Abstract
There has been little improvement in the prognosis for adolescent and young adult (AYA) tumor patients. Hence, there is an urgent need to understand the etiology of tumor development and identify actionable gene aberrations to improve prevention and therapy. Here, 76 sporadic tumors (48 breast, 22 ovarian, and six uterine) from 76 AYA females (age range, 25–39 years) were subjected to whole exome and RNA sequencing to determine their mutational signatures and actionable gene profiles. Two individuals with breast cancer (4.2% of cases) and one with ovarian cancer (5.3% of cases) carried germline BRCA2 mutations. The two cases with breast tumors also each carried an additional deleterious germline mutation: one in TP53 and the other in CHEK2. Mutational signature analysis of the 76 tumors indicated that spontaneous deamination of 5-methylcytosine and activity of the APOBEC cytidine deaminase protein family are major causes of mutagenesis. In addition, 18 breast or ovarian tumors (18/70, 26%), including the three cases with germline BRCA2 mutations, exhibited a predominant “BRCAness” mutational signature, an indicator of functional BRCA1/BRCA2 deficiency. Actionable aberrations and high tumor mutation burdens were detected in 24 breast (50%), 17 ovarian (77%), and five uterine (83%) tumor cases. Thus, mutational processes and aberrant genes in AYA tumors are largely shared with those identified in non-AYA tumors. The efficacy of molecular targeting and immune checkpoint inhibitory therapies should be explored for both AYA and non-AYA patients.
Highlights
68,000 adolescents and young adults (AYAs) aged 15 to 39 years were diagnosed with cancer in the US in 2002 [1], and females with breast, ovary, and uterine cancers constituted a large proportion of cases [2]
The histological and subtype distributions in the study cohort, including frequent luminal type carcinomas, were consistent with previous reports of breast tumors in Japanese AYAs [15]; they were different to the distributions among European/US patients, in whom both luminal and triple-negative tumors are common [16]
The 22 ovarian tumors consisted of 14 carcinomas, five borderline tumors, and three others, while the six uterine tumors consisted of five endometrioid carcinomas and one carcinosarcoma
Summary
68,000 adolescents and young adults (AYAs) aged 15 to 39 years were diagnosed with cancer in the US in 2002 [1], and females with breast, ovary, and uterine cancers constituted a large proportion of cases [2]. Malignant and borderline ovarian tumors are rare in adolescents compared with adults; they pose serious issues in that age group. Such ovarian tumors encompass a variety of subtypes; the most common are epithelial in origin; non-epithelial tumors, such as malignant germ cell and sex cord-stromal tumors, constitute a major fraction [5,6,7,8]. Cervical and endometrial carcinomas comprise a large proportion of AYA uterine tumors [9, 10]
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