Colorectal cancer (CRC) has a high incidence, and its complex genetics have been widely studied. Around 65% is known to be environmental, but there are also polygenic variations of both low and high penetrance among population.
We can try to stratify the risk of CRC and tailor the surgical treatment if we know these genetic syndromes.
Key features from the family history can reveal a familial clustering, even if more than 50% of familial cases have no genetic diagnosis.
Mendelian syndromes have a high risk of cancer during the patient’s life despite causing a small percentage of CRC overall.
The most common one is Lynch Syndrome (LS), which includes endometrial and ovarian cancer in females. The Amsterdam criteria define its diagnosis and a clinical carrier prediction tool is available. Prophylactic surgery for patients with LS but no CRC is not recommended. In cases of CRC in LS, the main consideration for the surgeon is the extension of surgery according to the patient’s characteristics and the risk of future tumors. Risk of metachronous CRC after the first tumor increases with time. For this reason, subtotal colectomy with ileorectal anastomosis (IRA) is suggested these tumors. Nevertheless, there is still rectal cancer risk for these operated patients. The overall consideration for females with LS is that prophylactic surgery should be considered.
Familial Adenomatous Polyposis (FAP) should be suspected when more than 100 colorectal adenomas are found. In attenuated forms the number of polyps is usually around 30. The risk of developing a CRC increases substantially after the age of 25. The number of polyps in the rectum, the kind of phenotype, the presence of desmoid tumors, and the patient’s preferences are important factors when considering preserving the rectum in prophylactic surgery. After IRA 64% of the patients have a spontaneous rectal polyp regression during the first decade, but it doesn’t prevent future rectal cancer.
Polyps in the ileal pouch have been also described following proctectomy, due to environment and fecal stasis. Surveillance is therefore mandatory even when surgery is performed.
MUTYH-associated polyposis (MAP syndrome) is a highly penetrant autosomal recessive polyposis that carries a lifetime CRC risk of more than 90%. Prophylactic surgery should also be considered in these cases.
Finally, common low penetrance loci have a low but cumulative effect, affecting a potentially wide fraction of the population.
In somatic mutations, microsatellite instability (MSI) is associated with a better prognosis in CRC. Microsatellite stability (MSS) and BRAF mutation is associated with a worse prognosis. This prognostic value is not observed in rectal cancers. Chemoradiotherapy (CRT) sensitivity has been tested according to the genetic characteristics of the tumor. It seems like the DNA mismatch repair deficiency in rectal cancer might have a better response to CRT. There might be some germline genes that can predict CRT response, as well as somatic mutations (such as KRAS and TP53).
Finally, Dr. Farhat Din questions whether single biopsies are enough to find the genetic architecture. There are differences between pre-treatment and post-treatment biopsies, and different mutations can be found in different areas of the tumor, so the single-biopsy method should be questioned.