Translated by Yuji
The number of somatic mutations has been believed to be associated with poor prognosis in patients with cancer. Methods to analyze genetic and chromosomal aberrations in cancer cells have been rapidly developing since the late 1980s. DNA markers reported by my group1 had contributed to characterize chromosomal aberrations in cancer cells because they could distinguish the parental origins of our chromosomes. Actually, this type of analysis established the “multistep carcinogenesis’ model.
Generally, a higher number of genetic and chromosomal alterations has been considered to reflect a more aggressive cancer phenotype. However, recent progress in cancer genome research suggests an unexpected hypothesis.
Previously, we showed that a germline mutation in the APC gene is responsible for familial adenomatous polyposis.2-3 On the other hand, hereditary non-polyposis colorectal cancer (HNPCC) is caused by mutations in various DNA mismatch repair genes.4 DNA mutations in cells can be accumulated by dysfunctional DNA mismatch repair genes, resulting in cancer development because caner is caused by accumulated mutations in oncogenes and tumor suppressor genes. As is well known, BRCA1 or 2 mutations are responsible for hereditary breast and ovarian cancer (HBOC) — particularly well publicized in a case of Angelina Jolie — which received prophylactic surgery because of her germline BRCA1 mutation.
However, paradoxically, the prognosis of HNPCC patients tends to be better than non-hereditary sporadic types, although genetic instability has been observed in cancers in HNPCC patients. Some possible reasons for this include: (i) good response to chemotherapy because of the lack or reduction of DNA repair function, and (ii) generation of cancer-specific antigens and higher immune reactions. Actually, the repair function mechanism was thought to be dominant because most people were skeptical about an immune therapy against cancer cell.
However, two interesting reports about the importance of an immunological response in cancer were published at the end of last year and the beginning of this year.5,6 The number of genetic mutations was positively correlated with improved overall survival in malignant melanoma patients treated with lpilimumab (CTLA4 antibody) (see Figure 1).5 In addition, the number of predicted MHC Class I-associated neo-antigens was correlated with cytolytic activity in colorectal and other tumors.6 Our report published last year also showed better prognostic outcomes of individuals with somatic mutations in DNA repair genes, indicating that these mutations were favorable prognostic events (see Figure 2).7
These findings are extremely important in identifying the mechanism of immune-checkpoint molecules. Simply said, a higher number of somatic mutations generate more cancer-specific antigens that are recognized by our immune system. Therefore, the immunological status in cancer tissues is more activated, which leads to a better response to anticancer treatment.
We are now in the era of big data and greater understanding of the multiple interacting systems involved in cancer. Understanding and integrating genomic information, environment conditions, and life-styles of cancer patients is critically important if we are to make significant improvements in cancer treatment.
P=0.0435, HR:0.46, 95% CI:0.22-0.98
Blue line; carriers of mutations in DNA repair gene (N=25)
Black line; non-carriers of mutations in DNA repair gene (N=54)
1 Variable number of tandem repeat (VNTR) markers for human gene mapping. Nakamura Y et al (Science 1987)
2 Identification of FAP locus genes from chromosome 5q21. Kinzler KW, Nakamura Y et al (Science 1991)
3 Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Nishisho I, Nakamura Y et al (Science 1991)
4 The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Fishel R et al (Cell 1993)
5 Genetic basis for clinical response to CTLA-4 blockade in melanoma. Snyder A et al (NEJM 2014)
6 Molecular and genetic properties of tumors associated with local immune cytolytic activity. Rooney MS et al (Cell 2015)
7 Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival. Yap KL, Nakamura Y et al (Clin Cancer Res 2014)