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Abstract
Objectives The genetic landscape of low-grade serous carcinomas (LGSCs) is poorly described. We sought to characterize somatic mutational profiles of LGSCs and correlate findings with clinical outcomes.
Methods Patients with LGSC (n=123) consented to an IRB-approved protocol of tumor-normal massively parallel sequencing that included 341–505 cancer-related genes. Clinical outcomes and frequency of genetic alterations, including somatic mutations and copy number alterations, were assessed and compared using the Fisher exact test.
Results Among 123 sequenced tumors, median tumor mutational burden was low (1.8 mutations/Mb). Recurrent alterations included those affecting KRAS (32%), NRAS (11%), BRAF (10%), CDKN2A (9%), and ERBB2 (5%) (see figure 1). KRAS mutations were more frequent in patients ≥50 years of age at LGSC diagnosis than in patients <50 years of age (41% vs 23%, respectively; p<0.05); in those with platinum-sensitive vs. platinum-resistant disease (41% vs 19%, respectively; p=0.05); and in patients surviving ≥5 years compared with <5 years (39% vs 11%, respectively; p<0.05). BRAF mutations were more frequent in platinum-resistant compared with platinum-sensitive disease (19% vs 3%, respectively; p<0.05). CDKN2A alterations were associated with risk of recurrence, while none of the patients with CDKN2A-wildtype tumors developed recurrence (13% vs 0%, respectively; p<0.05). Recurrence was also associated with higher median fraction of genome altered (p<0.05).
Conclusions The presence of KRAS mutations in LGSC may be associated with less aggressive phenotypes and older age at diagnosis. CDKN2A and BRAF alterations may be associated with recurrence and platinum resistance, respectively.