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Genetic susceptibility to non-polyposis colorectal cancer


Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APCgene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for approximately 5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1,MSH2, MSH6,PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still molecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example.

Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (1) tumours that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor β type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such asK-ras, APC, andp53, and behave aggressively, of which FAP is an example.

This review focuses most heavily on the clinical features, pathology, molecular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a detailed differential diagnosis of the several hereditary CRC variants is provided. The extant genetic and phenotypic heterogeneity in CRC leads to the conclusion that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Therefore, it is important to ascertain cancer of all anatomical sites, as well as non-cancer phenotypic stigmata (such as the perioral and mucosal pigmentations in Peutz-Jeghers syndrome), when taking a family cancer history.

  • colorectal cancer
  • hereditary non-polyposis colorectal cancer
  • genetic susceptibility
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    The prodigious advancements in knowledge about genetic risk, natural history, recommended available surveillance and management, DNA testing, and the need for genetic counselling collectively are having a significant impact on the standard of care for hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), as well as for patients with a variety of other hereditary cancer prone disorders. For example, a standard of care has been adjudicated in favour of a patient with the hereditary breast-ovarian cancer syndrome who followed the recommendations of her gynaecological oncologist and a cancer geneticist to undergo prophylactic oophorectomy but whose insurance company failed to reimburse her for this procedure. While her petition for reimbursement was denied at the district court level, the Nebraska Supreme Court rendered a favourable decision on her part, commanding the insurance company (Blue Cross/Blue Shield) to provide reimbursement for this indicated procedure.165
     In a legal decision involving a Lynch syndrome II patient, the family of the plaintiff received an out of court settlement from the defendant HMO for its failure to diagnose colorectal cancer. This patient had a positive family history of multiple occurrences of early onset colorectal cancer in her first and second degree relatives which were consistent with Lynch syndrome II. The plaintiff, a 16 year old girl, presented to the defendant HMO with symptoms for about one year consisting of constipation, weight loss, fatigue, and occasional abdominal pain, all of which had become progressive. A computed tomography (CT) scan of the abdomen failed to show any abnormality. Nurse practitioners subsequently shared in the bulk of her care during the following three years. The patient's mother requested that her daughter undergo colonoscopy because of her strong family history of early onset colorectal cancer (CRC). However, a flexible sigmoidoscopy was ordered because the physicians associated "hereditary" with FAP. The physician assistant who performed the flexible sigmoidoscopy reassured the mother that, owing to the relatively young age of her daughter, this procedure was sufficient, particularly since adenomas or other lesions were not observed in her at time of flexible sigmoidoscopy. However, the patient's weakness and weight loss persisted and at the age of 19 she presented with jaundice. A CT scan of the abdomen disclosed metastases to multiple sites in the liver and regional lymph nodes. At exploratory laparotomy, the diagnosis of moderately differentiated adenocarcinoma of the caecum was established, during which time biopsies of the liver disclosed metastatic adenocarcinoma consonant with CRC origin. The patient died at the age of 20.
     The expert witness (HTL) noted that the medical, pathology, and family history findings did not support a diagnosis of FAP as usually recognised,166 but nevertheless the attenuated form of FAP (AFAP)7167 was worthy of consideration. However, because of the proximal predominance of adenomas (in AFAP), colonoscopy is required.118168 Attention was called to the exclusion of atypical FAP in the patient, thereby necessitating colonoscopy as opposed to flexible sigmoidoscopy as the appropriate diagnostic procedure.
     Another litigation because of failure to meet the standard of care was brought against a physician in California.169 The plaintiff, during her initial pregnancy, related to her physician that her family had been involved in one of the original HNPCC studies. During a second pregnancy, she disclosed to the defendants that she was experiencing rectal bleeding and that she had a "mass" protruding from her rectum during defaecation. However, neither a rectal examination nor a stool Guiac was performed and she was told that her problem was because of  "haemorrhoids". However, the plaintiff demanded attention for the haemorrhoids and bleeding, and when endoscopy was performed a CRC was identified with metastasis to lymph nodes and liver. Because of the failure to establish a diagnosis over a two year period, it was argued that this contributed to her advanced stage of disease and a decrease in survivability. The jury verdict was in favour of the plaintiff.169
     Finally, in a case involving FAP referred to as the Safer case,170 at the age of 35 the father of the litigant had been evaluated by the defendant surgical oncologist. A retroperitoneal cancer was operated on and the diagnosis of FAP was established. The surviving spouse claimed that, although the surgeon discussed her husband's diagnosis, treatment, and cancer management, he failed to disclose the genetic risk for FAP even though the hereditary nature of FAP was known fully at the time the surgeon was treating the husband and thereby prevailing medical standards of care required a warning of risk for FAP so that the patient's children, then aged 10 and 17, might benefit from early colon surveillance. Subsequently, one of the children, at the age of 36, experienced lower abdominal pain and underwent surgery and extensive chemotherapy for CRC in concert with FAP. She examined her father's medical records and concluded that her condition was the same, namely FAP. Further inquiry led her to the following conclusions: (1) her condition was hereditary; (2) her father's surgeon knew of the hereditary nature of her father's disease; (3) she should have been suspected of being at increased risk for FAP; (4) because of this risk, she should have been warned to monitor for such a disease; and (5) her cancer would probably have been preventable had surveillance been done. "The daughter filed a claim of negligence against the estate of the surgeon, alleging the following: (1) that he had a duty to warn those known to be at risk of avoidable harm from a genetically transmissible condition existing in his patient, (2) that the physician's duty did extend to members of the immediate family of his patient, and (3) that he had breached these duties."171 The suit was won by the plaintiff in 1996.

    165 Lynch HT, Severin MJ, Mooney MJ, Lynch JF. Insurance adjudication favoring prophylactic surgery in hereditary breast-ovarian cancer syndrome. Gynecol Oncol 1995;57:23�6.
    166 Lynch HT, Smyrk T, Lynch J. Genetics and cancer of the gastrointestinal tract. In: Wanebo HJ, ed. Surgery for gastrointestinal cancer: a multidisciplinary approach. Philadelphia: Lippincott-Raven, 1997:59�86.
    167 Dugaw JE, Lynch HT. Medical students as "probation officers" for juvenile offenders. Nebr State Med J 1971;56:60�2.
    168 Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594�642.
    169 Seamon v Miller, Sacramento County Sup Ct, Docket 534952 (1994).
    170 Safer v Estate of Pack, 677 A.2d 1188 (1996).
    171 Lynch HT, Paulson J, Severin M, Lynch J, Lynch P. Failure to diagnose hereditary colorectal cancer and its medicolegal implications: a hereditary nonpolyposis colorectal cancer case. Dis Colon Rectum 1999;42:31�5.

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