Mediastinal Germ Cell Tumor and Acute Megakaryoblastic Leukemia With Co-occurring KRAS Mutation and Complex Cytogenetics

Abstract

Young males have a unique but rare predilection to develop mediastinal nonseminomatous germ cell tumors (NSGCTs) and concomitant acute megakaryoblastic leukemia (AMKL). Common cytogenetic and molecular abnormalities such as isochromosome 12p and somatic Tumor Protein P53(TP53) and Phosphatase And Tensin Homolog (PTEN) mutations have been reported in the presumed mutual neoplastic clones of origin. We report the case of a 17-year-old male who presented with a mediastinal NSGCT with high-grade sarcomatous transformation and a diagnosis of AMKL approximately 4 months later. Next-generation sequencing revealed identical KRAS Proto-Oncogene, GTPase (KRAS) p.Ala146Thr, TP53 p.Leu257Pro, and PTEN p.Leu181Pro missense mutations at similar variant allele frequencies in both the NSGCT and AMKL samples. Cytogenetic and microarray analyses detected shared copy gains in all chromosomes except chromosomes 9, 13, and Y. Multiple additional clonal chromosomal alterations were detected in the AMKL sample when compared with the NSGCT. This case emphasizes the shared clonal origins of these malignancies and identifies KRAS and other copy number alterations as potential molecular drivers in a subset of these combined diseases.

Genomic features of mediastinal germ cell tumors: a narrative review

“…Moreover, in PMGCTs with associated HMs, TP53 is the most frequently altered gene described in 90% of the patients and correlated to therapy resistance and poor prognosis ( 56 , 57 ). Additionally, KRAS/NRAS alterations are seen in 63% of PMGCT with concomitant HM, while PTEN mutation rates are similar between PMGCTs with or without HM ( 57 , 58 ).…”

Primary Mediastinal and Testicular Germ Cell Tumors in Adolescents and Adults: A Comparison of Genomic Alterations and Clinical Implications

“…For example, gain or isochromosome of 12p is an event not detectable in canonical AML [69], but it has been reported in 18 out of 38 HMs associated with MGCTs (approximately 47% of cases) (Table 2) [66,[68][69][70][71][72][73][74]76]. Conversely common alterations, including MLL rearrangements or mutations on genes such as FLT3, NPM1 and others, were not detected in AML coupled with MGCTs [67,69,72,77,78].…”

“…Evidence of a clonal relationship between HM and MGCT was discovered through the identification of molecular alterations shared between the two tumor types (i12p/12p gain, TP53, KRAS and PTEN mutations) (Table 1) [66,[68][69][70][71][72][73][74][75][76][77][78][79][80]. Moreover, the hematologic disease frequently carries alterations not typical of the specific type of HM and lacks the canonical aberrations detected in de novo diseases.…”

Primary germ cell tumours of the mediastinum: A review with emphasis on diagnostic challenges

“…KRAS mutations are found in up to 38% of PMNSGCTs. The highest rates of TP53 mutations and KRAS mutations were detected in PMGCT with associated HMs in 90 and 60% of cases, respectively 160,161,202,205 …”

“…In particular, i(12p) is the most common alteration found in both subsets in 48% of cases, 124,148,157–159 but HM also show other alterations determining the subtype of HM, such as del(5q) or trisomy 8 124 . Other molecular alterations include mutations of TP53, KRAS or PTEN 160,161 . A chemotherapy‐induced PMGCT‐independent malignant haematopoietic neoplasm has to be ruled out 124,148,151,153,159,162 …”