Background:BRCA1/2mutations are the most recognized causes of hereditary breast cancer (BC), but their penetrance is incomplete.BRCA1-driven tumors are often chromosomally unstable and exhibit increased antigenicity. We hypothesized that inherited variations in immune-related pathways may influenceBRCA1penetrance. Methods: Case–control comparison of BC-affected versus non-affectedBRCA1-mutated women is generally complicated because the latter groups are often low in numbers, represented by younger subjects and may contain relatives of the analyzed patients. We utilized a novel approach, i.e., we compared young-onset and late-onsetBRCA1-associated BC cases, assuming that the early age at disease manifestation may be an indicator of increasedBRCA1penetrance. Results: NGS for 353 genes implicated in inborn errors of immunity was performed on 42 young-onset (<39 y.o.) and 35 late-onset (>57 y.o.) BC patients carryingBRCA1pathogenic variants. This effort identified 22 potentially relevant variants, which were further analyzed in an extended cohort (up to 90 patients per group). ThePRF1p.Ala91Val variant, associated with familial hemophagocytic lymphohistiocytosis, was found in 9.6% of young-onset patients and none of the late-onset group (7/73 vs. 0/78,p= 0.005). The significance of this allele was further validated in an additional group of Russian patients (14/164 (8.5%) vs. 8/236 (3.4%),p= 0.042). This trend also retained upon the pooled analysis of Russian and Polish subjects (24/278 (8.6%) vs. 15/337 (4.4%),p= 0.045). Conclusions: Rare variants in immune-related genes, such asPRF1p.Ala91Val, may influenceBRCA1penetrance. Broader exome-wide analyses comparing affected vs. unaffectedBRCA1/2mutation carriers, or women stratified by age at cancer onset, could help identify additional genetic modifiers of cancer risk.
背景：BRCA1/2基因突变是遗传性乳腺癌（BC）最明确的致病因素，但其外显率并不完全。BRCA1驱动的肿瘤通常表现出染色体不稳定性并具有较高的抗原性。我们假设免疫相关通路的遗传变异可能影响BRCA1的外显率。方法：比较携带BRCA1突变且患病与未患病女性的病例对照研究通常存在复杂性，因为未患病组样本量较少、年龄偏轻，且可能包含已分析患者的亲属。本研究采用了一种新方法，即比较早发性与晚发性BRCA1相关乳腺癌病例，假设疾病早期发作可能是BRCA1外显率增高的指标。结果：我们对42例早发性（<39岁）和35例晚发性（>57岁）携带BRCA1致病性变异的乳腺癌患者进行了涉及先天性免疫缺陷的353个基因的二代测序。共鉴定出22个潜在相关变异，并在扩展队列（每组最多90例患者）中进一步分析。其中与家族性噬血细胞性淋巴组织细胞增生症相关的PRF1 p.Ala91Val变异在早发组中检出率为9.6%，而晚发组未检出（7/73 vs. 0/78，p=0.005）。该等位基因的显著性在俄罗斯患者队列中得到进一步验证（14/164（8.5%） vs. 8/236（3.4%），p=0.042）。合并分析俄罗斯与波兰受试者数据后该趋势仍然保持（24/278（8.6%） vs. 15/337（4.4%），p=0.045）。结论：免疫相关基因（如PRF1 p.Ala91Val）的罕见变异可能影响BRCA1的外显率。通过更广泛的全外显子组分析比较患病与未患病的BRCA1/2突变携带者，或按癌症发病年龄分层的女性群体，有助于发现更多癌症风险的遗传修饰因子。
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