Germline susceptibility variants impact clinical outcome and therapeutic strategies for stage III colorectal cancer

Peng-Chan Lin,Keng-Fu Hsu,Jang-Yang Chang,Pei-Ying Wu,Yu-Min Yeh,Meng-Ru Shen

doi:10.1038/s41598-019-40571-0

Abstract

Although somatic mutations are the main cause of cancer, underlying germline alterations may affect cancer outcome. There is little information on comprehensive analysis of germline genome sequencing for cancer healthcare strategy. Here we studied the implication of germline cancer-associated variants on cancer counselling and therapeutic strategies by germline whole genome and tumor targeted sequencing. Fifty-five gynecological and 104 colorectal cancer (CRC) patients were enrolled. We identified 22 germline pathogenic variants in 16 cancer-associated genes. Most of them are involved in DNA repair signaling, including MLH1, BRCA1/2, MUTYH, ATM, PMS2, MSH6, BAP1, and FANCA. About 6% of cancer patients presented the secondary findings of germline variants with non-oncogenic impact, mainly on the cardiovascular system which should be carefully monitored during chemotherapy. CRC patients carrying germline susceptibility variants had better disease-free survival than those without variants. Importantly, in the CRC model, the underlying germline alterations mold the tumor somatic alteration landscape. NOTCH1 mutation was the most common somatic mutation in recurrent CRC, implying a potential therapeutic target in adjuvant setting. In conclusion, both tumor genome and germline sequence data have to be analyzed to have a more complete picture of the overall genetic foundation of cancer.

Highlights

Genomic medicine has been widely applied in the diagnosis, treatment, and prevention of cancer
We demonstrate the application of germline whole genome sequencing (WGS) in the care of cancer patients and the impact of germline genetic variants on clinical outcome and therapeutic strategies
Our results highlight the following important points: (i) Germline variants of ACMG SF genes are associated with life threatening toxicities during chemotherapy. (ii) Germline variants of cancer-associated genes affect clinical outcome and screening for the variants should take the ethnicity into consideration. (iii) Notch signaling pathway might be a therapeutic target for colorectal cancer (CRC) patients without germline cancer-associated variants in adjuvant setting

Summary

Introduction

Genomic medicine has been widely applied in the diagnosis, treatment, and prevention of cancer. Germline WGS can detect pathogenic variants in the secondary finding genes recommended by the American College of Medical Genetics and Genomes (ACMG), which likely have an impact during cancer treatment. Cancer susceptibility genes may affect different molecular signal pathways in cancer formation which impact distinct responses to treatments[10]. Clinically favorable responses to actionable mutations with matched therapy are limited because there are few FDA-approved companion therapies, ambiguous scientific contexts, and loose treatment algorithms[13] Reviewing these clinical trials[14,15] with a molecular profiling approach indicates that the treatment algorithms for selecting matched molecularly-targeted agents might be inadequate, and knowing the underlying mechanism of biological pathways may be beneficial to the outcome of advanced or refractory cancer patients. We highlighted the secondary genomic findings on non-oncogenic phenotypes associated with life-threatening adverse events during cancer treatment

Objectives

Methods

Results

Conclusion