Molecular pathology combines molecular analysis with traditional morphology and immunohistochemistry to understand disease at its most fundamental level. The field continues to evolve as new discoveries enter clinical practice.

Through molecular pathology, our knowledge of genetic mutations and targeted therapies has expanded. It is now rare for a tumour report to omit genetic findings. This discipline, while distant from daily clinical work, underpins treatment algorithms and prognostic models.

The ten hallmarks of cancer include: genome instability and mutation, resistance to cell death, sustained proliferative signalling, evasion of growth suppressors, replicative immortality, angiogenesis, invasion and metastasis, altered metabolism, tumour-promoting inflammation, and immune evasion.

Normal DNA contains proto-oncogenes that promote growth and tumour suppressor genes that restrain it. When balanced, they regulate healthy proliferation. Mutations in either disturb this balance, driving uncontrolled growth.

Germline mutations are inherited and present in every cell, while somatic mutations are acquired, often influenced by smoking, ultraviolet exposure, or diet. When proto-oncogenes mutate, they become oncogenes.

The RAS and BRAF oncogenes are key in molecular pathology. RAS controls upstream signalling that triggers cell growth, differentiation, and survival. Mutated RAS genes cause constant activation, leading to excessive signalling. The three RAS genes, HRAS, KRAS, and NRAS, are found in 20 to 25 percent of all human tumours and in 90 percent of pancreatic cancers. The BRAF gene, on chromosome 7, regulates downstream signalling and cell growth. BRAF mutations occur in about 10 percent of colorectal cancers, up to 50 percent of papillary thyroid cancers, and 27 to 67 percent of melanomas.

Other oncogenes include MYC, EGFR, and HER2. HER2 amplification is seen in some breast and ovarian cancers. These findings are vital as targeted treatments, such as JAK inhibitors and monoclonal antibodies, act on these pathways. A single mutation can activate an oncogene.

Tumour suppressor genes perform repair functions including correcting DNA mismatches, regulating the cell cycle, and promoting apoptosis. As telomeres shorten with age, mismatch repair errors increase. Mutated genes lose this ability, causing abnormal protein synthesis. Reports often describe mismatch repair proficient (no mutation) or mismatch repair deficient (mutation present), particularly in colon cancer.

Key tumour suppressor genes include BRCA1, BRCA2, and the Lynch syndrome genes MLH1, MSH2, MSH6, and PMS2. When mutated, they increase the risk of breast, ovarian, prostate, colon, uterine, and pancreatic cancers. While often inherited, mutations can also arise spontaneously or through epigenetic silencing. Each gene has two copies; both must be affected before suppression is lost. This two-hit hypothesis, proposed by Knudson in 1971, explains tumour development with ageing.

Methylation, sometimes noted in reports, refers to chemical modification of CpG (cytosine-phosphate-guanine) sites within a gene, often influenced by epigenetic factors. Abnormal methylation disrupts DNA repair, leading to failed tumour suppression.

This is a brief overview of a complex and evolving field.

Joining me is Dr Pranav Dorwal, Molecular and Anatomical Pathologist at Monash Health, also working in Diagnostic Genomics. Dr Dorwal is an examiner for molecular pathology, researcher, and author of over 60 publications. He has held positions at MD Anderson Cancer Center (Houston, USA) and Memorial Sloan Kettering Cancer Center (New York, USA), completed a fellowship at ANU Canberra, and received the Chancellor’s Gold Medal for Clinical Pathology.

Please welcome Dr Pranav Dorwal to the podcast.

References:

Dr Pranav Dorwal – www.monashhealth.org | www.genomicdiagnostics.com.au
Oncology at a Glance, Graham Dark, Wiley-Blackwell
www.pmc.ncbi.nlm.nih.gov