotide polymorphisms previously associated with breast cancer in the general population, was noted to substantially increase the risk of breast cancer in women who received chest RT for HL (Opstal‐van Winden et al , ). Similarly, several polymorphisms that predict increased risk of anthracycline cardiomyopathy have been found.…”