TP53, WHSC1 Mutations Key to MCL Prognosis

Jason Harris

Mutations of <em>TP53</em> and <em>WHSC1 </em>predicted poorer overall survival in patients with mantle cell lymphoma, according to results from next-generation whole-exome sequencing of 16 Chinese patients.&nbsp;The presence of these mutations may provide physicians with an important biomarker in this patient population.

Mutations ofTP53andWHSC1predicted poorer overall survival (OS) in patients with mantle cell lymphoma (MCL), according to results from next-generation whole-exome sequencing of 16 Chinese patients.1The presence of these mutations may provide physicians with an important biomarker in this patient population.

In a retrospective analysis, co-authors Ping Yang, MD, and Weilong Zhang, MD, of Peking University Third Hospital, Beijing, China, and colleagues correlated OS to genes with a high mutation rate includingATM,TP53,WHSC1, andCCND1to determine whether those mutations had prognostic value. They found that the 3-year median OS rate was 40% for patients withTP53mutations, significantly worse than for patients without the mutation (P= .021). The median OS for patients withWHSC1was 17.0 months compared with 47.0 months for those without the mutation, though the difference was not significant (P= .070). Mutations inATM(P= 0.552) andCCND1(P= 0.566) were not predictors for survival.

Investigators then adjusted for MIPI and MIPI-c score, along with clinical prognostic factors, by combiningTP53andWHSC1mutations. ForTP53mutations, the MIPI-adjusted hazard ratio (HR) for OS was 3.427 (P= .028). HR was 4.047 (P= .040) forWHSC1mutations.

The inclusion of the MIPI-c index changed the prognostic effect for bothTP53(HR, 4.758,P= .015) andWHSC1mutations (P= .016).

“With the first draft of the genomic landscape of MCL in Chinese patients now defined, we identified the genetic heterogeneity in MCL,” Yang et al wrote. “The next step for the field should be to establish the functional consequence of the observed mutations. Our work underscores the importance ofTP53andWHSC1mutations for the prognosis of MCL. Patients may benefit from mutation analysis ofTP53andWHSC1at diagnosis, in addition to MIPI and MIPI-c score.”

In the West, MCL has an annual incidence of 0.5 per 100,000 population and accounts for 3% to 6% of non-Hodgkin lymphomas. MCL has a high rate of complete remission, especially with intensive upfront therapy, but most patients eventually relapse and become refractory to treatment. In results from an analysis of data collected in the SEER database from 1995 to 2013, Fu et al found a median OS for MCL of 4 to 5 years.2According to data published in theBritish Journal of Heamatologyin 2017, the relative 5-year survival rate for MCL improved from 50.7% from 2000 to 2006 to 54.5% from 2007 to 2013 (P=.01).3However, incidence grew from 0.711 to 0.800 per 100,000 population over that time period (P<.001), and Fu et al detected a steady annual increase in new diagnoses of 2.56%.2,3

Yang et al analyzed MCL and lymphoma tissue samples collected at Peking University Third Hospital from 2009 to 2016. All patients in the study had undergone combination therapy including CHOP, R-CHOP, and VR-CAP. Autologous hematopoietic stem cell transplantation as consolidation therapy was administered to 1 patient.

Following initial combination chemotherapy, the overall remission rate was 68.8%, including an 18.8% complete remission rate and 50% partial remission rate. Overall, 63.6% of patients relapsed following initial treatment.

Five patients were still alive at last follow-up. The median OS was 37.5 months (range, 8-104), with an estimated 3-year OS of 68.8% and an estimated and 5-year OS of 38.2%.

The median patient age was 61.5 years (range, 43-84 years) and 14 patients were men. The most commonly involved extranodal site was bone marrow (n = 14). Five patients had leukemic presentation and 9 had splenic involvement, 1 of whom had splenic rupture during treatment. Gastrointestinal tract involvement was present in 3 patients.

ATM,TP53, andWHSC1gene mutations were the most common mutation frequencies, and were detected in 68.75% of all samples. Seventy-five percent of patients had the translocation of t(11;14) (q13;q32).ATM,TP53, andWHSC1mutations and t(11;14) (q13;q32) translocation were present in all 16 samples.

“Mutations identified in our study overlapped significantly with recently published studies of tumor exomes and transcriptomes, such as mutations inATM,CCND1,TP53,WHSC1, andNOTCH2,” wrote Yang and colleagues. “Similar to other lymphomas, our data indicate a striking mutational heterogeneity underlying MCLs, with relatively few genes mutated in 6% to 20% of the cases. Our work implicates other mutated genes such asS1PR1,ATRX, andBRCA2that are rarely mentioned in MCL.”

Ki67 ≥30% is often an indicator of aggressive tumor growth and poor prognosis. While Yang et al tumor found that risk stratification with MIPI and Ki67 was a good prognostic model, Ki67 alone did not have prognostic significance (P= .339).

References:

  1. Yang P, Zhang W, Wang J, et al. Genomic landscape and prognostic analysis of mantle cell lymphoma.Cancer Gene Ther. 2018;25:129—140. doi: 10.1038/s41417-018-0022-5.
  2. Fu S, Wang M, Lairson DR, et al. Trends and variations in mantle cell lymphoma incidence from 1995 to 2013: A comparative study between Texas and National SEER areas.Oncotarget. 2017;8(68): 112516—112529. doi: 10.18632/oncotarget.22367.
  3. Epperla N, Hamadani M, Fenske TS, Costa LJ. Incidence and survival trends in mantle cell lymphoma.Br J Haematol. 2018;181(5):703-706. doi: 10.1111/bjh.14699.